Novel Gene Disruptions, Compositions And Methods Relating Thereto

Abstract

The present invention relates to transgenic animals, as well as compositions and methods relating to the characterization of gene function. Specifically, the present invention provides transgenic mice comprising disruptions in PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 genes. Such in vivo studies and characterizations may provide valuable identification and discovery of therapeutics and/or treatments useful in the prevention, amelioration or correction of diseases or dysfunctions associated with gene disruptions such as neurological disorders; cardiovascular, endothelial or angiogenic disorders; eye abnormalities; immunological disorders; oncological disorders; bone metabolic abnormalities or disorders; lipid metabolic disorders; or developmental abnormalities.

Description

FIELD OF THE INVENTION

[0001] The present invention relates to compositions, including transgenic and knockout animals and methods of using such compositions for the diagnosis and treatment of diseases or disorders.

BACKGROUND OF THE INVENTION

[0002] Extracellular proteins play important roles in, among other things, the formation, differentiation and maintenance of multicellular organisms. The fate of many individual cells, e.g., proliferation, migration, differentiation, or interaction with other cells, is typically governed by information received from other cells and/or the immediate environment. This information is often transmitted by secreted polypeptides (for instance, mitogenic factors, survival factors, cytotoxic factors, differentiation factors, neuropeptides, and hormones) which are, in turn, received and interpreted by diverse cell receptors or membrane-bound proteins. These secreted polypeptides or signaling molecules normally pass through the cellular secretory pathway to reach their site of action in the extracellular environment.

[0003] Secreted proteins have various industrial applications, including as pharmaceuticals, diagnostics, biosensors and bioreactors. Most protein drugs available at present, such as thrombolytic agents, interferons, interleukins, erythropoietins, colony stimulating factors, and various other cytokines, are secretory proteins. Their receptors, which are membrane proteins, also have potential as therapeutic or diagnostic agents. Efforts are being undertaken by both industry and academia to identify new, native secreted proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel secreted proteins. Examples of screening methods and techniques are described in the literature [see, for example, Klein et al., Proc. Natl. Acad. Sci. 93:7108-7113 (1996); U.S. Pat. No. 5,536,637)].

[0004] Membrane-bound proteins and receptors can play important roles in, among other things, the formation, differentiation and maintenance of multicellular organisms. The fate of many individual cells, e.g., proliferation, migration, differentiation, or interaction with other cells, is typically governed by information received from other cells and/or the immediate environment. This information is often transmitted by secreted polypeptides (for instance, mitogenic factors, survival factors, cytotoxic factors, differentiation factors, neuropeptides, and hormones) which are, in turn, received and interpreted by diverse cell receptors or membrane-bound proteins. Such membrane-bound proteins and cell receptors include, but are not limited to, cytokine receptors, receptor kinases, receptor phosphatases, receptors involved in cell-cell interactions, and cellular adhesion molecules like selectins and integrins. For instance, transduction of signals that regulate cell growth and differentiation is regulated in part by phosphorylation of various cellular proteins. Protein tyrosine kinases, enzymes that catalyze that process, can also act as growth factor receptors. Examples include fibroblast growth factor receptor and nerve growth factor receptor.

[0005] Membrane-bound proteins and receptor molecules have various industrial applications, including as pharmaceutical and diagnostic agents. Receptor immuno-adhesions, for instance, can be employed as therapeutic agents to block receptor-ligand interactions. The membrane-bound proteins can also be employed for screening of potential peptide or small molecule inhibitors of the relevant receptor/ligand interaction.

[0006] Efforts are being undertaken by both industry and academia to identify new, native receptor or membrane-bound proteins. Many efforts are focused on the screening of mammalian recombinant DNA libraries to identify the coding sequences for novel receptor or membrane-bound proteins.

[0007] Given the importance of secreted and membrane-bound proteins in biological and disease processes, in vivo studies and characterizations may provide valuable identification and discovery of therapeutics and/or, treatments useful in the prevention, amelioration or correction of diseases or dysfunctions. In this regard, genetically engineered mice have proven to be invaluable tools for the functional dissection of biological processes relevant to human disease, including immunology, cancer, neuro-biology, cardiovascular biology, obesity and many others. Gene knockouts can be viewed as modeling the biological mechanism of drug action by presaging the activity of highly specific antagonists in vivo. Knockout mice have been shown to model drug activity; phenotypes of mice deficient for specific pharmaceutical target proteins can resemble the human clinical phenotype caused by the corresponding antagonist drug. Gene knockouts enable the discovery of the mechanism of action of the target, the predominant physiological role of the target, and mechanism-based side-effects that might result from inhibition of the target in mammals. Examples of this type include mice deficient in the angiotensin converting enzyme (ACE) [Esther, C. R. et al., Lab. Invest., 74:953-965 (1996)] and cyclooxygenase-1 (COX1) genes [Langenbach, R. et al., Cell, 83:483-492 (1995)]. Conversely, knocking the gene out in the mouse can have an opposite phenotypic effect to that observed in humans after administration of an agonist drug to the corresponding target. Examples include the erythropoietin knockout [Wu, C. S. et al., Cell, 83:59-67 (1996)], in which a consequence of the mutation is deficient red blood cell production, and the GABA(A)-R-.beta.3 knockout [DeLorey, T. M., J. Neurosci., 18:8505-8514 (1998)], in which the mutant mice show hyperactivity and hyper-responsiveness. Both these phenotypes are opposite to the effects of erythropoietin and benzodiazepine administration in humans. A striking example of a target validated using mouse genetics is the ACC2 gene. Although the human ACC2 gene had been identified several years ago, interest in ACC2 as a target for drug development was stimulated only recently after analysis of ACC2 function using a knockout mouse. ACC2 mutant mice eat more than their wild-type littermates, yet burn more fat and store less fat in their adipocytes, making this enzyme a probable target for chemical antagonism in the treatment of obesity. [Abu-Elheiga, L. et al., Science, 291:2613-2616 (2001)].

[0008] In the instant application, mutated gene disruptions have resulted in phenotypic observations related to various disease conditions or dysfunctions including: CNS/neurological disturbances or disorders such as anxiety; eye abnormalities and associated diseases; cardiovascular, endothelial or angiogenic disorders including atherosclerosis; abnormal metabolic disorders including diabetes and dyslipidemias associated with elevated serum triglycerides and cholesterol levels; immunological and inflammatory disorders; oncological disorders; bone metabolic abnormalities or disorders such as arthritis, osteoporosis and osteopetrosis; or a developmental disease such as embryonic lethality.

SUMMARY OF THE INVENTION

A. Embodiments

[0009] The invention provides an isolated nucleic acid molecule comprising a nucleotide sequence that encodes a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide.

[0010] In one aspect, the isolated nucleic acid molecule comprises a nucleotide sequence having at least about 80% nucleic acid sequence identity, alternatively at least about 81% nucleic acid sequence identity, alternatively at least about 82% nucleic acid sequence identity, alternatively at least about 83% nucleic acid sequence identity, alternatively at least about 84% nucleic acid sequence identity, alternatively at least about 85% nucleic acid sequence identity, alternatively at least about 86% nucleic acid sequence identity, alternatively at least about 87% nucleic acid sequence identity, alternatively at least about 88% nucleic acid sequence identity, alternatively at least about 89% nucleic acid sequence identity, alternatively at least about 90% nucleic acid sequence identity, alternatively at least about 91% nucleic acid sequence identity, alternatively at least about 92% nucleic acid sequence identity, alternatively at least about 93% nucleic acid sequence identity, alternatively at least about 94% nucleic acid sequence identity, alternatively at least about 95% nucleic acid sequence identity, alternatively at least about 96% nucleic acid sequence identity, alternatively at least about 97% nucleic acid sequence identity, alternatively at least about 98% nucleic acid sequence identity and alternatively at least about 99% nucleic acid sequence identity to (a) a DNA molecule encoding a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide having a full-length amino acid sequence as disclosed herein, an amino acid sequence lacking the signal peptide as disclosed herein, an extracellular domain of a transmembrane protein, with or without the signal peptide, as disclosed herein or any other specifically defined fragment of the full-length amino acid sequence as disclosed herein, or (b) the complement of the DNA molecule of (a).

[0011] In other aspects, the isolated nucleic acid molecule comprises a nucleotide sequence having at least about 80% nucleic acid sequence identity, alternatively at least about 81% nucleic acid sequence identity, alternatively at least about 82% nucleic acid sequence identity, alternatively at least about 83% nucleic acid sequence identity, alternatively at least about 84% nucleic acid sequence identity, alternatively at least about 85% nucleic acid sequence identity, alternatively at least about 86% nucleic acid sequence identity, alternatively at least about 87% nucleic acid sequence identity, alternatively at least about 88% nucleic acid sequence identity, alternatively at least about 89% nucleic acid sequence identity, alternatively at least about 90% nucleic acid sequence identity, alternatively at least about 91% nucleic acid sequence identity, alternatively at least about 92% nucleic acid sequence identity, alternatively at least about 93% nucleic acid sequence identity, alternatively at least about 94% nucleic acid sequence identity, alternatively at least about 95% nucleic acid sequence identity, alternatively at least about 96% nucleic acid sequence identity, alternatively at least about 97% nucleic acid sequence identity, alternatively at least about 98% nucleic acid sequence identity and alternatively at least about 99% nucleic acid sequence identity to (a) a DNA molecule comprising the coding sequence of a full-length PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide cDNA as disclosed herein, the coding sequence of a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide lacking the signal peptide as disclosed herein, the coding sequence of an extracellular domain of a transmembrane PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, with or without the signal peptide, as disclosed herein or the coding sequence of any other specifically defined fragment of the full-length amino acid sequence as disclosed herein, or (b) the complement of the DNA molecule of (a).

[0012] In a further aspect, the invention concerns an isolated nucleic acid molecule comprising a nucleotide sequence having at least about 80% nucleic acid sequence identity, alternatively at least about 81% nucleic acid sequence identity, alternatively at least about 82% nucleic acid sequence identity, alternatively at least about 83% nucleic acid sequence identity, alternatively at least about 84% nucleic acid sequence identity, alternatively at least about 85% nucleic acid sequence identity, alternatively at least about 86% nucleic acid sequence identity, alternatively at least about 87% nucleic acid sequence identity, alternatively at least about 88% nucleic acid sequence identity, alternatively at least about 89% nucleic acid sequence identity, alternatively at least about 90% nucleic acid sequence identity, alternatively at least about 91% nucleic acid sequence identity, alternatively at least about 92% nucleic acid sequence identity, alternatively at least about 93% nucleic acid sequence identity, alternatively at east about 94% nucleic acid sequence identity, alternatively at least about 95% nucleic acid sequence identity, alternatively at least about 96% nucleic acid sequence identity, alternatively at least about 97% nucleic acid sequence identity, alternatively at least about 98% nucleic acid sequence identity and alternatively at least about 99% nucleic acid sequence identity to (a) a DNA molecule that encodes the same mature polypeptide encoded by any of the human protein cDNAs deposited with the ATCC as disclosed herein, or (b) the complement of the DNA molecule of (a).

[0013] Another aspect of the invention provides an isolated nucleic acid molecule comprising a nucleotide sequence encoding a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide which is either transmembrane domain-deleted or transmembrane domain-inactivated, or is complementary to such encoding nucleotide sequence, wherein the transmembrane domain(s) of such polypeptide are disclosed herein. Therefore, soluble extracellular domains of the herein described PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides are contemplated.

[0014] The invention also provides fragments of a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide coding sequence, or the complement thereof, that may find use as, for example, hybridization probes, for encoding fragments of a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979; PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide that may optionally encode a polypeptide comprising a binding site for an anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibody or as antisense oligonucleotide probes. Such nucleic acid fragments usually are or are at least about 10 nucleotides in length, alternatively are or are at least about 15 nucleotides in length, alternatively are or are at least about 20 nucleotides in length, alternatively are or are at least about 30 nucleotides in length, alternatively are or are at least about 40 nucleotides in length, alternatively are or are at least about 50 nucleotides in length, alternatively are or are at least about 60 nucleotides in length, alternatively are or are at least about 70 nucleotides in length, alternatively are or are at least about 80 nucleotides in length, alternatively are or are at least about 90 nucleotides in length, alternatively are or are at least about 100 nucleotides in length, alternatively are or are at least about 110 nucleotides in length, alternatively are or are at least about 120 nucleotides in length, alternatively are or are at least about 130 nucleotides in length, alternatively are or are at least about 140 nucleotides in length, alternatively are or are at least about 150 nucleotides in length, alternatively are or are at least about 160 nucleotides in length, alternatively are or are at least about 170 nucleotides in length, alternatively are or are at least about 180 nucleotides in length, alternatively are or are at least about 190 nucleotides in length, alternatively are or are at least about 200 nucleotides in length, alternatively are or are at least about 250 nucleotides in length, alternatively are or are at least about 300 nucleotides in length, alternatively are or are at least about 350 nucleotides in length, alternatively are or are at least about 400 nucleotides in length, alternatively are or are at least about 450 nucleotides in length, alternatively are or are at least about 500 nucleotides in length, alternatively are or are at least about 600 nucleotides in length, alternatively are or are at least about 700 nucleotides in length, alternatively are or are at least about 800 nucleotides in length, alternatively are or are at least about 900 nucleotides in length and alternatively are or are at least about 1000 nucleotides in length, wherein in this context the term "about" means the referenced nucleotide sequence length plus or minus 10% of that referenced length. It is noted that novel fragments of a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423; PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide-encoding nucleotide sequence may be determined in a routine manner by aligning the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001; PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide-encoding nucleotide sequence with other known nucleotide, sequences using any of a number of well known sequence alignment programs and determining which PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide-encoding nucleotide sequence fragment(s) are novel. All of such PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide-encoding nucleotide sequences are contemplated herein. Also contemplated are the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide fragments encoded by these nucleotide molecule fragments, preferably those PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide fragments that comprise a binding site for an anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibody.

[0015] The invention provides isolated PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides encoded by any of the isolated nucleic acid sequences hereinabove identified.

[0016] In a certain aspect, the invention concerns an isolated PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, comprising an amino acid sequence having at least about 80% amino acid sequence identity, alternatively at least about 81% amino acid sequence identity, alternatively at least about 82% amino acid sequence identity, alternatively at least about 83% amino acid sequence identity, alternatively at least about 84% amino acid sequence identity, alternatively at least about 85% amino acid sequence identity, alternatively at least about 86% amino acid sequence identity, alternatively at least about 87% amino acid sequence identity, alternatively at least about 88% amino acid sequence identity, alternatively at least about 89% amino acid sequence identity, alternatively at least about 90% amino acid sequence identity, alternatively at least about 91% amino acid sequence identity, alternatively at least about 92% amino acid sequence identity, alternatively at least about 93% amino acid sequence identity, alternatively at least about 94% amino acid sequence identity, alternatively at least about 95% amino acid sequence identity, alternatively at least about 96% amino acid sequence identity, alternatively at least about 97% amino acid sequence identity, alternatively at least about 98% amino acid sequence identity and alternatively at least about 99% amino acid sequence identity to a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide having a full-length amino acid sequence as disclosed herein, an amino acid sequence lacking the signal peptide as disclosed herein, an extracellular domain of a transmembrane protein, with or without the signal peptide, as disclosed herein or any other specifically defined fragment of the full-length amino acid sequence as disclosed herein.

[0017] In a further aspect, the invention concerns an isolated PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide comprising an amino acid sequence having at least about 80% amino acid sequence identity, alternatively at least about 81% amino acid sequence identity, alternatively at least about 82% amino acid sequence identity, alternatively at least about 83% amino acid sequence identity, alternatively at least about 84% amino acid sequence identity, alternatively at least about 85% amino acid sequence identity, alternatively at least about 86% amino acid sequence identity, alternatively at least about 87% amino acid sequence identity, alternatively at least about 88% amino acid sequence identity, alternatively at least about 89% amino acid sequence identity, alternatively at least about 90% amino acid sequence identity, alternatively at least about 91% amino acid sequence identity, alternatively at least about 92% amino acid sequence identity, alternatively at least about 93% amino acid sequence identity, alternatively at least about 94% amino acid sequence identity, alternatively at least about 95% amino acid sequence identity, alternatively at least about 96% amino acid sequence identity, alternatively at least about 97% amino acid sequence identity, alternatively at least about 98% amino acid sequence identity and alternatively at least about 99% amino acid sequence identity to an amino acid sequence encoded by any of the human protein cDNAs deposited with the ATCC as disclosed herein.

[0018] In one aspect, the invention concerns PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 variant polypeptides which are or are at least about 10 amino acids in length, alternatively are or are at least about 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600 amino acids in length, or more. Optionally, PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 variant polypeptides will have or have no more than one conservative amino acid substitution as compared to the native PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide sequence, alternatively will have or will have no more than 2, 3, 4, 5, 6, 7, 8, 9, or 10 conservative amino acid substitution as compared to the native PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide sequence.

[0019] In a specific aspect, the invention provides an isolated PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide without the N-terminal signal sequence and/or the initiating methionine and is encoded by a nucleotide sequence that encodes such an amino acid sequence as hereinbefore described. Processes for producing the same are also herein described, wherein those processes comprise culturing a host cell comprising a vector which comprises the appropriate encoding nucleic acid molecule under conditions suitable for expression of the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide and recovering the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332; PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide from the cell culture.

[0020] Another aspect the invention provides an isolated PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide which is either transmembrane domain-deleted or transmembrane domain-inactivated. Processes for producing the same are also herein described, wherein those processes comprise culturing a host cell comprising a vector which comprises the appropriate encoding nucleic acid molecule under conditions suitable for expression of the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide and recovering the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide from the cell culture.

[0021] The invention provides agonists and antagonists of a native PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide as defined herein. In particular, the agonist or antagonist is an anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibody or a small molecule.

[0022] The invention provides a method of identifying agonists or antagonists to a PRO69122, PRO204; PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide which comprise contacting the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide with a candidate molecule and monitoring a biological activity mediated by said PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide. Preferably, the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide is a native PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide.

[0023] The invention provides a composition of matter comprising a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, or an agonist or antagonist of a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912; PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide as herein described, or an anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibody, in combination with a carrier. Optionally, the carrier is a pharmaceutically acceptable carrier.

[0024] The invention provides the use of a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, or an agonist or antagonist thereof as hereinbefore described, or anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibody, for the preparation of a medicament useful in the treatment of a condition which is responsive to the anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibody.

[0025] The invention provides vectors comprising DNA encoding any of the herein described polypeptides. Host cell comprising any such vector are also provided. By way of example, the host cells may be CHO cells, E. coli, or yeast. A process for producing any of the herein described polypeptides is further provided and comprises culturing host cells under conditions suitable for expression of the desired polypeptide and recovering the desired polypeptide from the cell culture.

[0026] The invention provides chimeric molecules comprising any of the herein described polypeptides fused to a heterologous polypeptide or amino acid sequence. Example of such chimeric molecules comprise any of the herein described polypeptides fused to an epitope tag sequence or a Fc region of an immunoglobulin.

[0027] The invention provides an antibody which binds, preferably specifically, to any of the above or below described polypeptides. Optionally, the antibody is a monoclonal antibody, humanized antibody, antibody fragment or single-chain antibody.

[0028] The invention provides oligonucleotide probes which may be useful for isolating genomic and cDNA nucleotide sequences, measuring or detecting expression of an associated gene or as antisense probes, wherein those probes may be derived from any of the above or below described nucleotide sequences. Preferred probe lengths are described above.

[0029] The invention also provides a method of identifying a phenotype associated with a disruption of a gene which encodes for a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, the method comprising:

[0030] (a) providing a non-human transgenic animal whose genome comprises a disruption of the gene which encodes for a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide;

[0031] (b) measuring a physiological characteristic of the non-human transgenic animal; and

[0032] (c) comparing the measured physiological characteristic with that of a gender matched wild-type animal, wherein the physiological characteristic of the non-human transgenic animal that differs from the physiological characteristic of the wild-type animal is identified as a phenotype resulting from the gene disruption in the non-human transgenic animal. In one aspect, the non-human transgenic animal is a mammal. In another aspect, the mammal is a rodent. In still another aspect, the mammal is a rat or a mouse. In one aspect, the non-human transgenic animal is heterozygous for the disruption of a gene which encodes for a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide. In another aspect, the phenotype exhibited by the non-human transgenic animal as compared with gender matched wild-type littermates is at least one of the following: a neurological disorder; a cardiovascular, endothelial or angiogenic disorder; an eye abnormality; an immunological disorder; an oncological disorder; a bone metabolic abnormality or disorder; a lipid metabolic disorder; or a developmental abnormality.

[0033] In yet another aspect, the neurological disorder is an increased anxiety-like response during open field activity testing. In yet another aspect, the neurological disorder is a decreased anxiety-like response during open field activity testing. In yet another aspect, the neurological disorder is an abnormal circadian rhythm during home-cage activity testing. In yet another aspect, the neurological disorder is an enhanced motor coordination during inverted screen testing. In yet another aspect, the neurological disorder is impaired motor coordination during inverted screen testing. In yet another aspect, the neurological disorder includes depression, generalized anxiety disorders, attention deficit disorder, sleep disorder, hyperactivity disorder, obsessive compulsive disorder, schizophrenia, cognitive disorders, hyperalgesia and sensory disorders. Such neurological disorders include the category defined as "anxiety disorders" which include but are not limited to: mild to moderate anxiety, anxiety disorder due to a general medical condition, anxiety disorder not otherwise specified, generalized anxiety disorder, panic attack, panic disorder with agoraphobia, panic disorder without agoraphobia, posttraumatic stress disorder, social phobia, social anxiety, autism, specific phobia, substance-induced anxiety disorder, acute alcohol withdrawal, obsessive compulsive disorder, agoraphobia, monopolar disorders, bipolar disorder I or II, bipolar disorder not otherwise specified, cyclothymic disorder, depressive disorder, major depressive disorder, mood disorder, substance-induced mood disorder, enhancement of cognitive function, loss of cognitive function associated with but not limited to Alzheimer's disease, stroke, or traumatic injury to the brain, seizures resulting from disease or injury including but not limited to epilepsy, learning disorders/disabilities, cerebral palsy. In addition, anxiety disorders may apply to personality disorders including but not limited to the following types: paranoid, antisocial, avoidant behavior, borderline personality disorders, dependent, histronic, narcissistic, obsessive-compulsive, schizoid, and schizotypal.

[0034] In another aspect, the eye abnormality is a retinal abnormality. In still another aspect, the eye abnormality is consistent with vision problems or blindness. In yet another aspect, the retinal abnormality is consistent with retinitis pigmentosa or is characterized by retinal degeneration or retinal dysplasia.

[0035] In still another aspect, the retinal abnormalities are consistent with retinal dysplasia, various retinopathies, including retinopathy of prematurity, retrolental fibroplasia, neovascular glaucoma, age-related macular degeneration, diabetic macular edema, corneal neovascularization, corneal graft neovascularization, corneal graft rejection, retinal/choroidal neovascularization, neovascularization of the angle (rubeosis), ocular neovascular disease, vascular restenosis, arteriovenous malformations (AVM), meningioma, hemangioma, angiofibroma, thyroid hyperplasias (including Grave's disease), corneal and other tissue transplantation, retinal artery obstruction or occlusion; retinal degeneration causing secondary atrophy of the retinal vasculature, retinitis pigmentosa, macular dystrophies, Stargardt's disease, congenital stationary night blindness, choroideremia, gyrate atrophy, Leber's congenital amaurosis, retinoschisis disorders, Wagner's syndrome, Usher syndromes, Zellweger syndrome, Saldino-Mainzer syndrome, Senior-Loken syndrome, Bardet-Biedl syndrome, Alport's syndrome, Alstrom's syndrome, Cockayne's syndrome, dysplaisa spondyloepiphysaria congentia, Flynn-Aird syndrome, Friedreich ataxia, Hallgren syndrome, Marshall syndrome, Albers-Schnoberg disease, Refsum's disease, Kearns-Sayre syndrome, Waardenburg's syndrome, Alagile syndrome, myotonic dystrophy, olivopontocerebellar atrophy, Pierre-Marie dunsdrome, Stickler syndrome, carotinemeia, cystinosis, Wolfram syndrome, Bassen-Kornzweig syndrome, abetalipoproteinemia, incontinentia pigmenti, Batten's disease, mucopolysaccharidoses, homocystinuria, or mannosidosis.

[0036] In still another aspect, the eye abnormality is a cataract. In still yet another aspect, the cataract is a systemic disease such as human Down's syndrome, Hallerman-Streiff syndrome, Lowe syndrome, galactosemia, Marfan syndrome, Trismoy 13-15, Alport syndrome, myotonic dystrophy, Fabry disease, hypoparathroidism or Conradi syndrome.

[0037] In still another aspect, the developmental abnormality comprises embryonic lethality or reduced viability.

[0038] In still yet another aspect, the cardiovascular, endothelial or angiogenic disorders are arterial diseases, such as diabetes mellitus; papilledema; optic atrophy; atherosclerosis; angina; myocardial infarctions such as acute myocardial infarctions, cardiac hypertrophy, and heart failure such as congestive heart failure; hypertension; inflammatory vasculitides; Reynaud's disease and Reynaud's phenomenon; aneurysms and arterial restenosis; venous and lymphatic disorders such as thrombophlebitis, lymphangitis, and lymphedema; peripheral vascular disease; cancer such as vascular tumors, e.g., hemangioma (capillary and cavernous), glomus tumors, telangiectasia, bacillary angiomatosis, hemangioendothelioma, angiosarcoma, haemangiopericytoma, Kaposi's sarcoma, lymphangioma, and lymphangiosarcoma; tumor angiogenesis; trauma such as wounds, burns, and other injured tissue, implant fixation, scarring; ischemia reperfusion injury; rheumatoid arthritis; cerebrovascular disease; renal diseases such as acute renal failure, or osteoporosis.

[0039] In still another aspect, the immunological disorders are consistent with systemic lupus erythematosis; rheumatoid arthritis; juvenile chronic arthritis; spondyloarthropathies; systemic sclerosis (scleroderma); idiopathic inflammatory myopathies (dermatomyositis, polymyositis); Sjogren's syndrome; systemic vasculitis; sarcoidosis; autoimmune hemolytic anemia (immune pancytopenia, paroxysmal nocturnal hemoglobinuria); autoimmune thrombocytopenia (idiopathic thrombocytopenic purpura, immune-mediated thrombocytopenia); thyroiditis (Grave's disease, Hashimoto's thyroiditis, juvenile lymphocytic thyroiditis, atrophic thyroiditis); diabetes mellitus; immune-mediated renal disease (glomerulonephritis, tubulointerstitial nephritis); demyelinating diseases of the central and peripheral nervous systems such as multiple sclerosis, idiopathic demyelinating polyneuropathy or Guillain-Barre syndrome, and chronic inflammatory demyelinating polyneuropathy; hepatobiliary diseases such as infectious hepatitis (hepatitis A, B, C, D, E and other non-hepatotropic viruses), autoimmune chronic active hepatitis, primary biliary cirrhosis, granulomatous hepatitis, and sclerosing cholangitis; inflammatory bowel disease (ulcerative colitis: Crohn's disease); gluten-sensitive enteropathy, and Whipple's disease; autoimmune or immune-mediated skin diseases including bullous skin diseases, erythema multiforme and contact dermatitis, psoriasis; allergic diseases such as asthma, allergic rhinitis, atopic dermatitis, food hypersensitivity and urticaria; immunologic diseases of the lung such as eosinophilic pneumonia, idiopathic pulmonary fibrosis and hypersensitivity pneumonitis; or transplantation associated diseases including graft rejection and graft-versus-host disease.

[0040] In still another aspect, the bone metabolic abnormality or disorder is arthritis, osteoporosis, osteopenia or osteopetrosis.

[0041] In another aspect, the non-human transgenic animal exhibits at least one of the following physiological characteristics compared with gender matched wild-type littermates: increased anxiety-like response during open field testing; decreased anxiety during open field testing; hypoactivity with no circadian rhythm; increased total distance traveled during open field testing (hyperactivity); decreased locomotor activity during open field testing; abnormal circadian rhythm during home-cage activity testing (low activity during the light phase); abnormal circadian rhythm during home-cage activity testing including decreased ambulatory counts; abnormal circadian rhythm during home-cage activity testing including increased ambulatory counts; whiskers absent due to anxiety phenotype; enhanced circadian rhythm; increased stress induced hyperthermia with increased stress response (increased anxiety); increased resistance to stress induced hyperthermia; decreased resistance to stress induced hyperthermia; enhanced motor coordination during inverted screen testing; impaired motor coordination during inverted screen testing; increased immobility in tail suspension (increased depressive-like response); increased depressive-like response during tail suspension testing; decreased depressive-like response during tail suspension testing; clutched hind limbs during tail suspension testing; decreased startle response during prepulse inhibition testing; no startle response indicating deafness; increased prepulse inhibition with enhanced sensorimotor gating/attention; increased latency on hotplate indicative of decreased sensitivity to heat-induced pain; opthamological abnormalities; corneal epidermidalization of the corneal stroma with scarring and blocked vision; metaplasia of the cornea and sclera; attenuated retinal arteries; retinal hemorrhage; optic nerve abnormalities; dilated optic disc; increased intraocular pressure; corneal epithelialization with underdeveloped eyelids; retinal degeneration; agenesis of the Harderian gland; retinal vessel disorganization, microaneurysms and retinal capillary leakage; impaired vision; decreased heart rate; decreased mean systolic blood pressure; increased mean systolic blood pressure; increased insulin sensitivity; increased mean fasting serum glucose levels; decreased mean serum glucose levels; increased mean serum cholesterol levels; decreased mean serum cholesterol levels; increased mean serum triglyceride levels; enhanced glucose tolerance; impaired glucose tolerance; decreased mean serum insulin levels; ketonemia; decreased mean serum calcium; blood urobilinogen, nitrites, protein and ketones; decreased sodium and chloride; increased bilirubin; notable lipemia; increased uric acid and potassium levels; increased mean serum alkaline phosphatase levels; decreased mean serum alkaline phosphatase levels; blood in the urine; glucosuria; increased nitrituria; ketonuria; increased mean percentage of natural killer cells; decreased mean percentage of natural killer cells; abnormal leukocyte count; leukopenia due to lymphopenia and granulocytopenia; increased mean percentage of CD4 cells; decreased mean percentage of CD4 cells; decreased mean percentage of CD8 cells; reduced percentage of naive CD4 and CD8 T cells in lymph nodes; increased mean percentage of B cells in peripheral blood; decrease total white blood cells and lymphocyte counts; decreased absolute lymphocyte counts; increased mean absolute monocyte count; increased mean absolute neutrophil count; decreased in mean serum IgA levels; increase in mean serum IgA levels; increase in IgG1 levels; decreased mean serum IgG1 levels; decreased mean serum IgG1, IgG3, IgG2b and IgG2a levels; decreased mean serum IgG2a levels; decreased mean serum IgG2b levels; decreased mean serum IgG3 and IgM levels; increase in mean serum IgG2a levels; increase in mean serum IgG1, IgG2a and IgG3 levels; increase in mean serum IgG3 levels; anemia; decreased red blood cell count, decreased hemoglobin and decreased hematocrit with increased mean red blood cell count; increased mean corpuscular volume; decreased mean corpuscular volume; decreased mean corpuscular hemoglobin; increased red blood cell distribution width; defect in erythropoiesis; increased IgM+ IgD+ and B220hi/CD43- cells in bone marrow; decreased percentage of B220hi/CD43- IgM+ IgD+ cells in bone marrow; increased percentage of TCRB+ cells in Peyer's patches; reduction in naive T cells (especially CD4) in lymph nodes; increased percentage of CD11b+CD11c- cells (monocytes) in spleen; increased percentage of IgM+, CD117+ cells in bone marrow, higher percentage of dead B cells, decreased B cells, increased CD4 and CD8 T cells in lymph; B cells increased in bone marrow and significantly decreased in lymph node; notably decreased CD21hiCD23med B cells in spleen; decrease in Peyer's patch B220+ cells; decreased mean percentages of CD8 and natural killer cells with increased mean percentage of B cells; reduced number of TCRB+ CD38+ activated T cells in Peyer's patches; decreased mean percentage of CD4 cells with increased mean percentage of B cells; decreased B220+ CD38low and IgM in Payer's patches; increased mean platelet count; decreased mean platelet count; widespread apoptosis and loss of T lymphocytes in the thymic cortex and depletion of T cells in spleen; increased mean serum IgG2a response to an ovalbumin challenge; decreased to no serum IgG1 and IgG2a response to ovalbumin challenge; increased mean serum IgG1 response to an ovalbumin challenge; decreased mean serum TNF-alpha, MCP-1 and IL-6 responses to LPS challenge; increased mean serum MCP-1 response to a LPS challenge; increased mean serum TNF-alpha response to a LPS challenge; increased mean serum IL-6 response to a LPS challenge; increased skin fibroblast proliferation; decreased skin fibroblast proliferation; increased mean percent of total body fat and total fat mass; increased mean body weight; increased mean body length; increased total tissue mass (TTM); increased lean body mass (LBM); increased femoral bone mineral density (BMD); increased vertebral bone mineral density (BMD); increased bone mineral density (BMD); increased total body volumetric bone mineral density (vBMD); increased bone mineral content (BMC); increased mean femoral midshaft cortical thickness and cross-sectional area; increased mean vertebral trabecular bone volume, number and connectivity density; decreased mean percent of total body fat and total fat mass; decreased mean body weight; decreased mean body length; decreased total tissue mass (TTM); decreased lean body mass (LBM); decreased femoral bone mineral density (BMD); decreased vertebral bone mineral density (BMD); decreased bone mineral density (BMD); decreased bone mineral content (BMC); decreased bone mineral density index; decreased volumetric bone mineral density (vBMD); decreased mean femoral midshaft cortical thickness and cross-sectional area; decreased mean vertebral trabecular bone volume, number and connectivity density; marked osteopetrosis with increased bone mineralization; chronic inflammation in various tissues; thymic atrophy; systemic histiocytic storage disease affecting macrophages in liver, spleen and mesenteric lymph nodes; reduced liver size; chronic active hepatitis with focal hepatocyte necrosis; fatty changes in the liver; increased intracytoplasmic vacuolization of glycogen in hepatocytes; pancreatic dyserythropoietic anemia (type 1); multifocal neuronal necrosis; diffuse abiotrophy of the cerebellum granule cell layer; multifocal developmental malformation of the brain; hydronephosis; diffuse alopecia; epidermal hyperkeratosis; hypochromasia and anisocytosis characterized by abnormal erythrocytes (abnormally low hemoglobin and decreased erythropoiesis); growth retardation; development abnormalities; granulocytic hypoplasia of bone marrow; decreased numbers of myeloid granulocytic cell precursors; decreased granulocytopoiesis; no teeth; stunted growth with general reduction in all organ size; myocardial defects with defective structure and arrangement of the cardiac myocytes; cardiomyopathy with condensed eosinophilic sarcoplasm; congestive heart failure; pancreatic islets of Langerhans smaller and distribution of alpha (glycogen) and beta (insulin) cells altered; notable histopathologic alteration in cytoplasm of all cells in the zona fasciculata of the adrenal gland consistent with altered lipid/cholesterol uptake or metabolism (elevated cholesterol and triglycerides); infertility; testicular degeneration; vacuolar degeneration of seminiferous tubules; hypospermia; atrophic testes; ovarian and uterine hypoplasia; mammary gland was represented with just a few ducts; growth retardation with reduced viability; and embryonic lethality.

[0042] The invention also provides an isolated cell derived from a non-human transgenic animal whose genome comprises a disruption of the gene which encodes for a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide. In one aspect, the isolated cell is a murine cell. In yet another aspect, the murine cell is an embryonic stem cell. In still another aspect, the isolated cell is derived from a non-human transgenic animal which exhibits at least one of the following phenotypes compared with gender matched wild-type littermates: a neurological disorder; a cardiovascular, endothelial or angiogenic disorder; an eye abnormality; an immunological disorder; an oncological disorder; a bone metabolic abnormality or disorder; a lipid metabolic disorder; or a developmental abnormality. The invention also provides a method of identifying an agent that modulates a phenotype associated with a disruption of a gene which encodes for a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, the method comprising:

[0043] (a) providing a non-human transgenic animal whose genome comprises a disruption of the gene which encodes for the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide;

[0044] (b) measuring a physiological characteristic of the non-human transgenic animal of (a);

[0045] (c) comparing the measured physiological characteristic of (b) with that of a gender matched wild-type animal, wherein the physiological characteristic of the non-human transgenic animal that differs from the physiological characteristic of the wild-type animal is identified as a phenotype resulting from the gene disruption in the non-human transgenic animal;

[0046] (d) administering a test agent to the non-human transgenic animal of (a); and

[0047] (e) determining whether the test agent modulates the identified phenotype associated with gene disruption in the non-human transgenic animal.

[0048] In one aspect, the phenotype associated with the gene disruption comprises a neurological disorder; a cardiovascular, endothelial or angiogenic disorder; an eye abnormality; an immunological disorder; an oncological disorder; a bone metabolic abnormality or disorder; a lipid metabolic disorder; or a developmental abnormality.

[0049] In yet another aspect, the neurological disorder is an increased anxiety-like response during open field activity testing. In yet another aspect, the neurological disorder is a decreased anxiety-like response during open field activity testing. In yet another aspect, the neurological disorder is an abnormal circadian rhythm during home-cage activity testing. In yet another aspect, the neurological disorder is an enhanced motor coordination during inverted screen testing. In yet another aspect, the neurological disorder is impaired motor coordination during inverted screen testing. In yet another aspect, the neurological disorder includes depression, generalized anxiety disorders, attention deficit disorder, sleep disorder, hyperactivity disorder, obsessive compulsive disorder, schizophrenia, cognitive disorders, hyperalgesia and sensory disorders. Such neurological disorders include the category defined as "anxiety disorders" which include but are not limited to: mild to moderate anxiety, anxiety disorder due to a general medical condition, anxiety disorder not otherwise specified, generalized anxiety disorder, panic attack, panic disorder with agoraphobia, panic disorder without agoraphobia, posttraumatic stress disorder, social phobia, social anxiety, autism, specific phobia, substance-induced anxiety disorder, acute alcohol withdrawal, obsessive compulsive disorder, agoraphobia, monopolar disorders, bipolar disorder I or II, bipolar disorder not otherwise specified, cyclothymic disorder, depressive disorder, major depressive disorder, mood disorder, substance-induced mood disorder, enhancement of cognitive function, loss of cognitive function associated with but not limited to Alzheimer's disease, stroke, or traumatic injury to the brain, seizures resulting from disease or injury including but not limited to epilepsy, learning disorders/disabilities, cerebral palsy. In addition, anxiety disorders may apply to personality disorders including but not limited to the following types: paranoid, antisocial, avoidant behavior, borderline personality disorders, dependent, histronic, narcissistic, obsessive-compulsive, schizoid, and schizotypal.

[0050] In yet another aspect, the eye abnormality is a retinal abnormality. In still another aspect, the eye abnormality is consistent with vision problems or blindness. In yet another aspect, the retinal abnormality is consistent with retinitis pigmentosa or is characterized by retinal degeneration or retinal dysplasia.

[0051] In still another aspect, the retinal abnormalities are consistent with retinal dysplasia, various retinopathies, including retinopathy of prematurity, retrolental fibroplasia, neovascular glaucoma, age-related macular degeneration, diabetic macular edema, corneal neovascularization, corneal graft neovascularization, corneal graft rejection, retinal/choroidal neovascularization, neovascularization of the angle (rubeosis), ocular neovascular disease, vascular restenosis, arteriovenous malformations (AVM), meningioma, hemangioma, angiofibroma, thyroid hyperplasias (including Grave's disease), corneal and other tissue transplantation, retinal artery obstruction or occlusion; retinal degeneration causing secondary atrophy of the retinal vasculature, retinitis pigmentosa, macular dystrophies, Stargardt's disease, congenital stationary night blindness, choroideremia, gyrate atrophy, Leber's congenital amaurosis, retinoschisis disorders, Wagner's syndrome, Usher syndromes, Zellweger syndrome, Saldino-Mainzer syndrome, Senior-Loken syndrome, Bardet-Biedl syndrome, Alport's syndrome, Alstrom's syndrome, Cockayne's syndrome, dysplaisa spondyloepiphysaria congentia, Flynn-Aird syndrome, Friedreich ataxia, Hallgren syndrome, Marshall syndrome, Albers-Schnoberg disease, Refsum's disease, Kearns-Sayre syndrome, Waardenburg's syndrome, Alagile syndrome, myotonic dystrophy, olivopontocerebellar atrophy, Pierre-Marie dunsdrome, Stickler syndrome, carotinemeia, cystinosis, Wolfram syndrome, Bassen-Kornzweig syndrome, abetalipoproteinemia, incontinentia pigmenti, Batten's disease, mucopolysaccharidoses, homocystinuria, or mannosidosis.

[0052] In still another aspect, the eye abnormality is a cataract. In still yet another aspect, the cataract is a systemic disease such as human Down's syndrome, Hallerman-Streiff syndrome, Lowe syndrome, galactosemia, Marfan syndrome, Trismoy 13-15, Alport syndrome, myotonic dystrophy, Fabry disease, hypoparathroidism, or Conradi syndrome.

[0053] In still another aspect, the developmental abnormality comprises embryonic lethality or reduced viability.

[0054] In still another aspect, the cardiovascular, endothelial or angiogenic disorders are arterial diseases, such as diabetes mellitus; papilledema; optic atrophy; atherosclerosis; angina; myocardial infarctions such as acute myocardial infarctions, cardiac hypertrophy, and heart failure such as congestive heart failure; hypertension; inflammatory vasculitides; Reynaud's disease and Reynaud's phenomenon; aneurysms and arterial restenosis; venous and lymphatic disorders such as thrombophlebitis, lymphangitis, and lymphedema; peripheral vascular disease; cancer such as vascular tumors, e.g., hemangioma (capillary and cavernous), glomus tumors, telangiectasia, bacillary angiomatosis, hemangioendothelioma, angiosarcoma, haemangiopericytoma, Kaposi's sarcoma, lymphangioma, and lymphangiosarcoma; tumor angiogenesis; trauma such as wounds, burns, and other injured tissue, implant fixation, scarring; ischemia reperfusion injury; rheumatoid arthritis; cerebrovascular disease; renal diseases such as acute renal failure, or osteoporosis.

[0055] In still another aspect, the immunological disorders are consistent with systemic lupus erythematosis; rheumatoid arthritis; juvenile chronic arthritis; spondyloarthropathies; systemic sclerosis (scleroderma); idiopathic inflammatory myopathies (dermatomyositis, polymyositis); Sjogren's syndrome; systemic vasculitis; sarcoidosis; autoimmune hemolytic anemia (immune pancytopenia, paroxysmal nocturnal hemoglobinuria); autoimmune thrombocytopenia (idiopathic thrombocytopenic purpura, immune-mediated thrombocytopenia); thyroiditis (Grave's disease, Hashimoto's thyroiditis, juvenile lymphocytic thyroiditis, atrophic thyroiditis); diabetes mellitus; immune-mediated renal disease (glomerulonephritis, tubulointerstitial nephritis); demyelinating diseases of the central and peripheral nervous systems such as multiple sclerosis, idiopathic demyelinating polyneuropathy or Guillain-Barre syndrome, and chronic inflammatory demyelinating polyneuropathy; hepatobiliary diseases such as infectious hepatitis (hepatitis A, B, C, D, E and other non-hepatotropic viruses), autoimmune chronic active hepatitis, primary biliary cirrhosis, granulomatous hepatitis, and sclerosing cholangitis; inflammatory bowel disease (ulcerative colitis: Crohn's disease); gluten-sensitive enteropathy, and Whipple's disease; autoimmune or immune-mediated skin diseases including bullous skin diseases, erythema multiforme and contact dermatitis, psoriasis; allergic diseases such as asthma, allergic rhinitis, atopic dermatitis, food hypersensitivity and urticaria; immunologic diseases of the lung such as eosinophilic pneumonia, idiopathic pulmonary fibrosis and hypersensitivity pneumonitis; or transplantation associated diseases including graft rejection and graft-versus-host disease.

[0056] In yet another aspect, the bone metabolic abnormality or disorder is arthritis, osteoporosis, osteopenia or osteopetrosis.

[0057] In another aspect, the non-human transgenic animal exhibits at least one of the following physiological characteristics compared with gender matched wild-type littermates: increased anxiety-like response during open field testing; decreased anxiety during open field testing; hypoactivity with no circadian rhythm; increased total distance traveled during open field testing (hyperactivity); decreased locomotor activity during open field testing; abnormal circadian rhythm during home-cage activity testing (low activity during the light phase); abnormal circadian rhythm during home-cage activity testing including decreased ambulatory counts; abnormal circadian rhythm during home-cage activity testing including increased ambulatory counts; whiskers absent due to anxiety phenotype; enhanced circadian rhythm; increased stress induced hyperthermia with increased stress response (increased anxiety); increased resistance to stress induced hyperthermia; decreased resistance to stress induced hyperthermia; enhanced motor coordination during inverted screen testing; impaired motor coordination during inverted screen testing; increased immobility in tail suspension (increased depressive-like response); increased depressive-like response during tail suspension testing; decreased depressive-like response during tail suspension testing; clutched hind limbs during tail suspension testing; decreased startle response during prepulse inhibition testing; no startle response indicating deafness; increased prepulse inhibition with enhanced sensorimotor gating/attention; increased latency on hotplate indicative of decreased sensitivity to heat-induced pain; opthamological abnormalities; corneal epidermidalization of the corneal stroma with scarring and blocked vision; metaplasia of the cornea and sclera; attenuated retinal arteries; retinal hemorrhage; optic nerve abnormalities; dilated optic disc; increased intraocular pressure; corneal epithelialization with underdeveloped eyelids; retinal degeneration; agenesis of the Harderian gland; retinal vessel disorganization, microaneurysms and retinal capillary leakage; impaired vision; decreased heart rate; decreased mean systolic blood pressure; increased mean systolic blood pressure; increased insulin sensitivity; increased mean fasting serum glucose levels; decreased mean serum glucose levels; increased mean serum cholesterol levels; decreased mean serum cholesterol levels; increased mean serum triglyceride levels; enhanced glucose tolerance; impaired glucose tolerance; decreased mean serum insulin levels; ketonemia; decreased mean serum calcium; blood urobilinogen, nitrites, protein and ketones; decreased sodium and chloride; increased bilirubin; notable lipemia; increased uric acid and potassium levels; increased mean serum alkaline phosphatase levels; decreased mean serum alkaline phosphatase levels; blood in the urine; glucosuria; increased nitrituria; ketonuria; increased mean percentage of natural killer cells; decreased mean percentage of natural killer cells; abnormal leukocyte count; leukopenia due to lymphopenia and granulocytopenia; increased mean percentage of CD4 cells; decreased mean percentage of CD4 cells; decreased mean percentage of CD8 cells; reduced percentage of naive CD4 and CD8 T cells in lymph nodes; increased mean percentage of B cells in peripheral blood; decrease total white blood cells and lymphocyte counts; decreased absolute lymphocyte counts; increased mean absolute monocyte count; increased mean absolute neutrophil count; decreased in mean serum IgA levels; increase in mean serum IgA levels; increase in IgG1 levels; decreased mean serum IgG1 levels; decreased mean serum IgG1, IgG3, IgG2b and IgG2a levels; decreased mean serum IgG2a levels; decreased mean serum IgG2b levels; decreased mean serum IgG3 and IgM levels; increase in mean serum IgG2a levels; increase in mean serum IgG1, IgG2a and IgG3 levels; increase in mean serum IgG3 levels; anemia; decreased red blood cell count, decreased hemoglobin and decreased hematocrit with increased mean red blood cell count; increased mean corpuscular volume; decreased mean corpuscular volume; decreased mean corpuscular hemoglobin; increased red blood cell distribution width; defect in erythropoiesis; increased IgM+ IgD+ and B220hi/CD43- cells in bone marrow; decreased percentage of B220hi/CD43- IgM+ IgD+ cells in bone marrow; increased percentage of TCRB+ cells in Peyer's patches; reduction in naive T cells (especially CD4) in lymph nodes; increased percentage of CD11b+CD11c- cells (monocytes) in spleen; increased percentage of IgM+, CD117+ cells in bone marrow, higher percentage of dead B cells, decreased B cells, increased CD4 and CD8 T cells in lymph; B cells increased in bone marrow and significantly decreased in lymph node; notably decreased CD21hiCD23med B cells in spleen; decrease in Peyer's patch B220+ cells; decreased mean percentages of CD8 and natural killer cells with increased mean percentage of B cells; reduced number of TCRB+ CD38+ activated T cells in Peyer's patches; decreased mean percentage of CD4 cells with increased mean percentage of B cells; decreased B220+ CD38low and IgM in Payer's patches; increased mean platelet count; decreased mean platelet count; widespread apoptosis and loss of T lymphocytes in the thymic cortex and depletion of T cells in spleen; increased mean serum IgG2a response to an ovalbumin challenge; decreased to no serum IgG1 and IgG2a response to ovalbumin challenge; increased mean serum IgG1 response to an ovalbumin challenge; decreased mean serum TNF-alpha, MCP-1 and IL-6 responses to LPS challenge; increased mean serum MCP-1 response to a LPS challenge; increased mean serum TNF-alpha response to a LPS challenge; increased mean serum IL-6 response to a LPS challenge; increased skin fibroblast proliferation; decreased skin fibroblast proliferation; increased mean percent of total body fat and total fat mass; increased mean body weight; increased mean body length; increased total tissue mass (TTM); increased lean body mass (LBM); increased femoral bone mineral density (BMD); increased vertebral bone mineral density (BMD); increased bone mineral density (BMD); increased total body volumetric bone mineral density (vBMD); increased bone mineral content (BMC); increased mean femoral midshaft cortical thickness and cross-sectional area; increased mean vertebral trabecular bone volume, number and connectivity density; decreased mean percent of total body fat and total fat mass; decreased mean body weight; decreased mean body length; decreased total tissue mass (TTM); decreased lean body mass (LBM); decreased femoral bone mineral density (BMD); decreased vertebral bone mineral density (BMD); decreased bone mineral density (BMD); decreased bone mineral content (BMC); decreased bone mineral density index; decreased volumetric bone mineral density (vBMD); decreased mean femoral midshaft cortical thickness and cross-sectional area; decreased mean vertebral trabecular bone volume, number and connectivity density; marked osteopetrosis with increased bone mineralization; chronic inflammation in various tissues; thymic atrophy; systemic histiocytic storage disease affecting macrophages in liver, spleen and mesenteric lymph nodes; reduced liver size; chronic active hepatitis with focal hepatocyte necrosis; fatty changes in the liver; increased intracytoplasmic vacuolization of glycogen in hepatocytes; pancreatic dyserythropoietic anemia (type 1); multifocal neuronal necrosis; diffuse abiotrophy of the cerebellum granule cell layer; multifocal developmental malformation of the brain; hydronephosis; diffuse alopecia; epidermal hyperkeratosis; hypochromasia and anisocytosis characterized by abnormal erythrocytes (abnormally low hemoglobin and decreased erythropoiesis); growth retardation; development abnormalities; granulocytic hypoplasia of bone marrow; decreased numbers of myeloid granulocytic cell precursors; decreased granulocytopoiesis; no teeth; stunted growth with general reduction in all organ size; myocardial defects with defective structure and arrangement of the cardiac myocytes; cardiomyopathy with condensed eosinophilic sarcoplasm; congestive heart failure; pancreatic islets of Langerhans smaller and distribution of alpha (glycogen) and beta (insulin) cells altered; notable histopathologic alteration in cytoplasm of all cells in the zona fasciculata of the adrenal gland consistent with altered lipid/cholesterol uptake or metabolism (elevated cholesterol and triglycerides); infertility; testicular degeneration; vacuolar degeneration of seminiferous tubules; hypospermia; atrophic testes; ovarian and uterine hypoplasia; mammary gland was represented with just a few ducts; growth retardation with reduced viability; and embryonic lethality.

[0058] The invention also provides an agent which modulates the phenotype associated with gene disruption. In one aspect, the agent is an agonist or antagonist of a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide. In yet another aspect, the agonist agent is an anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibody. In still another aspect, the antagonist agent is an anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibody.

[0059] The invention also provides a method of identifying an agent that modulates a physiological characteristic associated with a disruption of the gene which encodes for a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, the method comprising:

[0060] (a) providing a non-human transgenic animal whose genome comprises a disruption of the gene which encodes for a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide;

[0061] (b) measuring a physiological characteristic exhibited by the non-human transgenic animal of (a);

[0062] (c) comparing the measured physiological characteristic of (b) with that of a gender matched wild-type animal, wherein the physiological characteristic exhibited by the non-human transgenic animal that differs from the physiological characteristic exhibited by the wild-type animal is identified as a physiological characteristic associated with gene disruption;

[0063] (d) administering a test agent to the non-human transgenic animal of (a); and

[0064] (e) determining whether the physiological characteristic associated with gene disruption is modulated.

[0065] In one aspect, the non-human transgenic animal exhibits at least one of the following physiological characteristics compared with gender matched wild-type littermates: increased anxiety-like response during open field testing; decreased anxiety during open field testing; hypoactivity with no circadian rhythm; increased total distance traveled during open field testing (hyperactivity); decreased locomotor activity during open field testing; abnormal circadian rhythm during home-cage activity testing (low activity during the light phase); abnormal circadian rhythm during home-cage activity testing including decreased ambulatory counts; abnormal circadian rhythm during home-cage activity testing including increased ambulatory counts; whiskers absent due to anxiety phenotype; enhanced circadian rhythm; increased stress induced hyperthermia with increased stress response (increased anxiety); increased resistance to stress induced hyperthermia; decreased resistance to stress induced hyperthermia; enhanced motor coordination during inverted screen testing; impaired motor coordination during inverted screen testing; increased immobility in tail suspension (increased depressive-like response); increased depressive-like response during tail suspension testing; decreased depressive-like response during tail suspension testing; clutched hind limbs during tail suspension testing; decreased startle response during prepulse inhibition testing; no startle response indicating deafness; increased prepulse inhibition with enhanced sensorimotor gating/attention; increased latency on hotplate indicative of decreased sensitivity to heat-induced pain; opthamological abnormalities; corneal epidermidalization of the corneal stroma with scarring and blocked vision; metaplasia of the cornea and sclera; attenuated retinal arteries; retinal hemorrhage; optic nerve abnormalities; dilated optic disc; increased intraocular pressure; corneal epithelialization with underdeveloped eyelids; retinal degeneration; agenesis of the Harderian gland; retinal vessel disorganization, microaneurysms and retinal capillary leakage; impaired vision; decreased heart rate; decreased mean systolic blood pressure; increased mean systolic blood pressure; increased insulin sensitivity; increased mean fasting serum glucose levels; decreased mean serum glucose levels; increased mean serum cholesterol levels; decreased mean serum cholesterol levels; increased mean serum triglyceride levels; enhanced glucose tolerance; impaired glucose tolerance; decreased mean serum insulin levels; ketonemia; decreased mean serum calcium; blood urobilinogen, nitrites, protein and ketones; decreased sodium and chloride; increased bilirubin; notable lipemia; increased uric acid and potassium levels; increased mean serum alkaline phosphatase levels; decreased mean serum alkaline phosphatase levels; blood in the urine; glucosuria; increased nitrituria; ketonuria; increased mean percentage of natural killer cells; decreased mean percentage of natural killer cells; abnormal leukocyte count; leukopenia due to lymphopenia and granulocytopenia; increased mean percentage of CD4 cells; decreased mean percentage of CD4 cells; decreased mean percentage of CD8 cells; reduced percentage of naive CD4 and CD8 T cells in lymph nodes; increased mean percentage of B cells in peripheral blood; decrease total white blood cells and lymphocyte counts; decreased absolute lymphocyte counts; increased mean absolute monocyte count; increased mean absolute neutrophil count; decreased in mean serum IgA levels; increase in mean serum IgA levels; increase in IgG1 levels; decreased mean serum IgG1 levels; decreased mean serum IgG1, IgG3, IgG2b and IgG2a levels; decreased mean serum IgG2a levels; decreased mean serum IgG2b levels; decreased mean serum IgG3 and IgM levels; increase in mean serum IgG2a levels; increase in mean serum IgG1, IgG2a and IgG3 levels; increase in mean serum IgG3 levels; anemia; decreased red blood cell count, decreased hemoglobin and decreased hematocrit with increased mean red blood cell count; increased mean corpuscular volume; decreased mean corpuscular volume; decreased mean corpuscular hemoglobin; increased red blood cell distribution width; defect in erythropoiesis; increased IgM+ IgD+ and B220hi/CD43- cells in bone marrow; decreased percentage of B220hi/CD43- IgM+ IgD+ cells in bone marrow; increased percentage of TCRB+ cells in Peyer's patches; reduction in naive T cells (especially CD4) in lymph nodes; increased percentage of CD11b+CD11c- cells (monocytes) in spleen; increased percentage of IgM+, CD117+ cells in bone marrow, higher percentage of dead B cells, decreased B cells, increased CD4 and CD8 T cells in lymph; B cells increased in bone marrow and significantly decreased in lymph node; notably decreased CD21hiCD23med B cells in spleen; decrease in Peyer's patch B220+ cells; decreased mean percentages of CD8 and natural killer cells with increased mean percentage of B cells; reduced number of TCRB+ CD38+ activated T cells in Peyer's patches; decreased mean percentage of CD4 cells with increased mean percentage of B cells; decreased B220+ CD38low and IgM in Payer's patches; increased mean platelet count; decreased mean platelet count; widespread apoptosis and loss of T lymphocytes in the thymic cortex and depletion of T cells in spleen; increased mean serum IgG2a response to an ovalbumin challenge; decreased to no serum IgG1 and IgG2a response to ovalbumin challenge; increased mean serum IgG1 response to an ovalbumin challenge; decreased mean serum TNF-alpha, MCP-1 and IL-6 responses to LPS challenge; increased mean serum MCP-1 response to a LPS challenge; increased mean serum TNF-alpha response to a LPS challenge; increased mean serum IL-6 response to a LPS challenge; increased skin fibroblast proliferation; decreased skin fibroblast proliferation; increased mean percent of total body fat and total fat mass; increased mean body weight; increased mean body length; increased total tissue mass (TTM); increased lean body mass (LBM); increased femoral bone mineral density (BMD); increased vertebral bone mineral density (BMD); increased bone mineral density (BMD); increased total body volumetric bone mineral density (vBMD); increased bone mineral content (BMC); increased mean femoral midshaft cortical thickness and cross-sectional area; increased mean vertebral trabecular bone volume, number and connectivity density; decreased mean percent of total body fat and total fat mass; decreased mean body weight; decreased mean body length; decreased total tissue mass (TTM); decreased lean body mass (LBM); decreased femoral bone mineral density (BMD); decreased vertebral bone mineral density (BMD); decreased bone mineral density (BMD); decreased bone mineral content (BMC); decreased bone mineral density index; decreased volumetric bone mineral density (vBMD); decreased mean femoral midshaft cortical thickness and cross-sectional area; decreased mean vertebral trabecular bone volume, number and connectivity density; marked osteopetrosis with increased bone mineralization; chronic inflammation in various tissues; thymic atrophy; systemic histiocytic storage disease affecting macrophages in liver, spleen and mesenteric lymph nodes; reduced liver size; chronic active hepatitis with focal hepatocyte necrosis; fatty changes in the liver; increased intracytoplasmic vacuolization of glycogen in hepatocytes; pancreatic dyserythropoietic anemia (type 1); multifocal neuronal necrosis; diffuse abiotrophy of the cerebellum granule cell layer; multifocal developmental malformation of the brain; hydronephosis; diffuse alopecia; epidermal hyperkeratosis; hypochromasia and anisocytosis characterized by abnormal erythrocytes (abnormally low hemoglobin and decreased erythropoiesis); growth retardation; development abnormalities; granulocytic hypoplasia of bone marrow; decreased numbers of myeloid granulocytic cell precursors; decreased granulocytopoiesis; no teeth; stunted growth with general reduction in all organ size; myocardial defects with defective structure and arrangement of the cardiac myocytes; cardiomyopathy with condensed eosinophilic sarcoplasm; congestive heart failure; pancreatic islets of Langerhans smaller and distribution of alpha (glycogen) and beta (insulin) cells altered; notable histopathologic alteration in cytoplasm of all cells in the zona fasciculata of the adrenal gland consistent with altered lipid/cholesterol uptake or metabolism (elevated cholesterol and triglycerides); infertility; testicular degeneration; vacuolar degeneration of seminiferous tubules; hypospermia; atrophic testes; ovarian and uterine hypoplasia; mammary gland was represented with just a few ducts; growth retardation with reduced viability; and embryonic lethality.

[0066] The invention also provides an agent that modulates a physiological characteristic which is associated with gene disruption. In one aspect, the agent is an agonist or antagonist of the phenotype associated with a disruption of a gene which encodes for a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide. In yet another aspect, the agent is an agonist or antagonist of a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide. In yet another aspect, the agonist agent is an anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibody. In still another aspect, the antagonist agent is an anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibody.

[0067] The invention also provides a method of identifying an agent which modulates a behavior associated with a disruption of the gene which encodes for a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, the method comprising:

[0068] (a) providing a non-human transgenic animal whose genome comprises a disruption of the gene which encodes for a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide;

[0069] (b) observing the behavior exhibited by the non-human transgenic animal of (a);

[0070] (c) comparing the observed behavior of (b) with that of a gender matched wild-type animal, wherein the observed behavior exhibited by the non-human transgenic animal that differs from the observed behavior exhibited by the wild-type animal is identified as a behavior associated with gene disruption;

[0071] (d) administering a test agent to the non-human transgenic animal of (a); and

[0072] (e) determining whether the agent modulates the behavior associated with gene disruption.

[0073] In one aspect, the observed behavior is an increased anxiety-like response during open field activity testing. In yet another aspect, the observed behavior is a decreased anxiety-like response during open field activity testing. In yet another aspect, the observed behavior is an abnormal circadian rhythm during home-cage activity testing. In yet another aspect, the observed behavior is an enhanced motor coordination during inverted screen testing. In yet another aspect, the observed behavior is impaired motor coordination during inverted screen testing. In yet another aspect, the observed behavior includes depression, generalized anxiety disorders, attention deficit disorder, sleep disorder, hyperactivity disorder, obsessive compulsive disorder, schizophrenia, cognitive disorders, hyperalgesia and sensory disorders. Such disorders include the category defined as "anxiety disorders" which include but are not limited to: mild to moderate anxiety, anxiety disorder due to a general medical condition, anxiety disorder not otherwise specified, generalized anxiety disorder, panic attack, panic disorder with agoraphobia, panic disorder without agoraphobia, posttraumatic stress disorder, social phobia, social anxiety, autism, specific phobia, substance-induced anxiety disorder, acute alcohol withdrawal, obsessive compulsive disorder, agoraphobia, monopolar disorders, bipolar disorder I or II, bipolar disorder not otherwise specified, cyclothymic disorder, depressive disorder, major depressive disorder, mood disorder, substance-induced mood disorder, enhancement of cognitive function, loss of cognitive function associated with but not limited to Alzheimer's disease, stroke, or traumatic injury to the brain, seizures resulting from disease or injury including but not limited to epilepsy, learning disorders/disabilities, cerebral palsy. In addition, anxiety disorders may apply to personality disorders including but not limited to the following types: paranoid, antisocial, avoidant behavior, borderline personality disorders, dependent, histronic, narcissistic, obsessive-compulsive, schizoid, and schizotypal.

[0074] The invention also provides an agent that modulates a behavior which is associated with gene disruption. In one aspect, the agent is an agonist or antagonist of the phenotype associated with a disruption of a gene which encodes for a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide. In yet another aspect, the agent is an agonist or antagonist of a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide. In yet another aspect, the agonist agent is an anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibody. In still another aspect, the antagonist agent is an anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibody.

[0075] The invention also provides a method of identifying an agent that ameliorates or modulates a neurological disorder; a cardiovascular, endothelial or angiogenic disorder; an eye abnormality; an immunological disorder; an oncological disorder; a bone metabolic abnormality or disorder; a lipid metabolic disorder; or a developmental abnormality associated with a disruption in the gene which encodes for a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, the method comprising:

[0076] (a) providing a non-human transgenic animal whose genome comprises a disruption of the gene which encodes for a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide;

[0077] (b) administering a test agent to said non-human transgenic animal; and

[0078] (c) determining whether the test agent ameliorates or modulates the neurological disorder; cardiovascular, endothelial or angiogenic disorder; eye abnormality; immunological disorder; oncological disorder; bone metabolic abnormality or disorder; lipid metabolic disorder; or developmental abnormality associated with the gene disruption in the non-human transgenic animal.

[0079] In yet another aspect, the neurological disorder is an increased anxiety-like response during open field activity testing. In yet another aspect, the neurological disorder is a decreased anxiety-like response during open field activity testing. In yet another aspect, the neurological disorder is an abnormal circadian rhythm during home-cage activity testing. In yet another aspect, the neurological disorder is an enhanced motor coordination during inverted screen testing. In yet another aspect, the neurological disorder is impaired motor coordination during inverted screen testing. In yet another aspect, the neurological disorder includes depression, generalized anxiety disorders, attention deficit disorder, sleep disorder, hyperactivity disorder, obsessive compulsive disorder, schizophrenia, cognitive disorders, hyperalgesia and sensory disorders. Such neurological disorders include the category defined as "anxiety disorders" which include but are not limited to: mild to moderate anxiety, anxiety disorder due to a general medical condition, anxiety disorder not otherwise specified, generalized anxiety disorder, panic attack, panic disorder with agoraphobia, panic disorder without agoraphobia, posttraumatic stress disorder, social phobia, social anxiety, autism, specific phobia, substance-induced anxiety disorder, acute alcohol withdrawal, obsessive compulsive disorder, agoraphobia, monopolar disorders, bipolar disorder I or II, bipolar disorder not otherwise specified, cyclothymic disorder, depressive disorder, major depressive disorder, mood disorder, substance-induced mood disorder, enhancement of cognitive function, loss of cognitive function associated with but not limited to Alzheimer's disease, stroke, or traumatic injury to the brain, seizures resulting from disease or injury including but not limited to epilepsy, learning disorders/disabilities, cerebral palsy. In addition, anxiety disorders may apply to personality disorders including but not limited to the following types: paranoid, antisocial, avoidant behavior, borderline personality disorders, dependent, histronic, narcissistic, obsessive-compulsive, schizoid, and schizotypal.

[0080] In another aspect, the eye abnormality is a retinal abnormality. In still another aspect, the eye abnormality is consistent with vision problems or blindness. In yet another aspect, the retinal abnormality is consistent with retinitis pigmentosa or is characterized by retinal degeneration or retinal dysplasia.

[0081] In still another aspect, the retinal abnormalities the retinal abnormalities are consistent with retinal dysplasia, various retinopathies, including retinopathy of prematurity, retrolental fibroplasia, neovascular glaucoma, age-related macular degeneration, diabetic macular edema, corneal neovascularization, corneal graft neovascularization, corneal graft rejection, retinal/choroidal neovascularization, neovascularization of the angle (rubeosis), ocular neovascular disease, vascular restenosis, arteriovenous malformations (AVM), meningioma, hemangioma, angiofibroma, thyroid hyperplasias (including Grave's disease), corneal and other tissue transplantation, retinal artery obstruction or occlusion; retinal degeneration causing secondary atrophy of the retinal vasculature, retinitis pigmentosa, macular dystrophies, Stargardt's disease, congenital stationary night blindness, choroideremia, gyrate atrophy, Leber's congenital amaurosis, retinoschisis disorders, Wagner's syndrome, Usher syndromes, Zellweger syndrome, Saldino-Mainzer syndrome, Senior-Loken syndrome, Bardet-Biedl syndrome, Alport's syndrome, Alstrom's syndrome, Cockayne's syndrome, dysplaisa spondyloepiphysaria congentia, Flynn-Aird syndrome, Friedreich ataxia, Hallgren syndrome, Marshall syndrome, Albers-Schnoberg disease, Refsum's disease, Kearns-Sayre syndrome, Waardenburg's syndrome, Alagile syndrome, myotonic dystrophy, olivopontocerebellar atrophy, Pierre-Marie dunsdrome, Sticker syndrome, carotinemeia, cystinosis, Wolfram syndrome, Bassen-Kornzweig syndrome, abetalipoproteinemia, incontinentia pigmenti, Batten's disease, mucopolysaccharidoses, homocystinuria, or mannosidosis.

[0082] In still another aspect, the eye abnormality is a cataract. In still yet another aspect, the cataract is a systemic disease such as human Down's syndrome, Hallerman-Streiff syndrome, Lowe syndrome, galactosemia, Marfan syndrome, Trismoy 13-15, Alport syndrome, myotonic dystrophy, Fabry disease, hypoparathroidism, or Conradi syndrome.

[0083] In still another aspect, the developmental abnormality comprises embryonic lethality or reduced viability.

[0084] In yet another aspect, the cardiovascular, endothelial or angiogenic disorders are arterial diseases, such as diabetes mellitus; papilledema; optic atrophy; atherosclerosis; angina; myocardial infarctions such as acute myocardial infarctions, cardiac hypertrophy, and heart failure such as congestive heart failure; hypertension; inflammatory vasculitides; Reynaud's disease and Reynaud's phenomenon; aneurysms and arterial restenosis; venous and lymphatic disorders such as thrombophlebitis, lymphangitis, and lymphedema; peripheral vascular disease; cancer such as vascular tumors, e.g., hemangioma (capillary and cavernous), glomus tumors, telangiectasia, bacillary angiomatosis, hemangioendothelioma, angiosarcoma, haemangiopericytoma, Kaposi's sarcoma, lymphangioma, and lymphangiosarcoma; tumor angiogenesis; trauma such as wounds, burns, and other injured tissue, implant fixation, scarring; ischemia reperfusion injury; rheumatoid arthritis; cerebrovascular disease; renal diseases such as acute renal failure, or osteoporosis.

[0085] In still yet another aspect, the immunological disorders are consistent with systemic lupus erythematosis; rheumatoid arthritis; juvenile chronic arthritis; spondyloarthropathies; systemic sclerosis (scleroderma); idiopathic inflammatory myopathies (dermatomyositis, polymyositis); Sjogren's syndrome; systemic vasculitis; sarcoidosis; autoimmune hemolytic anemia (immune pancytopenia, paroxysmal nocturnal hemoglobinuria); autoimmune thrombocytopenia (idiopathic thrombocytopenic purpura, immune-mediated thrombocytopenia); thyroiditis (Grave's disease, Hashimoto's thyroiditis, juvenile lymphocytic thyroiditis, atrophic thyroiditis); diabetes mellitus; immune-mediated renal disease (glomerulonephritis, tubulointerstitial nephritis); demyelinating diseases of the central and peripheral nervous systems such as multiple sclerosis, idiopathic demyelinating polyneuropathy or Guillain-Barresyndrome, and chronic inflammatory demyelinating polyneuropathy; hepatobiliary diseases such as infectious hepatitis (hepatitis A, B, C, D, E and other non-hepatotropic viruses), autoimmune chronic active hepatitis, primary biliary cirrhosis, granulomatous hepatitis, and sclerosing cholangitis; inflammatory bowel disease (ulcerative colitis: Crohn's disease); gluten-sensitive enteropathy, and Whipple's disease; autoimmune or immune-mediated skin diseases including bullous skin diseases, erythema multiforme and contact dermatitis, psoriasis; allergic diseases such as asthma, allergic rhinitis, atopic dermatitis, food hypersensitivity and urticaria; immunologic diseases of the lung such as eosinophilic pneumonia, idiopathic pulmonary fibrosis and hypersensitivity pneumonitis; or transplantation associated diseases including graft rejection and graft-versus-host disease.

[0086] In yet another aspect, the bone metabolic abnormality or disorder is arthritis, osteoporosis, osteopenia or osteopetrosis.

[0087] In another aspect, the non-human transgenic animal exhibits at least one of the following physiological characteristics compared with gender matched wild-type littermates: increased anxiety-like response during open field testing; decreased anxiety during open field testing; hypoactivity with no circadian rhythm; increased total distance traveled during open field testing (hyperactivity); decreased locomotor activity during open field testing; abnormal circadian rhythm during home-cage activity testing (low activity during the light phase); abnormal circadian rhythm during home-cage activity testing including decreased ambulatory counts; abnormal circadian rhythm during home-cage activity testing including increased ambulatory counts; whiskers absent due to anxiety phenotype; enhanced circadian rhythm; increased stress induced hyperthermia with increased stress response (increased anxiety); increased resistance to stress induced hyperthermia; decreased resistance to stress induced hyperthermia; enhanced motor coordination during inverted screen testing; impaired motor coordination during inverted screen testing; increased immobility in tail suspension (increased depressive-like response); increased depressive-like response during tail suspension testing; decreased depressive-like response during tail suspension testing; clutched hind limbs during tail suspension testing; decreased startle response during prepulse inhibition testing; no startle response indicating deafness; increased prepulse inhibition with enhanced sensorimotor gating/attention; increased latency on hotplate indicative of decreased sensitivity to heat-induced pain; opthamological abnormalities; corneal epidermidalization of the corneal stroma with scarring and blocked vision; metaplasia of the cornea and sclera; attenuated retinal arteries; retinal hemorrhage; optic nerve abnormalities; dilated optic disc; increased intraocular pressure; corneal epithelialization with underdeveloped eyelids; retinal degeneration; agenesis of the Harderian gland; retinal vessel disorganization, microaneurysms and retinal capillary leakage; impaired vision; decreased heart rate; decreased mean systolic blood pressure; increased mean systolic blood pressure; increased insulin sensitivity; increased mean fasting serum glucose levels; decreased mean serum glucose levels; increased mean serum cholesterol levels; decreased mean serum cholesterol levels; increased mean serum triglyceride levels; enhanced glucose tolerance; impaired glucose tolerance; decreased mean serum insulin levels; ketonemia; decreased mean serum calcium; blood urobilinogen, nitrites, protein and ketones; decreased sodium and chloride; increased bilirubin; notable lipemia; increased uric acid and potassium levels; increased mean serum alkaline phosphatase levels; decreased mean serum alkaline phosphatase levels; blood in the urine; glucosuria; increased nitrituria; ketonuria; increased mean percentage of natural killer cells; decreased mean percentage of natural killer cells; abnormal leukocyte count; leukopenia due to lymphopenia and granulocytopenia; increased mean percentage of CD4 cells; decreased mean percentage of CD4 cells; decreased mean percentage of CD8 cells; reduced percentage of naive CD4 and CD8 T cells in lymph nodes; increased mean percentage of B cells in peripheral blood; decrease total white blood cells and lymphocyte counts; decreased absolute lymphocyte counts; increased mean absolute monocyte count; increased mean absolute neutrophil count; decreased in mean serum IgA levels; increase in mean serum IgA levels; increase in IgG1 levels; decreased mean serum IgG1 levels; decreased mean serum IgG1, IgG3, IgG2b and IgG2a levels; decreased mean serum IgG2a levels; decreased mean serum IgG2b levels; decreased mean serum IgG3 and IgM levels; increase in mean serum IgG2a levels; increase in mean serum IgG1, IgG2a and IgG3 levels; increase in mean serum IgG3 levels; anemia; decreased red blood cell count, decreased hemoglobin and decreased hematocrit with increased mean red blood cell count; increased mean corpuscular volume; decreased mean corpuscular volume; decreased mean corpuscular hemoglobin; increased red blood cell distribution width; defect in erythropoiesis; increased IgM+ IgD+ and B220hi/CD43- cells in bone marrow; decreased percentage of B220hi/CD43- IgM+ IgD+ cells in bone marrow; increased percentage of TCRB+ cells in Peyer's patches; reduction in naive T cells (especially CD4) in lymph nodes; increased percentage of CD11b+CD11c- cells (monocytes) in spleen; increased percentage of IgM+, CD117+ cells in bone marrow, higher percentage of dead B cells, decreased B cells, increased CD4 and CD8 T cells in lymph; B cells increased in bone marrow and significantly decreased in lymph node; notably decreased CD21hiCD23med B cells in spleen; decrease in Peyer's patch B220+ cells; decreased mean percentages of CD8 and natural killer cells with increased mean percentage of B cells; reduced number of TCRB+ CD38+ activated T cells in Peyer's patches; decreased mean percentage of CD4 cells with increased mean percentage of B cells; decreased B220+ CD38low and IgM in Payer's patches; increased mean platelet count; decreased mean platelet count; widespread apoptosis and loss of T lymphocytes in the thymic cortex and depletion of T cells in spleen; increased mean serum IgG2a response to an ovalbumin challenge; decreased to no serum IgG1 and IgG2a response to ovalbumin challenge; increased mean serum IgG 1 response to an ovalbumin challenge; decreased mean serum TNF-alpha, MCP-1 and IL-6 responses to LPS challenge; increased mean serum MCP-1 response to a LPS challenge; increased mean serum TNF-alpha response to a LPS challenge; increased mean serum IL-6 response to a LPS challenge; increased skin fibroblast proliferation; decreased skin fibroblast proliferation; increased mean percent of total body fat and total fat mass; increased mean body weight; increased mean body length; increased total tissue mass (TTM); increased lean body mass (LBM); increased femoral bone mineral density (BMD); increased vertebral bone mineral density (BMD); increased bone mineral density (BMD); increased total body volumetric bone mineral density (vBMD); increased bone mineral content (BMC); increased mean femoral midshaft cortical thickness and cross-sectional area; increased mean vertebral trabecular bone volume, number and connectivity density; decreased mean percent of total body fat and total fat mass; decreased mean body weight; decreased mean body length; decreased total tissue mass (TTM); decreased lean body mass (LBM); decreased femoral bone mineral density (BMD); decreased vertebral bone mineral density (BMD); decreased bone mineral density (BMD); decreased bone mineral content (BMC); decreased bone mineral density index; decreased volumetric bone mineral density (vBMD); decreased mean femoral midshaft cortical thickness and cross-sectional area; decreased mean vertebral trabecular bone volume, number and connectivity density; marked osteopetrosis with increased bone mineralization; chronic inflammation in various tissues; thymic atrophy; systemic histiocytic storage disease affecting macrophages in liver, spleen and mesenteric lymph nodes; reduced liver size; chronic active hepatitis with focal hepatocyte necrosis; fatty changes in the liver; increased intracytoplasmic vacuolization of glycogen in hepatocytes; pancreatic dyserythropoietic anemia (type 1); multifocal neuronal necrosis; diffuse abiotrophy of the cerebellum granule cell layer; multifocal developmental malformation of the brain; hydronephosis; diffuse alopecia; epidermal hyperkeratosis; hypochromasia and anisocytosis characterized by abnormal erythrocytes (abnormally low hemoglobin and decreased erythropoiesis); growth retardation; development abnormalities; granulocytic hypoplasia of bone marrow; decreased numbers of myeloid granulocytic cell precursors; decreased granulocytopoiesis; no teeth; stunted growth with general reduction in all organ size; myocardial defects with defective structure and arrangement of the cardiac myocytes; cardiomyopathy with condensed eosinophilic sarcoplasm; congestive heart failure; pancreatic islets of Langerhans smaller and distribution of alpha (glycogen) and beta (insulin) cells altered; notable histopathologic alteration in cytoplasm of all cells in the zona fasciculata of the adrenal gland consistent with altered lipid/cholesterol uptake or metabolism (elevated cholesterol and triglycerides); infertility; testicular degeneration; vacuolar degeneration of seminiferous tubules; hypospermia; atrophic testes; ovarian and uterine hypoplasia; mammary gland was represented with just a few ducts; growth retardation with reduced viability; and embryonic lethality.

[0088] The invention also provides an agent that ameliorates or modulates a neurological disorder; a cardiovascular, endothelial or angiogenic disorder; an eye abnormality; an immunological disorder; an ontological disorder; a bone metabolic abnormality or disorder; a lipid metabolic disorder; or a developmental abnormality which is associated with gene disruption. In one aspect, the agent is an agonist or antagonist of the phenotype associated with a disruption of a gene which encodes for a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide. In yet another aspect, the agent is an agonist or antagonist of a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926; PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide. In yet another aspect, the agonist agent is an anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibody. In still another aspect, the antagonist agent is an anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibody.

[0089] The invention also provides a therapeutic agent for the treatment of a neurological disorder; a cardiovascular, endothelial or angiogenic disorder; an eye abnormality; an immunological disorder; an oncological disorder; a bone metabolic abnormality or disorder; a lipid metabolic disorder; or a developmental abnormality.

[0090] The invention also provides a method of identifying an agent that modulates the expression of a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, the method comprising:

[0091] (a) contacting a test agent with a host cell expressing a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide; and

[0092] (b) determining whether the test agent modulates the expression of the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide by the host cell.

[0093] The invention also provides an agent that modulates the expression of a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide. In one aspect, the agent is an agonist or antagonist of the phenotype associated with a disruption of a gene which encodes for a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide. In yet another aspect, the agent is an agonist or antagonist of a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide. In yet another aspect, the agonist agent is an anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibody. In still another aspect, the antagonist agent is an anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibody.

[0094] The invention also provides a method of evaluating a therapeutic agent capable of affecting a condition associated with a disruption of a gene which encodes for a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, the method comprising:

[0095] (a) providing a non-human transgenic animal whose genome comprises a disruption of the gene which encodes for the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide;

[0096] (b) measuring a physiological characteristic of the non-human transgenic animal of (a);

[0097] (c) comparing the measured physiological characteristic of (b) with that of a gender matched wild-type animal, wherein the physiological characteristic of the non-human transgenic animal that differs from the physiological characteristic of the wild-type animal is identified as a condition resulting from the gene disruption in the non-human transgenic animal;

[0098] (d) administering a test agent to the non-human transgenic animal of (a); and

[0099] (e) evaluating the effects of the test agent on the identified condition associated with gene disruption in the non-human transgenic animal.

[0100] In one aspect, the condition is a neurological disorder; a cardiovascular, endothelial or angiogenic disorder; an eye abnormality; an immunological disorder; an ontological disorder; a bone metabolic abnormality or disorder; a lipid metabolic disorder; or a developmental abnormality.

[0101] The invention also provides a therapeutic agent which is capable of affecting a condition associated with gene disruption. In one aspect, the agent is an agonist or antagonist of the phenotype associated with a disruption of a gene which encodes for a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide. In yet another aspect, the agent is an agonist or antagonist of a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide. In yet another aspect, the agonist agent is an anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibody. In still another aspect, the antagonist agent is an anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibody.

[0102] The invention also provides a pharmaceutical composition comprising a therapeutic agent capable of affecting the condition associated with gene disruption.

[0103] The invention also provides a method of treating or preventing or ameliorating a neurological disorder; cardiovascular, endothelial or angiogenic disorder; immunological disorder; oncological disorder; bone metabolic abnormality or disorder, or embryonic lethality associated with the disruption of a gene which encodes for a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, the method comprising administering to a subject in need of such treatment whom may already have the disorder, or may be prone to have the disorder or may be in whom the disorder is to be prevented, a therapeutically effective amount of a therapeutic agent, or agonists or antagonists thereof, thereby effectively treating or preventing or ameliorating said disorder or disease.

[0104] In yet another aspect, the neurological disorder is an increased anxiety-like response during open field activity testing. In yet another aspect, the neurological disorder is a decreased anxiety-like response during open field activity testing. In yet another aspect, the neurological disorder is an abnormal circadian rhythm during home-cage activity testing. In yet another aspect, the neurological disorder is an enhanced motor coordination during inverted screen testing. In yet another aspect, the neurological disorder is impaired motor coordination during inverted screen testing. In yet another aspect, the neurological disorder includes depression, generalized anxiety disorders, attention deficit disorder, sleep disorder, hyperactivity disorder, obsessive compulsive disorder, schizophrenia, cognitive disorders, hyperalgesia and sensory disorders. Such neurological disorders include the category defined as "anxiety disorders" which include but are not limited to: mild to moderate anxiety, anxiety disorder due to a general medical condition, anxiety disorder not otherwise specified, generalized anxiety disorder, panic attack, panic disorder with agoraphobia, panic disorder without agoraphobia, posttraumatic stress disorder, social phobia, social anxiety, autism, specific phobia, substance-induced anxiety disorder, acute alcohol withdrawal, obsessive compulsive disorder, agoraphobia, monopolar disorders, bipolar disorder I or II, bipolar disorder not otherwise specified, cyclothymic disorder, depressive disorder, major depressive disorder, mood disorder, substance-induced mood disorder, enhancement of cognitive function, loss of cognitive function associated with but not limited to Alzheimer's disease, stroke, or traumatic injury to the brain, seizures resulting from disease or injury including but not limited to epilepsy, learning disorders/disabilities, cerebral palsy. In addition, anxiety disorders may apply to personality disorders including but not limited to the following types: paranoid, antisocial, avoidant behavior, borderline personality disorders, dependent, histronic, narcissistic, obsessive-compulsive, schizoid, and schizotypal.

[0105] In another aspect, the eye abnormality is a retinal abnormality. In still another aspect, the eye abnormality is consistent with vision problems or blindness. In yet another aspect, the retinal abnormality is consistent with retinitis pigmentosa or is characterized by retinal degeneration or retinal dysplasia.

[0106] In still another aspect, the retinal abnormalities are consistent with retinal dysplasia, various retinopathies, including retinopathy of prematurity, retrolental fibroplasia, neovascular glaucoma, age-related macular degeneration, diabetic macular edema, corneal neovascularization, corneal graft neovascularization, corneal graft rejection, retinal/choroidal neovascularization, neovascularization of the angle (rubeosis), ocular neovascular disease, vascular restenosis, arteriovenous malformations (AVM), meningioma, hemangioma, angiofibroma, thyroid hyperplasias (including Grave's disease), corneal and other tissue transplantation, retinal artery obstruction or occlusion; retinal degeneration causing secondary atrophy of the retinal vasculature, retinitis pigmentosa, macular dystrophies, Stargardt's disease, congenital stationary night blindness, choroideremia, gyrate atrophy, Leber's congenital amaurosis, retinoschisis disorders, Wagner's syndrome, Usher syndromes, Zellweger syndrome, Saldino-Mainzer syndrome, Senior-Loken syndrome, Bardet-Biedl syndrome, Alport's syndrome, Alstrom's syndrome, Cockayne's syndrome, dysplaisa spondyloepiphysaria congentia, Flynn-Aird syndrome, Friedreich ataxia, Hallgren syndrome, Marshall syndrome, Albers-Schnoberg disease, Refsum's disease, Kearns-Sayre syndrome, Waardenburg's syndrome, Alagile syndrome, myotonic dystrophy, olivopontocerebellar atrophy, Pierre-Marie dunsdrome, Stickler syndrome, carotinemeia, cystinosis, Wolfram syndrome, Bassen-Kornzweig syndrome, abetalipoproteinemia, incontinentia pigmenti, Batten's disease, mucopolysaccharidoses, homocystinuria, or mannosidosis.

[0107] In still another aspect, the eye abnormality is a cataract. In still yet another aspect, the cataract is a systemic disease such as human Down's syndrome, Hallerman-Streiff syndrome, Lowe syndrome, galactosemia, Marfan syndrome, Trismoy 13-15, Alport syndrome, myotonic dystrophy, Fabry disease, hypoparathroidism or Conradi syndrome.

[0108] In still another aspect, the developmental abnormality comprises embryonic lethality or reduced viability.

[0109] In yet another aspect, the cardiovascular, endothelial or angiogenic disorders are arterial diseases, such as diabetes mellitus; papilledema; optic atrophy; atherosclerosis; angina; myocardial infarctions such as acute myocardial infarctions, cardiac hypertrophy, and heart failure such as congestive heart failure; hypertension; inflammatory vasculitides; Reynaud's disease and Reynaud's phenomenon; aneurysms and arterial restenosis; venous and lymphatic disorders such as thrombophlebitis, lymphangitis, and lymphedema; peripheral vascular disease; cancer such as vascular tumors, e.g., hemangioma (capillary and cavernous), glomus tumors, telangiectasia, bacillary angiomatosis, hemangioendothelioma, angiosarcoma, haemangiopericytoma, Kaposi's sarcoma, lymphangioma, and lymphangiosarcoma; tumor angiogenesis; trauma such as wounds, burns, and other injured tissue, implant fixation, scarring; ischemia reperfusion injury; rheumatoid arthritis; cerebrovascular disease; renal diseases such as acute renal failure, or osteoporosis.

[0110] In still yet another aspect, the immunological disorders are consistent with systemic lupus erythematosis; rheumatoid arthritis; juvenile chronic arthritis; spondyloarthropathies; systemic sclerosis (scleroderma); idiopathic inflammatory myopathies (dermatomyositis, polymyositis); Sjogren's syndrome; systemic vasculitis; sarcoidosis; autoimmune hemolytic anemia (immune pancytopenia, paroxysmal nocturnal hemoglobinuria); autoimmune thrombocytopenia (idiopathic thrombocytopenic purpura, immune-mediated thrombocytopenia); thyroiditis (Grave's disease, Hashimoto's thyroiditis, juvenile lymphocytic thyroiditis, atrophic thyroiditis); diabetes mellitus; immune-mediated renal disease (glomerulonephritis, tubulointerstitial nephritis); demyelinating diseases of the central and peripheral nervous systems such as multiple sclerosis, idiopathic demyelinating polyneuropathy or Guillain-Barre syndrome, and chronic inflammatory demyelinating polyneuropathy; hepatobiliary diseases such as infectious hepatitis (hepatitis A, B, C, D, E and other non-hepatotropic viruses), autoimmune chronic active hepatitis, primary biliary cirrhosis, granulomatous hepatitis, and sclerosing cholangitis; inflammatory bowel disease (ulcerative colitis: Crohn's disease); gluten-sensitive enteropathy, and Whipple's disease; autoimmune or immune-mediated skin diseases including bullous skin diseases, erythema multiforme and contact dermatitis, psoriasis; allergic diseases such as asthma, allergic rhinitis, atopic dermatitis, food hypersensitivity and urticaria; immunologic diseases of the lung such as eosinophilic pneumonia, idiopathic pulmonary fibrosis and hypersensitivity pneumonitis; or transplantation associated diseases including graft rejection and graft-versus-host disease.

[0111] In yet another aspect, the bone metabolic abnormality or disorder is arthritis, osteoporosis, osteopenia or osteopetrosis.

[0112] In another aspect the therapeutic agent is an agonist or antagonist of the phenotype associated with a disruption of a gene which encodes for a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO1110, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide. In yet another aspect, the agent is an agonist or antagonist of a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide. In yet another aspect, the agonist agent is an anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibody. In still another aspect, the antagonist agent is an anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibody.

[0113] The invention also provides a method of identifying an agent that ameliorates or modulates a neurological disorder; a cardiovascular, endothelial or angiogenic disorder; an eye abnormality; an immunological disorder; an oncological disorder; a bone metabolic abnormality or disorder; a lipid metabolic disorder; or a developmental abnormality associated with a disruption in the gene which encodes for a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, the method comprising:

[0114] (a) providing a non-human transgenic animal cell culture, each cell of said culture comprising a disruption of the gene which encodes for a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide;

[0115] (b) administering a test agent to said cell culture; and

[0116] (c) determining whether the test agent ameliorates or modulates the neurological disorder; cardiovascular, endothelial or angiogenic disorder; eye abnormality; immunological disorder; oncological disorder; bone metabolic abnormality or disorder; lipid metabolic disorder; or developmental abnormality in said culture.

[0117] In yet another aspect, the neurological disorder is an increased anxiety-like response during open field activity testing. In yet another aspect, the neurological disorder is a decreased anxiety-like response during open field activity testing. In yet another aspect, the neurological disorder is an abnormal circadian rhythm during home-cage activity testing. In yet another aspect, the neurological disorder is an enhanced motor coordination during inverted screen testing. In yet another aspect, the neurological disorder is impaired motor coordination during inverted screen testing. In yet another aspect, the neurological disorder includes depression, generalized anxiety disorders, attention deficit disorder, sleep disorder, hyperactivity disorder, obsessive compulsive disorder, schizophrenia, cognitive disorders, hyperalgesia and sensory disorders. Such neurological disorders include the category defined as "anxiety disorders" which include but are not limited to: mild to moderate anxiety, anxiety disorder due to a general medical condition, anxiety disorder not otherwise specified, generalized anxiety disorder, panic attack, panic disorder with agoraphobia, panic disorder without agoraphobia, posttraumatic stress disorder, social phobia, social anxiety, autism, specific phobia, substance-induced anxiety disorder, acute alcohol withdrawal, obsessive compulsive disorder, agoraphobia, monopolar disorders, bipolar disorder I or II, bipolar disorder not otherwise specified, cyclothymic disorder, depressive disorder, major depressive disorder, mood disorder, substance-induced mood disorder, enhancement of cognitive function, loss of cognitive function associated with but not limited to Alzheimer's disease, stroke, or traumatic injury to the brain, seizures resulting from disease or injury including but not limited to epilepsy, learning disorders/disabilities, cerebral palsy. In addition, anxiety disorders may apply to personality disorders including but not limited to the following types: paranoid, antisocial, avoidant behavior, borderline personality disorders, dependent, histronic, narcissistic, obsessive-compulsive, schizoid, and schizotypal.

[0118] In another aspect, the eye abnormality is a retinal abnormality. In still another aspect, the eye abnormality is consistent with vision problems or blindness. In yet another aspect, the retinal abnormality is consistent with retinitis pigmentosa or is characterized by retinal degeneration or retinal dysplasia.

[0119] In still another aspect, the retinal abnormalities are consistent with retinal dysplasia, various retinopathies, including retinopathy of prematurity, retrolental fibroplasia, neovascular glaucoma, age-related macular degeneration, diabetic macular edema, corneal neovascularization, corneal graft neovascularization, corneal graft rejection, retinal/choroidal neovascularization, neovascularization of the angle (rubeosis), ocular neovascular disease, vascular restenosis, arteriovenous malformations (AVM), meningioma, hemangioma, angiofibroma, thyroid hyperplasias (including Grave's disease), corneal and other tissue transplantation, retinal artery obstruction or occlusion; retinal degeneration causing secondary atrophy of the retinal vasculature, retinitis pigmentosa, macular dystrophies, Stargardt's disease, congenital stationary night blindness, choroideremia, gyrate atrophy, Leber's congenital amaurosis, retinoschisis disorders, Wagner's syndrome, Usher syndromes, Zellweger syndrome, Saldino-Mainzer syndrome, Senior-Loken syndrome, Bardet-Biedl syndrome, Alport's syndrome, Alstrom's syndrome, Cockayne's syndrome, dysplaisa spondyloepiphysaria congentia, Flynn-Aird syndrome, Friedreich ataxia, Hallgren syndrome, Marshall syndrome, Albers-Schnoberg disease, Refsum's disease, Kearns-Sayre syndrome, Waardenburg's syndrome, Alagile syndrome, myotonic dystrophy, olivopontocerebellar atrophy, Pierre-Marie dunsdrome, Stickler syndrome, carotinemeia, cystinosis, Wolfram syndrome, Bassen-Kornzweig syndrome, abetalipoproteinemia, incontinentia pigmenti, Batten's disease, mucopolysaccharidoses, homocystinuria, or mannosidosis.

[0120] In still another aspect, the eye abnormality is a cataract. In still yet another aspect, the cataract is a systemic disease such as human Down's syndrome, Hallerman-Streiff syndrome, Lowe syndrome, galactosemia, Marfan syndrome, Trismoy 13-15, Alport syndrome, myotonic dystrophy, Fabry disease, hypoparathroidism or Conradi syndrome.

[0121] In still another aspect, the developmental abnormality comprises embryonic lethality or reduced viability.

[0122] In yet another aspect, the cardiovascular, endothelial or angiogenic disorders are arterial diseases, such as diabetes mellitus; papilledema; optic atrophy; atherosclerosis; angina; myocardial infarctions such as acute myocardial infarctions, cardiac hypertrophy, and heart failure such as congestive heart failure; hypertension; inflammatory vasculitides; Reynaud's disease and Reynaud's phenomenon; aneurysms and arterial restenosis; venous and lymphatic disorders such as thrombophlebitis, lymphangitis, and lymphedema; peripheral vascular disease; cancer such as vascular tumors, e.g., hemangioma (capillary and cavernous), glomus tumors, telangiectasia, bacillary angiomatosis, hemangioendothelioma, angiosarcoma, haemangiopericytoma, Kaposi's sarcoma, lymphangioma, and lymphangiosarcoma; tumor angiogenesis; trauma such as wounds, burns, and other injured tissue, implant fixation, scarring; ischemia reperfusion injury; rheumatoid arthritis; cerebrovascular disease; renal diseases such as acute renal failure, or osteoporosis.

[0123] In still yet another aspect, the immunological disorders are consistent with systemic lupus erythematosis; rheumatoid arthritis; juvenile chronic arthritis; spondyloarthropathies; systemic sclerosis (scleroderma); idiopathic inflammatory myopathies (dermatomyositis, polymyositis); Sjogren's syndrome; systemic vasculitis; sarcoidosis; autoimmune hemolytic anemia (immune pancytopenia, paroxysmal nocturnal hemoglobinuria); autoimmune thrombocytopenia (idiopathic thrombocytopenic purpura, immune-mediated thrombocytopenia); thyroiditis (Grave's disease, Hashimoto's thyroiditis, juvenile lymphocytic thyroiditis, atrophic thyroiditis); diabetes mellitus; immune-mediated renal disease (glomerulonephritis, tubulointerstitial nephritis); demyelinating diseases of the central and peripheral nervous systems such as multiple sclerosis, idiopathic demyelinating polyneuropathy or Guillain-Barre syndrome, and chronic inflammatory demyelinating polyneuropathy; hepatobiliary diseases such as infectious hepatitis (hepatitis A, B, C, D, E and other non-hepatotropic viruses), autoimmune chronic active hepatitis, primary biliary cirrhosis, granulomatous hepatitis, and sclerosing cholangitis; inflammatory bowel disease (ulcerative colitis: Crohn's disease); gluten-sensitive enteropathy, and Whipple's disease; autoimmune or immune-mediated skin diseases including bullous skin diseases, erythema multiforme and contact dermatitis, psoriasis; allergic diseases such as asthma, allergic rhinitis, atopic dermatitis, food hypersensitivity and urticaria; immunologic diseases of the lung such as eosinophilic pneumonia, idiopathic pulmonary fibrosis and hypersensitivity pneumonitis; or transplantation associated diseases including graft rejection and graft-versus-host disease.

[0124] In yet another aspect, the bone metabolic abnormality or disorder is arthritis, osteoporosis, osteopenia or osteopetrosis.

[0125] The invention also provides an agent that ameliorates or modulates a neurological disorder; a cardiovascular, endothelial or angiogenic disorder; an eye abnormality; an immunological disorder; an oncological disorder; a bone metabolic abnormality or disorder; a lipid metabolic disorder; or a developmental abnormality which is associated with gene disruption in said culture. In one aspect, the agent is an agonist or antagonist of the phenotype associated with a disruption of a gene which encodes for a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide. In yet another aspect, the agent is an agonist or antagonist of a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide. In yet another aspect, the agonist agent is an anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibody. In still another aspect, the antagonist agent is an anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibody.

[0126] The invention also provides a method of modulating a phenotype associated with a disruption of a gene which encodes for a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, the method comprising administering to a subject whom may already have the phenotype, or may be prone to have the phenotype or may be in whom the phenotype is to be prevented, an effective amount of an agent identified as modulating said phenotype, or agonists or antagonists thereof, thereby effectively modulating the phenotype.

[0127] The invention also provides a method of modulating a physiological characteristic associated with a disruption of a gene which encodes for a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, the method comprising administering to a subject whom may already exhibit the physiological characteristic, or may be prone to exhibit the physiological characteristic or may be in whom the physiological characteristic is to be prevented, an effective amount of an agent identified as modulating said physiological characteristic, or agonists or antagonists thereof, thereby effectively modulating the physiological characteristic.

[0128] The invention also provides a method of modulating a behavior associated with a disruption of a gene which encodes for a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, the method comprising administering to a subject whom may already exhibit the behavior, or may be prone to exhibit the behavior or may be in whom the exhibited behavior is to be prevented, an effective amount of an agent identified as modulating said behavior, or agonists or antagonists thereof, thereby effectively modulating the behavior.

[0129] The invention also provides a method of modulating the expression of a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, the method comprising administering to a host cell expressing said PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, an effective amount of an agent identified as modulating said expression, or agonists or antagonists thereof, thereby effectively modulating the expression of said polypeptide.

[0130] The invention also provides a method of modulating a condition associated with a disruption of a gene which encodes for a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, the method comprising administering to a subject whom may have the condition, or may be prone to have the condition or may be in whom the condition is to be prevented, a therapeutically effective amount of a therapeutic agent identified as modulating said condition, or agonists or antagonists thereof, thereby effectively modulating the condition.

[0131] The invention also provides a method of treating or preventing or ameliorating a neurological disorder; cardiovascular, endothelial or angiogenic disorder; immunological disorder; oncological disorder; bone metabolic abnormality or disorder, or embryonic lethality associated with the disruption of a gene which encodes for a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, the method comprising administering to a non-human transgenic animal cell culture, each cell of said culture comprising a disruption of the gene which encodes for a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, an effective amount of an agent identified as treating or preventing or ameliorating said disorder, or agonists or antagonists thereof, thereby effectively treating or preventing or ameliorating said disorder.

B. Further Embodiments

[0132] In yet further embodiments, the invention is directed to the following set of potential claims for this application:

1. A method of identifying a phenotype associated with a disruption of a gene which encodes for a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, the method comprising:

[0133] (a) providing a non-human transgenic animal whose genome comprises a disruption of the gene which encodes for a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide;

[0134] (b) measuring a physiological characteristic of the non-human transgenic animal; and

[0135] (c) comparing the measured physiological characteristic with that of a gender matched wild-type animal, wherein the physiological characteristic of the non-human transgenic animal that differs from the physiological characteristic of the wild-type animal is identified as a phenotype resulting from the gene disruption in the non-human transgenic animal.

2. The method of Claim 1, wherein the non-human transgenic animal is heterozygous for the disruption of a gene which encodes for a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide. 3. The method of Claim 1, wherein the phenotype exhibited by the non-human transgenic animal as compared with gender matched wild-type littermates is at least one of the following: a neurological disorder; a cardiovascular, endothelial or angiogenic disorder; an eye abnormality; an immunological disorder; an oncological disorder; a bone metabolic abnormality or disorder; a lipid metabolic disorder; or a developmental abnormality. 4. The method of Claim 3, wherein the neurological disorder is an increased anxiety-like response during open field activity testing. 5. The method of Claim 3, wherein the neurological disorder is a decreased anxiety-like response during open field activity testing. 6. The method of Claim 3, wherein the neurological disorder is an abnormal circadian rhythm during home-cage activity testing. 7. The method of Claim 3, wherein the neurological disorder is an enhanced motor coordination during inverted screen testing. 8. The method of Claim 3, wherein the neurological disorder is an impaired motor coordination during inverted screen testing. 9. The method of Claim 3, wherein the neurological disorder is depression, generalized anxiety disorders, attention deficit disorder, sleep disorder, hyperactivity disorder, obsessive compulsive disorder, schizophrenia, cognitive disorders, hyperalgesia or sensory disorders. 10. The method of Claim 3, wherein the eye abnormality is a retinal abnormality. 11. The method of Claim 3, wherein the eye abnormality is consistent with vision problems or blindness. 12. The method of Claim 10, wherein the retinal abnormality is consistent with retinitis pigmentosa. 13. The method of Claim 10, wherein the retinal abnormality is characterized by retinal degeneration or retinal dysplasia. 14. The method of Claim 10, wherein the retinal abnormality is consistent with retinal dysplasia, various retinopathies, including retinopathy of prematurity, retrolental fibroplasia, neovascular glaucoma, age-related macular degeneration, diabetic macular edema, corneal neovascularization, corneal graft neovascularization, corneal graft rejection, retinal choroidal neovascularization, neovascularization of the angle (rubeosis), ocular neovascular disease, vascular restenosis, arteriovenous malformations (AVM), meningioma, hemangioma, angiofibroma, thyroid hyperplasias (including Grave's disease), corneal and other tissue transplantation, retinal artery obstruction or occlusion; retinal degeneration causing secondary atrophy of the retinal vasculature, retinitis pigmentosa, macular dystrophies, Stargardt's disease, congenital stationary night blindness, choroideremia, gyrate atrophy, Leber's congenital amaurosis, retinoschisis disorders, Wagner's syndrome, Usher syndromes, Zellweger syndrome, Saldino-Mainzer syndrome, Senior-Loken syndrome, Bardet-Biedl syndrome, Alport's syndrome, Alstrom's syndrome, Cockayne's syndrome, dysplaisa spondyloepiphysaria congentia, Flynn-Aird syndrome, Friedreich ataxia, Hallgren syndrome, Marshall syndrome, Albers-Schnoberg disease, Refsum's disease, Kearns-Sayre syndrome, Waardenburg's syndrome, Alagile syndrome, myotonic dystrophy, olivopontocerebellar atrophy, Pierre-Marie dunsdrome, Stickler syndrome, carotinemeia, cystinosis, Wolfram syndrome, Bassen-Kornzweig syndrome, abetalipoproteinemia, incontinentia pigmenti, Batten's disease, mucopolysaccharidoses, homocystinuria, or mannosidosis. 15. The method of Claim 3, wherein the eye abnormality is a cataract. 16. The method of Claim 15, wherein the cataract is consistent with systemic diseases such as human Down's syndrome, Hallerman-Streiff syndrome, Lowe syndrome, galactosemia, Marfan syndrome, Trismoy 13-15, Alport syndrome, myotonic dystrophy, Fabry disease, hypoparathroidism or Conradi syndrome. 17. The method of Claim 3, wherein the developmental abnormality comprises embryonic lethality or reduced viability. 18. The method of Claim 3, wherein the cardiovascular, endothelial or angiogenic disorders are arterial diseases, such as diabetes mellitus; papilledema; optic atrophy; atherosclerosis; angina; myocardial infarctions such as acute myocardial infarctions, cardiac hypertrophy, and heart failure such as congestive heart failure; hypertension; inflammatory vasculitides; Reynaud's disease and Reynaud's phenomenon; aneurysms and arterial restenosis; venous and lymphatic disorders such as thrombophlebitis, lymphangitis, and lymphedema; peripheral vascular disease; cancer such as vascular tumors, e.g., hemangioma (capillary and cavernous), glomus tumors, telangiectasia, bacillary angiomatosis, hemangioendothelioma, angiosarcoma, haemangiopericytoma, Kaposi's sarcoma, lymphangioma, and lymphangiosarcoma; tumor angiogenesis; trauma such as wounds, burns, and other injured tissue, implant fixation, scarring; ischemia reperfusion injury; rheumatoid arthritis; cerebrovascular disease; renal diseases such as acute renal failure, or osteoporosis. 19. The method of Claim 3, wherein the immunological disorders are systemic lupus erythematosis; rheumatoid arthritis; juvenile chronic arthritis; spondyloarthropathies; systemic sclerosis (scleroderma); idiopathic inflammatory myopathies (dermatomyositis, polymyositis); Sjogren's syndrome; systemic vasculitis; sarcoidosis; autoimmune hemolytic anemia (immune pancytopenia, paroxysmal nocturnal hemoglobinuria); autoimmune thrombocytopenia (idiopathic thrombocytopenic purpura, immune-mediated thrombocytopenia); thyroiditis (Grave's disease, Hashimoto's thyroiditis, juvenile lymphocytic thyroiditis, atrophic thyroiditis); diabetes mellitus; immune-mediated renal disease (glomerulonephritis, tubulointerstitial nephritis); demyelinating diseases of the central and peripheral nervous systems such as multiple sclerosis, idiopathic demyelinating polyneuropathy or Guillain-Barre syndrome, and chronic inflammatory demyelinating polyneuropathy; hepatobiliary diseases such as infectious hepatitis (hepatitis A, B, C, D, E and other non-hepatotropic viruses), autoimmune chronic active hepatitis, primary biliary cirrhosis, granulomatous hepatitis, and sclerosing cholangitis; inflammatory bowel disease (ulcerative colitis: Crohn's disease); gluten-sensitive enteropathy, and Whipple's disease; autoimmune or immune-mediated skin diseases including bullous skin diseases, erythema multiforme and contact dermatitis, psoriasis; allergic diseases such as asthma, allergic rhinitis, atopic dermatitis, food hypersensitivity and urticaria; immunologic diseases of the lung such as eosinophilic pneumonia, idiopathic pulmonary fibrosis and hypersensitivity pneumonitis; or transplantation associated diseases including graft rejection and graft-versus-host disease. 20. The method of Claim 3, wherein the bone metabolic abnormality or disorder is arthritis, osteoporosis or osteopetrosis. 21. The method of Claim 1, wherein the non-human transgenic animal exhibits at least one of the following physiological characteristics compared with gender matched wild-type littermates: increased anxiety-like response during open field testing; decreased anxiety during open field testing; hypoactivity with no circadian rhythm; increased total distance traveled during open field testing (hyperactivity); decreased locomotor activity during open field testing; abnormal circadian rhythm during home-cage activity testing (low activity during the light phase); abnormal circadian rhythm during home-cage activity testing including decreased ambulatory counts; abnormal circadian rhythm during home-cage activity testing including increased ambulatory counts; whiskers absent due to anxiety phenotype; enhanced circadian rhythm; increased stress induced hyperthermia with increased stress response (increased anxiety); increased resistance to stress induced hyperthermia; decreased resistance to stress induced hyperthermia; enhanced motor coordination during inverted screen testing; impaired motor coordination during inverted screen testing; increased immobility in tail suspension (increased depressive-like response); increased depressive-like response during tail suspension testing; decreased depressive-like response during tail suspension testing; clutched hind limbs during tail suspension testing; decreased startle response during prepulse inhibition testing; no startle response indicating deafness; increased prepulse inhibition with enhanced sensorimotor gating/attention; increased latency on hotplate indicative of decreased sensitivity to heat-induced pain; opthamological abnormalities; corneal epidermidalization of the corneal stroma with scarring and blocked vision; metaplasia of the cornea and sclera; attenuated retinal arteries; retinal hemorrhage; optic nerve abnormalities; dilated optic disc; increased intraocular pressure; corneal epithelialization with underdeveloped eyelids; retinal degeneration; agenesis of the Harderian gland; retinal vessel disorganization, microaneurysms and retinal capillary leakage; impaired vision; decreased heart rate; decreased mean systolic blood pressure; increased mean systolic blood pressure; increased insulin sensitivity; increased mean fasting serum glucose levels; decreased mean serum glucose levels; increased mean serum cholesterol levels; decreased mean serum cholesterol levels; increased mean serum triglyceride levels; enhanced glucose tolerance; impaired glucose tolerance; decreased mean serum insulin levels; ketonemia; decreased mean serum calcium; blood urobilinogen, nitrites, protein and ketones; decreased sodium and chloride; increased bilirubin; notable lipemia; increased uric acid and potassium levels; increased mean serum alkaline phosphatase levels; decreased mean serum alkaline phosphatase levels; blood in the urine; glucosuria; increased nitrituria; ketonuria; increased mean percentage of natural killer cells; decreased mean percentage of natural killer cells; abnormal leukocyte count; leukopenia due to lymphopenia and granulocytopenia; increased mean percentage of CD4 cells; decreased mean percentage of CD4 cells; decreased mean percentage of CD8 cells; reduced percentage of naive CD4 and CD8 T cells in lymph nodes; increased mean percentage of B cells in peripheral blood; decrease total white blood cells and lymphocyte counts; decreased absolute lymphocyte counts; increased mean absolute monocyte count; increased mean absolute neutrophil count; decreased in mean serum IgA levels; increase in mean serum IgA levels; increase in IgG1 levels; decreased mean serum IgG1 levels; decreased mean serum IgG1, IgG3, IgG2b and IgG2a levels; decreased mean serum IgG2a levels; decreased mean serum IgG2b levels; decreased mean serum IgG3 and IgM levels; increase in mean serum IgG2a levels; increase in mean serum IgG1, IgG2a and IgG3 levels; increase in mean serum IgG3 levels; anemia; decreased red blood cell count, decreased hemoglobin and decreased hematocrit with increased mean red blood cell count; increased mean corpuscular volume; decreased mean corpuscular volume; decreased mean corpuscular hemoglobin; increased red blood cell distribution width; defect in erythropoiesis; increased IgM+ IgD+ and B220hi/CD43- cells in bone marrow; decreased percentage of B220hi/CD43- IgM+ IgD+ cells in bone marrow; increased percentage of TCRB+ cells in Peyer's patches; reduction in naive T cells (especially CD4) in lymph nodes; increased percentage of CD11b+CD11c- cells (monocytes) in spleen; increased percentage of IgM+, CD117+ cells in bone marrow, higher percentage of dead B cells, decreased B cells, increased CD4 and CD8 T cells in lymph; B cells increased in bone marrow and significantly decreased in lymph node; notably decreased CD21hiCD23med B cells in spleen; decrease in Peyer's patch B220+ cells; decreased mean percentages of CD8 and natural killer cells with increased mean percentage of B cells; reduced number of TCRB+ CD38+ activated T cells in Peyer's patches; decreased mean percentage of CD4 cells with increased mean percentage of B cells; decreased B220+ CD38low and IgM in Payer's patches; increased mean platelet count; decreased mean platelet count; widespread apoptosis and loss of T lymphocytes in the thymic cortex and depletion of T cells in spleen; increased mean serum IgG2a response to an ovalbumin challenge; decreased to no serum IgG1 and IgG2a response to ovalbumin challenge; increased mean serum IgG1 response to an ovalbumin challenge; decreased mean serum TNF-alpha, MCP-1 and IL-6 responses to LPS challenge; increased mean serum MCP-1 response to a LPS challenge; increased mean serum TNF-alpha response to a LPS challenge; increased mean serum IL-6 response to a LPS challenge; increased skin fibroblast proliferation; decreased skin fibroblast proliferation; increased mean percent of total body fat and total fat mass; increased mean body weight; increased mean body length; increased total tissue mass (TTM); increased lean body mass (LBM); increased femoral bone mineral density (BMD); increased vertebral bone mineral density (BMD); increased bone mineral density (BMD); increased total body volumetric bone mineral density (vBMD); increased bone mineral content (BMC); increased mean femoral midshaft cortical thickness and cross-sectional area; increased mean vertebral trabecular bone volume, number and connectivity density; decreased mean percent of total body fat and total fat mass; decreased mean body weight; decreased mean body length; decreased total tissue mass (TTM); decreased lean body mass (LBM); decreased femoral bone mineral density (BMD); decreased vertebral bone mineral density (BMD); decreased bone mineral density (BMD); decreased bone mineral content (BMC); decreased bone mineral density index; decreased volumetric bone mineral density (vBMD); decreased mean femoral midshaft cortical thickness and cross-sectional area; decreased mean vertebral trabecular bone volume, number and connectivity density; marked osteopetrosis with increased bone mineralization; chronic inflammation in various tissues; thymic atrophy; systemic histiocytic storage disease affecting macrophages in liver, spleen and mesenteric lymph nodes; reduced liver size; chronic active hepatitis with focal hepatocyte necrosis; fatty changes in the liver; increased intracytoplasmic vacuolization of glycogen in hepatocytes; pancreatic dyserythropoietic anemia (type 1); multifocal neuronal necrosis; diffuse abiotrophy of the cerebellum granule cell layer; multifocal developmental malformation of the brain; hydronephosis; diffuse alopecia; epidermal hyperkeratosis; hypochromasia and anisocytosis characterized by abnormal erythrocytes (abnormally low hemoglobin and decreased erythropoiesis); growth retardation; development abnormalities; granulocytic hypoplasia of bone marrow; decreased numbers of myeloid granulocytic cell precursors; decreased granulocytopoiesis; no teeth; stunted growth with general reduction in all organ size; myocardial defects with defective structure and arrangement of the cardiac myocytes; cardiomyopathy with condensed eosinophilic sarcoplasm; congestive heart failure; pancreatic islets of Langerhans smaller and distribution of alpha (glycogen) and beta (insulin) cells altered; notable histopathologic alteration in cytoplasm of all cells in the zona fasciculata of the adrenal gland consistent with altered lipid/cholesterol uptake or metabolism (elevated cholesterol and triglycerides); infertility; testicular degeneration; vacuolar degeneration of seminiferous tubules; hypospermia; atrophic testes; ovarian and uterine hypoplasia; mammary gland was represented with just a few ducts; growth retardation with reduced viability; and embryonic lethality. 22. An isolated cell derived from a non-human transgenic animal whose genome comprises a disruption of the gene which encodes for a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide. 23. The isolated cell of Claim 22 which is a murine cell. 24. The isolated cell of Claim 23, wherein the murine cell is an embryonic stem cell. 25. The isolated cell of Claim 22, wherein the non-human transgenic animal exhibits at least one of the following

phenotypes compared with gender matched wild-type littermates: a neurological disorder; a cardiovascular, endothelial or angiogenic disorder; an eye abnormality; an immunological disorder; an oncological disorder; a bone metabolic abnormality or disorder; a lipid metabolic disorder; or a developmental abnormality. 26. A method of identifying an agent that modulates a phenotype associated with a disruption of a gene which encodes for a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, the method comprising:

[0136] (a) providing a non-human transgenic animal whose genome comprises a disruption of the gene which encodes for the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide;

[0137] (b) measuring a physiological characteristic of the non-human transgenic animal of (a);

[0138] (c) comparing the measured physiological characteristic of (b) with that of a gender matched wild-type animal, wherein the physiological characteristic of the non-human transgenic animal that differs from the physiological characteristic of the wild-type animal is identified as a phenotype resulting from the gene disruption in the non-human transgenic animal;

[0139] (d) administering a test agent to the non-human transgenic animal of (a); and

[0140] (e) determining whether the test agent modulates the identified phenotype associated with gene disruption in the non-human transgenic animal.

27. The method of Claim 26, wherein the phenotype associated with the gene disruption comprises a neurological disorder; a cardiovascular, endothelial or angiogenic disorder; an eye abnormality; an immunological disorder; an oncological disorder; a bone metabolic abnormality or disorder; a lipid metabolic disorder; or a developmental abnormality. 28. The method of Claim 27, wherein the neurological disorder is an increased anxiety-like response during open field activity testing. 29. The method of Claim 27, wherein the neurological disorder is a decreased anxiety-like response during open field activity testing. 30. The method of Claim 27, wherein the neurological disorder is an abnormal circadian rhythm during home-cage activity testing. 31. The method of Claim 27, wherein the neurological disorder is an enhanced motor coordination during inverted screen testing. 32. The method of Claim 27, wherein the neurological disorder is an impaired motor coordination during inverted screen testing. 33. The method of Claim 27, wherein the neurological disorder is depression, generalized anxiety disorders, attention deficit disorder, sleep disorder, hyperactivity disorder, obsessive compulsive disorder, schizophrenia, cognitive disorders, hyperalgesia or sensory disorders. 34. The method of Claim 27, wherein the eye abnormality is a retinal abnormality. 35. The method of Claim 27, wherein the eye abnormality is consistent with vision problems or blindness. 36. The method of Claim 34, wherein the retinal abnormality is consistent with retinitis pigmentosa. 37. The method of Claim 34, wherein the retinal abnormality is characterized by retinal degeneration or retinal dysplasia. 38. The method of Claim 34, wherein the retinal abnormality is consistent with retinal dysplasia, various retinopathies, including retinopathy of prematurity, retrolental fibroplasia, neovascular glaucoma, age-related macular degeneration, diabetic macular edema, corneal neovascularization, corneal graft neovascularization, corneal graft rejection, retinal/choroidal neovascularization, neovascularization of the angle (rubeosis), ocular neovascular disease, vascular restenosis, arteriovenous malformations (AVM), meningioma, hemangioma, angiofibroma, thyroid hyperplasias (including Grave's disease), corneal and other tissue transplantation, retinal artery obstruction or occlusion; retinal degeneration causing secondary atrophy of the retinal vasculature, retinitis pigmentosa, macular dystrophies, Stargardt's disease, congenital stationary night blindness, choroideremia, gyrate atrophy, Leber's congenital amaurosis, retinoschisis disorders, Wagner's syndrome, Usher syndromes, Zellweger syndrome, Saldino-Mainzer syndrome, Senior-Loken syndrome, Bardet-Biedl syndrome, Alport's syndrome, Alstrom's syndrome, Cockayne's syndrome, dysplaisa spondyloepiphysaria congentia, Flynn-Aird syndrome, Friedreich ataxia, Hallgren syndrome, Marshall syndrome, Albers-Schnoberg disease, Refsum's disease, Kearns-Sayre syndrome, Waardenburg's syndrome, Alagile syndrome, myotonic dystrophy, olivopontocerebellar atrophy, Pierre-Marie dunsdrome, Stickler syndrome, carotinemeia, cystinosis, Wolfram syndrome, Bassen-Kornzweig syndrome, abetalipoproteinemia, incontinentia pigmenti, Batten's disease, mucopolysaccharidoses, homocystinuria, or mannosidosis. 39. The method of Claim 27, wherein the eye abnormality is a cataract. 40. The method of Claim 39, wherein the cataract is consistent with systemic diseases such as human Down's syndrome, Hallerman-Streiff syndrome, Lowe syndrome, galactosemia, Marfan syndrome, Trismoy 13-15, Alport syndrome, myotonic dystrophy, Fabry disease, hypoparathroidism or Conradi syndrome. 41. The method of Claim 27, wherein the developmental abnormality comprises embryonic lethality or reduced viability. 42. The method of Claim 27, wherein the cardiovascular, endothelial or angiogenic disorders are arterial diseases, such as diabetes mellitus; papilledema; optic atrophy; atherosclerosis; angina; myocardial infarctions such as acute myocardial infarctions, cardiac hypertrophy, and heart failure such as congestive heart failure; hypertension; inflammatory vasculitides; Reynaud's disease and Reynaud's phenomenon; aneurysms and arterial restenosis; venous and lymphatic disorders such as thrombophlebitis, lymphangitis, and lymphedema; peripheral vascular disease; cancer such as vascular tumors, e.g., hemangioma (capillary and cavernous), glomus tumors, telangiectasia, bacillary angiomatosis, hemangioendothelioma, angiosarcoma, haemangiopericytoma, Kaposi's sarcoma, lymphangioma, and lymphangiosarcoma; tumor angiogenesis; trauma such as wounds, burns, and other injured tissue, implant fixation, scarring; ischemia reperfusion injury; rheumatoid arthritis; cerebrovascular disease; renal diseases such as acute renal failure, or osteoporosis. 43. The method of Claim 27, wherein the immunological disorders are systemic lupus erythematosis; rheumatoid arthritis; juvenile chronic arthritis; spondyloarthropathies; systemic sclerosis (scleroderma); idiopathic inflammatory myopathies (dermatomyositis, polymyositis); Sjogren's syndrome; systemic vasculitis; sarcoidosis; autoimmune hemolytic anemia (immune pancytopenia, paroxysmal nocturnal hemoglobinuria); autoimmune thrombocytopenia (idiopathic thrombocytopenic purpura, immune-mediated thrombocytopenia); thyroiditis (Grave's disease, Hashimoto's thyroiditis, juvenile lymphocytic thyroiditis, atrophic thyroiditis); diabetes mellitus; immune-mediated renal disease (glomerulonephritis, tubulointerstitial nephritis); demyelinating diseases of the central and peripheral nervous systems such as multiple sclerosis, idiopathic demyelinating polyneuropathy or Guillain-Barre syndrome, and chronic inflammatory demyelinating polyneuropathy; hepatobiliary diseases such as infectious hepatitis (hepatitis A, B, C, D, E and other non-hepatotropic viruses), autoimmune chronic active hepatitis, primary biliary cirrhosis, granulomatous hepatitis, and sclerosing cholangitis; inflammatory bowel disease (ulcerative colitis: Crohn's disease); gluten-sensitive enteropathy, and Whipple's disease; autoimmune or immune-mediated skin diseases including bullous skin diseases, erythema multiforme and contact dermatitis, psoriasis; allergic diseases such as asthma, allergic rhinitis, atopic dermatitis, food hypersensitivity and urticaria; immunologic diseases of the lung such as eosinophilic pneumonia, idiopathic pulmonary fibrosis and hypersensitivity pneumonitis; or transplantation-associated diseases including graft rejection and graft-versus-host disease. 44. The method of Claim 27, wherein said bone metabolic abnormality or disorder is arthritis, osteoporosis or osteopetrosis. 45. The method of Claim 26, wherein the non-human transgenic animal exhibits at least one of the following physiological characteristics compared with gender matched wild-type littermates: increased anxiety-like response during open field testing; decreased anxiety during open field testing; hypoactivity with no circadian rhythm; increased total distance traveled during open field testing (hyperactivity); decreased locomotor activity during open field testing; abnormal circadian rhythm during home-cage activity testing (low activity during the light phase); abnormal circadian rhythm during home-cage activity testing including decreased ambulatory counts; abnormal circadian rhythm during home-cage activity testing including increased ambulatory counts; whiskers absent due to anxiety phenotype; enhanced circadian rhythm; increased stress induced hyperthermia with increased stress response (increased anxiety); increased resistance to stress induced hyperthermia; decreased resistance to stress induced hyperthermia; enhanced motor coordination during inverted screen testing; impaired motor coordination during inverted screen testing; increased immobility in tail suspension (increased depressive-like response); increased depressive-like response during tail suspension testing; decreased depressive-like response during tail suspension testing; clutched hind limbs during tail suspension testing; decreased startle response during prepulse inhibition testing; no startle response indicating deafness; increased prepulse inhibition with enhanced sensorimotor gating/attention; increased latency on hotplate indicative of decreased sensitivity to heat-induced pain; opthamological abnormalities; corneal epidermidalization of the corneal stroma with scarring and blocked vision; metaplasia of the cornea and sclera; attenuated retinal arteries; retinal hemorrhage; optic nerve abnormalities; dilated optic disc; increased intraocular pressure; corneal epithelialization with underdeveloped eyelids; retinal degeneration; agenesis of the Harderian gland; retinal vessel disorganization, microaneurysms and retinal capillary leakage; impaired vision; decreased heart rate; decreased mean systolic blood pressure; increased mean systolic blood pressure; increased insulin sensitivity; increased mean fasting serum glucose levels; decreased mean serum glucose levels; increased mean serum cholesterol levels; decreased mean serum cholesterol levels; increased mean serum triglyceride levels; enhanced glucose tolerance; impaired glucose tolerance; decreased mean serum insulin levels; ketonemia; decreased mean serum calcium; blood urobilinogen, nitrites, protein and ketones; decreased sodium and chloride; increased bilirubin; notable lipemia; increased uric acid and potassium levels; increased mean serum alkaline phosphatase levels; decreased mean serum alkaline phosphatase levels; blood in the urine; glucosuria; increased nitrituria; ketonuria; increased mean percentage of natural killer cells; decreased mean percentage of natural killer cells; abnormal leukocyte count; leukopenia due to lymphopenia and granulocytopenia; increased mean percentage of CD4 cells; decreased mean percentage of CD4 cells; decreased mean percentage of CD8 cells; reduced percentage of naive CD4 and CD8 T cells in lymph nodes; increased mean percentage of B cells in peripheral blood; decrease total white blood cells and lymphocyte counts; decreased absolute lymphocyte counts; increased mean absolute monocyte count; increased mean absolute neutrophil count; decreased in mean serum IgA levels; increase in mean serum IgA levels; increase in IgG1 levels; decreased mean serum IgG1 levels; decreased mean serum IgG1, IgG3, IgG2b and IgG2a levels; decreased mean serum IgG2a levels; decreased mean serum IgG2b levels; decreased mean serum IgG3 and IgM levels; increase in mean serum IgG2a levels; increase in mean serum IgG1, IgG2a and IgG3 levels; increase in mean serum IgG3 levels; anemia; decreased red blood cell count, decreased hemoglobin and decreased hematocrit with increased mean red blood cell count; increased mean corpuscular volume; decreased mean corpuscular volume; decreased mean corpuscular hemoglobin; increased red blood cell distribution width; defect in erythropoiesis; increased IgM+ IgD+ and B220hi/CD43- cells in bone marrow; decreased percentage of B220hi/CD43- IgM+ IgD+ cells in bone marrow; increased percentage of TCRB+ cells in Peyer's patches; reduction in naive T cells (especially CD4) in lymph nodes; increased percentage of CD11b+CD11c- cells (monocytes) in spleen; increased percentage of IgM+, CD117+ cells in bone marrow, higher percentage of dead B cells, decreased B cells, increased CD4 and CD8 T cells in lymph; B cells increased in bone marrow and significantly decreased in lymph node; notably decreased CD21hiCD23med B cells in spleen; decrease in Peyer's patch B220+ cells; decreased mean percentages of CD8 and natural killer cells with increased mean percentage of B cells; reduced number of TCRB+ CD38+ activated T cells in Peyer's patches; decreased mean percentage of CD4 cells with increased mean percentage of B cells; decreased B220+ CD38low and IgM in Payer's patches; increased mean platelet count; decreased mean platelet count; widespread apoptosis and loss of T lymphocytes in the thymic cortex and depletion of T cells in spleen; increased mean serum IgG2a response to an ovalbumin challenge; decreased to no serum IgG1 and IgG2a response to ovalbumin challenge; increased mean serum IgG1 response to an ovalbumin challenge; decreased mean serum TNF-alpha, MCP-1 and IL-6 responses to LPS challenge; increased mean serum MCP-1 response to a LPS challenge; increased mean serum TNF-alpha response to a LPS challenge; increased mean serum IL-6 response to a LPS challenge; increased skin fibroblast proliferation; decreased skin fibroblast proliferation; increased mean percent of total body fat and total fat mass; increased mean body weight; increased mean body length; increased total tissue mass (TTM); increased lean body mass (LBM); increased femoral bone mineral density (BMD); increased vertebral bone mineral density (BMD); increased bone mineral density (BMD); increased total body volumetric bone mineral density (vBMD); increased bone mineral content (BMC); increased mean femoral midshaft cortical thickness and cross-sectional area; increased mean vertebral trabecular bone volume, number and connectivity density; decreased mean percent of total body fat and total fat mass; decreased mean body weight; decreased mean body length; decreased total tissue mass (TTM); decreased lean body mass (LBM); decreased femoral bone mineral density (BMD); decreased vertebral bone mineral density (BMD); decreased bone mineral density (BMD); decreased bone mineral content (BMC); decreased bone mineral density index; decreased volumetric bone mineral density (vBMD); decreased mean femoral midshaft cortical thickness and cross-sectional area; decreased mean vertebral trabecular bone volume, number and connectivity density; marked osteopetrosis with increased bone mineralization; chronic inflammation in various tissues; thymic atrophy; systemic histiocytic storage disease affecting macrophages in liver, spleen and mesenteric lymph nodes; reduced liver size; chronic active hepatitis with focal hepatocyte necrosis; fatty changes in the liver; increased intracytoplasmic vacuolization of glycogen in hepatocytes; pancreatic dyserythropoietic anemia (type 1); multifocal neuronal necrosis; diffuse abiotrophy of the cerebellum granule cell layer; multifocal developmental malformation of the brain; hydronephosis; diffuse alopecia; epidermal hyperkeratosis; hypochromasia and anisocytosis characterized by abnormal erythrocytes (abnormally low hemoglobin and decreased erythropoiesis); growth retardation; development abnormalities; granulocytic hypoplasia of bone marrow; decreased numbers of myeloid granulocytic cell precursors; decreased granulocytopoiesis; no teeth; stunted growth with general reduction in all organ size; myocardial defects with defective structure and arrangement of the cardiac myocytes; cardiomyopathy with condensed eosinophilic sarcoplasm; congestive heart failure; pancreatic islets of Langerhans smaller and distribution of alpha (glycogen) and beta (insulin) cells altered; notable histopathologic alteration in cytoplasm of all cells in the zona fasciculata of the adrenal gland consistent with altered lipid/cholesterol uptake or metabolism (elevated cholesterol and triglycerides); infertility; testicular degeneration; vacuolar degeneration of seminiferous tubules; hypospermia; atrophic testes; ovarian and uterine hypoplasia; mammary gland was represented with just a few ducts; growth retardation with reduced viability; and embryonic lethality. 46. An agent identified by the method of Claim 26. 47. The agent of Claim 46 which is an agonist or antagonist of a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide. 48. The agent of Claim 47, wherein the agonist is an anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibody. 49. The agent of Claim 47, wherein the

antagonist is an anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibody. 50. A method of identifying an agent that modulates a physiological characteristic associated with a disruption of the gene which encodes for a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, the method comprising:

[0141] (a) providing a non-human transgenic animal whose genome comprises a disruption of the gene which encodes for a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide;

[0142] (b) measuring a physiological characteristic exhibited by the non-human transgenic animal of (a);

[0143] (c) comparing the measured physiological characteristic of (b) with that of a gender matched wild-type animal, wherein the physiological characteristic exhibited by the non-human transgenic animal that differs from the physiological characteristic exhibited by the wild-type animal is identified as a physiological characteristic associated with gene disruption;

[0144] (d) administering a test agent to the non-human transgenic animal of (a); and

[0145] (e) determining whether the physiological characteristic associated with gene disruption is modulated.

51. The method of Claim 50, wherein the non-human transgenic animal exhibits at least one of the following physiological characteristics compared with gender matched wild-type littermates: increased anxiety-like response during open field testing; decreased anxiety during open field testing; hypoactivity with no circadian rhythm; increased total distance traveled during open field testing (hyperactivity); decreased locomotor activity during open field testing; abnormal circadian rhythm during home-cage activity testing (low activity during the light phase); abnormal circadian rhythm during home-cage activity testing including decreased ambulatory counts; abnormal circadian rhythm during home-cage activity testing including increased ambulatory counts; whiskers absent due to anxiety phenotype; enhanced circadian rhythm; increased stress induced hyperthermia with increased stress response (increased anxiety); increased resistance to stress induced hyperthermia; decreased resistance to stress induced hyperthermia; enhanced motor coordination during inverted screen testing; impaired motor coordination during inverted screen testing; increased immobility in tail suspension (increased depressive-like response); increased depressive-like response during tail suspension testing; decreased depressive-like response during tail suspension testing; clutched hind limbs during tail suspension testing; decreased startle response during prepulse inhibition testing; no startle response indicating deafness; increased prepulse inhibition with enhanced sensorimotor gating/attention; increased latency on hotplate indicative of decreased sensitivity to heat-induced pain; opthamological abnormalities; corneal epidermidalization of the corneal stroma with scarring and blocked vision; metaplasia of the cornea and sclera; attenuated retinal arteries; retinal hemorrhage; optic nerve abnormalities; dilated optic disc; increased intraocular pressure; corneal epithelialization with underdeveloped eyelids; retinal degeneration; agenesis of the Harderian gland; retinal vessel disorganization, microaneurysms and retinal capillary leakage; impaired vision; decreased heart rate; decreased mean systolic blood pressure; increased mean systolic blood pressure; increased insulin sensitivity; increased mean fasting serum glucose levels; decreased mean serum glucose levels; increased mean serum cholesterol levels; decreased mean serum cholesterol levels; increased mean serum triglyceride levels; enhanced glucose tolerance; impaired glucose tolerance; decreased mean serum insulin levels; ketonemia; decreased mean serum calcium; blood urobilinogen, nitrites, protein and ketones; decreased sodium and chloride; increased bilirubin; notable lipemia; increased uric acid and potassium levels; increased mean serum alkaline phosphatase levels; decreased mean serum alkaline phosphatase levels; blood in the urine; glucosuria; increased nitrituria; ketonuria; increased mean percentage of natural killer cells; decreased mean percentage of natural killer cells; abnormal leukocyte count; leukopenia due to lymphopenia and granulocytopenia; increased mean percentage of CD4 cells; decreased mean percentage of CD4 cells; decreased mean percentage of CD8 cells; reduced percentage of naive CD4 and CD8 T cells in lymph nodes; increased mean percentage of B cells in peripheral blood; decrease total white blood cells and lymphocyte counts; decreased absolute lymphocyte counts; increased mean absolute monocyte count; increased mean absolute neutrophil count; decreased in mean serum IgA levels; increase in mean serum IgA levels; increase in IgG1 levels; decreased mean serum IgG1 levels; decreased mean serum IgG1, IgG3, IgG2b and IgG2a levels; decreased mean serum IgG2a levels; decreased mean serum IgG2b levels; decreased mean serum IgG3 and IgM levels; increase in mean serum IgG2a levels; increase in mean serum IgG1, IgG2a and IgG3 levels; increase in mean serum IgG3 levels; anemia; decreased red blood cell count, decreased hemoglobin and decreased hematocrit with increased mean red blood cell count; increased mean corpuscular volume; decreased mean corpuscular volume; decreased mean corpuscular hemoglobin; increased red blood cell distribution width; defect in erythropoiesis; increased IgM+ IgD+ and B220hi/CD43- cells in bone marrow; decreased percentage of B220hi/CD43- IgM+ IgD+ cells in bone marrow; increased percentage of TCRB+ cells in Peyer's patches; reduction in naive T cells (especially CD4) in lymph nodes; increased percentage of CD11b+CD11c- cells (monocytes) in spleen; increased percentage of IgM+, CD117+ cells in bone marrow, higher percentage of dead B cells, decreased B cells, increased CD4 and CD8 T cells in lymph; B cells increased in bone marrow and significantly decreased in lymph node; notably decreased CD21hiCD23med B cells in spleen; decrease in Peyer's patch B220+ cells; decreased mean percentages of CD8 and natural killer cells with increased mean percentage of B cells; reduced number of TCRB+ CD38+ activated T cells in Peyer's patches; decreased mean percentage of CD4 cells with increased mean percentage of B cells; decreased B220+ CD38low and IgM in Payer's patches; increased mean platelet count; decreased mean platelet count; widespread apoptosis and loss of T lymphocytes in the thymic cortex and depletion of T cells in spleen; increased mean serum IgG2a response to an ovalbumin challenge; decreased to no serum IgG1 and IgG2a response to ovalbumin challenge; increased mean serum IgG1 response to an ovalbumin challenge; decreased mean serum TNF-alpha, MCP-1 and IL-6 responses to LPS challenge; increased mean serum MCP-1 response to a LPS challenge; increased mean serum TNF-alpha response to a LPS challenge; increased mean serum IL-6 response to a LPS challenge; increased skin fibroblast proliferation; decreased skin fibroblast proliferation; increased mean percent of total body fat and total fat mass; increased mean body weight; increased mean body length; increased total tissue mass (TTM); increased lean body mass (LBM); increased femoral bone mineral density (BMD); increased vertebral bone mineral density (BMD); increased bone mineral density (BMD); increased total body volumetric bone mineral density (vBMD); increased bone mineral content (BMC); increased mean femoral midshaft cortical thickness and cross-sectional area; increased mean vertebral trabecular bone volume, number and connectivity density; decreased mean percent of total body fat and total fat mass; decreased mean body weight; decreased mean body length; decreased total tissue mass (TTM); decreased lean body mass (LBM); decreased femoral bone mineral density (BMD); decreased vertebral bone mineral density (BMD); decreased bone mineral density (BMD); decreased bone mineral content (BMC); decreased bone mineral density index; decreased volumetric bone mineral density (vBMD); decreased mean femoral midshaft cortical thickness and cross-sectional area; decreased mean vertebral trabecular bone volume, number and connectivity density; marked osteopetrosis with increased bone mineralization; chronic inflammation in various tissues; thymic atrophy; systemic histiocytic storage disease affecting macrophages in liver, spleen and mesenteric lymph nodes; reduced liver size; chronic active hepatitis with focal hepatocyte necrosis; fatty changes in the liver; increased intracytoplasmic vacuolization of glycogen in hepatocytes; pancreatic dyserythropoietic anemia (type 1); multifocal neuronal necrosis; diffuse abiotrophy of the cerebellum granule cell layer; multifocal developmental malformation of the brain; hydronephosis; diffuse alopecia; epidermal hyperkeratosis; hypochromasia and anisocytosis characterized by abnormal erythrocytes (abnormally low hemoglobin and decreased erythropoiesis); growth retardation; development abnormalities; granulocytic hypoplasia of bone marrow; decreased numbers of myeloid granulocytic cell precursors; decreased granulocytopoiesis; no teeth; stunted growth with general reduction in all organ size; myocardial defects with defective structure and arrangement of the cardiac myocytes; cardiomyopathy with condensed eosinophilic sarcoplasm; congestive heart failure; pancreatic islets of Langerhans smaller and distribution of alpha (glycogen) and beta (insulin) cells altered; notable histopathologic alteration in cytoplasm of all cells in the zona fasciculata of the adrenal gland consistent with altered lipid/cholesterol uptake or metabolism (elevated cholesterol and triglycerides); infertility; testicular degeneration; vacuolar degeneration of seminiferous tubules; hypospermia; atrophic testes; ovarian and uterine hypoplasia; mammary gland was represented with just a few ducts; growth retardation with reduced viability; and embryonic lethality. 52. An agent identified by the method of Claim 50. 53. The agent of Claim 52 which is an agonist or antagonist of a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935; PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide. 54. The agent of Claim 53, wherein the agonist is an anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibody. 55. The agent of Claim 53, wherein the antagonist is an anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibody. 56. A method of identifying an agent which modulates a behavior associated with a disruption of the gene which encodes for a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, the method comprising:

[0146] (a) providing a non-human transgenic animal whose genome comprises a disruption of the gene which encodes for a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide;

[0147] (b) observing the behavior exhibited by the non-human transgenic animal of (a);

[0148] (c) comparing the observed behavior of (b) with that of a gender matched wild-type animal, wherein the observed behavior exhibited by the non-human transgenic animal that differs from the observed behavior exhibited by the wild-type animal is identified as a behavior associated with gene disruption;

[0149] (d) administering a test agent to the non-human transgenic animal of (a); and

[0150] (e) determining whether the agent modulates the behavior associated with gene disruption.

57. The method of Claim 56, wherein the behavior is an increased anxiety-like response during open field activity testing. 58. The method of Claim 56, wherein the behavior is a decreased anxiety-like response during open field activity testing. 59. The method of Claim 56, wherein the behavior is an abnormal circadian rhythm during home-cage activity testing. 60. The method of Claim 56, wherein the behavior is an enhanced motor coordination during inverted screen testing. 61. The method of Claim 56, wherein the behavior is an impaired motor coordination during inverted screen testing. 62. The method of Claim 56, wherein the behavior is depression, generalized anxiety disorders, attention deficit disorder, sleep disorder, hyperactivity disorder, obsessive compulsive disorder, schizophrenia, cognitive disorders, hyperalgesia or sensory disorders. 63. An agent identified by the method of Claim 56. 64. The agent of Claim 63 which is an agonist or antagonist of a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide. 65. The agent of Claim 64, wherein the agonist is an anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibody. 66. The agent of Claim 64, wherein the antagonist is an anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibody. 67. A method of identifying an agent that ameliorates or modulates a neurological disorder; a cardiovascular, endothelial or angiogenic disorder; an eye abnormality; an immunological disorder; an oncological disorder; a bone metabolic abnormality or disorder; a lipid metabolic disorder; or a developmental abnormality associated with a disruption in the gene which encodes for a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, the method comprising:

[0151] (a) providing a non-human transgenic animal whose genome comprises a disruption of the gene which encodes for a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide;

[0152] (b) administering a test agent to said non-human transgenic animal; and

[0153] (c) determining whether said test agent ameliorates or modulates the neurological disorder; cardiovascular, endothelial or angiogenic disorder; eye abnormality; immunological disorder; oncological disorder; bone metabolic abnormality or disorder; lipid metabolic disorder; or developmental abnormality in the non-human transgenic animal.

68. The method of Claim 67, wherein the neurological disorder is an increased anxiety-like response during open field activity testing. 69. The method of Claim 67, wherein the neurological disorder is a decreased anxiety-like response during open field activity testing. 70. The method of Claim 67, wherein the neurological disorder is an abnormal circadian rhythm during home-cage activity testing. 71. The method of Claim 67, wherein the neurological disorder is an enhanced motor coordination during inverted screen testing. 72. The method of Claim 67, wherein the neurological disorder is an impaired motor coordination during inverted screen testing. 73. The method of Claim 73, wherein the neurological disorder is depression, generalized anxiety disorders, attention deficit disorder, sleep disorder, hyperactivity disorder, obsessive compulsive disorder, schizophrenia, cognitive disorders, hyperalgesia or sensory disorders. 74. The method of Claim 67, wherein the eye abnormality is a retinal abnormality. 75. The method of Claim 67, wherein the eye abnormality is consistent with vision problems or blindness. 76. The method of Claim 74, wherein the retinal abnormality is consistent with retinitis pigmentosa. 77. The method of Claim 74, wherein the retinal abnormality is characterized by retinal degeneration or retinal dysplasia. 78. The method of Claim 74, wherein the retinal abnormality is consistent with retinal dysplasia, various retinopathies, including retinopathy of prematurity, retrolental fibroplasia, neovascular glaucoma, age-related macular degeneration, diabetic macular edema, corneal neovascularization, corneal graft neovascularization, corneal graft rejection, retinal/choroidal neovascularization, neovascularization of the angle (rubeosis), ocular neovascular disease, vascular restenosis, arteriovenous malformations (AVM), meningioma, hemangioma, angiofibroma, thyroid hyperplasias (including Grave's disease), corneal and other tissue transplantation, retinal artery obstruction or occlusion; retinal degeneration causing secondary atrophy of the retinal vasculature, retinitis pigmentosa, macular dystrophies, Stargardt's disease, congenital stationary night blindness, choroideremia, gyrate atrophy, Leber's congenital amaurosis, retinoschisis disorders, Wagner's syndrome, Usher syndromes, Zellweger syndrome, Saldino-Mainzer syndrome, Senior-Loken syndrome, Bardet-Biedl syndrome, Alport's syndrome, Alstrom's syndrome, Cockayne's syndrome, dysplaisa spondyloepiphysaria congentia, Flynn-Aird syndrome, Friedreich ataxia, Hallgren syndrome, Marshall syndrome, Albers-Schnoberg disease, Refsum's disease, Kearns-Sayre syndrome, Waardenburg's syndrome, Alagile syndrome, myotonic dystrophy, olivopontocerebellar atrophy, Pierre-Marie dunsdrome, Stickler syndrome, carotinemeia, cystinosis, Wolfram syndrome, Bassen-Kornzweig syndrome, abetalipoproteinemia, incontinentia pigmenti, Batten's disease, mucopolysaccharidoses, homocystinuria, or mannosidosis. 79. The method of Claim 67, wherein the eye abnormality is a cataract. 80. The method of Claim 79, wherein the cataract is a systemic disease such as human Down's syndrome, Hallerman-Streiff syndrome, Lowe syndrome, galactosemia, Marfan syndrome, Trismoy 13-15, Alport syndrome, myotonic dystrophy, Fabry disease, hypoparathroidism or Conradi syndrome. 81. The method of Claim 67, wherein the developmental abnormality comprises embryonic lethality or reduced viability. 82. The method of Claim 67, wherein the cardiovascular, endothelial or angiogenic disorders are arterial diseases, such as diabetes mellitus; papilledema; optic atrophy; atherosclerosis; angina; myocardial infarctions such as acute myocardial infarctions, cardiac hypertrophy, and heart failure such as congestive heart failure; hypertension; inflammatory vasculitides; Reynaud's disease and Reynaud's phenomenon; aneurysms and arterial restenosis; venous and lymphatic disorders such as thrombophlebitis, lymphangitis, and lymphedema; peripheral vascular disease; cancer such as vascular tumors, e.g., hemangioma (capillary and cavernous), glomus tumors, telangiectasia, bacillary angiomatosis, hemangioendothelioma, angiosarcoma, haemangiopericytoma, Kaposi's sarcoma, lymphangioma, and lymphangiosarcoma; tumor angiogenesis; trauma such as wounds, burns, and other injured tissue, implant fixation, scarring; ischemia reperfusion injury; rheumatoid arthritis; cerebrovascular disease; renal diseases such as acute renal failure, or osteoporosis. 83. The method of Claim 67, wherein the immunological disorders are systemic lupus erythematosis; rheumatoid arthritis; juvenile chronic arthritis; spondyloarthropathies; systemic sclerosis (scleroderma); idiopathic inflammatory myopathies (dermatomyositis, polymyositis); Sjogren's syndrome; systemic vasculitis; sarcoidosis; autoimmune hemolytic anemia (immune pancytopenia, paroxysmal nocturnal hemoglobinuria); autoimmune thrombocytopenia (idiopathic thrombocytopenic purpura, immune-mediated thrombocytopenia); thyroiditis (Grave's disease, Hashimoto's thyroiditis, juvenile Lymphocytic thyroiditis, atrophic thyroiditis); diabetes mellitus; immune-mediated renal disease (glomerulonephritis, tubulointerstitial nephritis); demyelinating diseases of the central and peripheral nervous systems such as multiple sclerosis, idiopathic demyelinating polyneuropathy or Guillain-Barre syndrome, and chronic inflammatory demyelinating polyneuropathy; hepatobiliary diseases such as infectious hepatitis (hepatitis A, B, C, D, E and other non-hepatotropic viruses), autoimmune chronic active hepatitis, primary biliary cirrhosis, granulomatous hepatitis, and sclerosing cholangitis; inflammatory bowel disease (ulcerative colitis: Crohn's disease); gluten-sensitive enteropathy, and Whipple's disease; autoimmune or immune-mediated skin diseases including bullous skin diseases, erythema multiforme and contact dermatitis, psoriasis; allergic diseases such as asthma, allergic rhinitis, atopic dermatitis, food hypersensitivity and urticaria; immunologic diseases of the lung such as eosinophilic pneumonia, idiopathic pulmonary fibrosis and hypersensitivity pneumonitis; or transplantation associated diseases including graft rejection and graft-versus-host disease. 84. The method of Claim 67, wherein said bone metabolic abnormality or disorder is arthritis, osteoporosis or osteopetrosis. 85. The method of Claim 67, wherein the non-human transgenic animal exhibits at least one of the following physiological characteristics compared with gender matched wild-type littermates: increased anxiety-like response during open field testing; decreased anxiety during open field testing; hypoactivity with no circadian rhythm; increased total distance traveled during open field testing (hyperactivity); decreased locomotor activity during open field testing; abnormal circadian rhythm during home-cage activity testing (low activity during the light phase); abnormal circadian rhythm during home-cage activity testing including decreased ambulatory counts; abnormal circadian rhythm during home-cage activity testing including increased ambulatory counts; whiskers absent due to anxiety phenotype; enhanced circadian rhythm; increased stress induced hyperthermia with increased stress response (increased anxiety); increased resistance to stress induced hyperthermia; decreased resistance to stress induced hyperthermia; enhanced motor coordination during inverted screen testing; impaired motor coordination during inverted screen testing; increased immobility in tail suspension (increased depressive-like response); increased depressive-like response during tail suspension testing; decreased depressive-like response during tail suspension testing; clutched hind limbs during tail suspension testing; decreased startle response during prepulse inhibition testing; no startle response indicating deafness; increased prepulse inhibition with enhanced sensorimotor gating/attention; increased latency on hotplate indicative of decreased sensitivity to heat-induced pain; opthamological abnormalities; corneal epidermidalization of the corneal stroma with scarring and blocked vision; metaplasia of the cornea and sclera; attenuated retinal arteries; retinal hemorrhage; optic nerve abnormalities; dilated optic disc; increased intraocular pressure; corneal epithelialization with underdeveloped eyelids; retinal degeneration; agenesis of the Harderian gland; retinal vessel disorganization, microaneurysms and retinal capillary leakage; impaired vision; decreased heart rate; decreased mean systolic blood pressure; increased mean systolic blood pressure; increased insulin sensitivity; increased mean fasting serum glucose levels; decreased mean serum glucose levels; increased mean serum cholesterol levels; decreased mean serum cholesterol levels; increased mean serum triglyceride levels; enhanced glucose tolerance; impaired glucose tolerance; decreased mean serum insulin levels; ketonemia; decreased mean serum calcium; blood urobilinogen, nitrites, protein and ketones; decreased sodium and chloride; increased bilirubin; notable lipemia; increased uric acid and potassium levels; increased mean serum alkaline phosphatase levels; decreased mean serum alkaline phosphatase levels; blood in the urine; glucosuria; increased nitrituria; ketonuria; increased mean percentage of natural killer cells; decreased mean percentage of natural killer cells; abnormal leukocyte count; leukopenia due to lymphopenia and granulocytopenia; increased mean percentage of CD4 cells; decreased mean percentage of CD4 cells; decreased mean percentage of CD8 cells; reduced percentage of naive CD4 and CD8 T cells in lymph nodes; increased mean percentage of B cells in peripheral blood; decrease total white blood cells and lymphocyte counts; decreased absolute lymphocyte counts; increased mean absolute monocyte count; increased mean absolute neutrophil count; decreased in mean serum IgA levels; increase in mean serum IgA levels; increase in IgG1 levels; decreased mean serum IgG1 levels; decreased mean serum IgG1, IgG3, IgG2b and IgG2a levels; decreased mean serum IgG2a levels; decreased mean serum IgG2b levels; decreased mean serum IgG3 and IgM levels; increase in mean serum IgG2a levels; increase in mean serum IgG1, IgG2a and IgG3 levels; increase in mean serum IgG3 levels; anemia; decreased red blood cell count, decreased hemoglobin and decreased hematocrit with increased mean red blood cell count; increased mean corpuscular volume; decreased mean corpuscular volume; decreased mean corpuscular hemoglobin; increased red blood cell distribution width; defect in erythropoiesis; increased IgM+ IgD+ and B220hi/CD43- cells in bone marrow; decreased percentage of B220hi/CD43- IgM+ IgD+ cells in bone marrow; increased percentage of TCRB+ cells in Peyer's patches; reduction in naive T cells (especially CD4) in lymph nodes; increased percentage of CD11b+CD11c- cells (monocytes) in spleen; increased percentage of IgM+, CD117+ cells in bone marrow, higher percentage of dead B cells, decreased B cells, increased CD4 and CD8 T cells in lymph; B cells increased in bone marrow and significantly decreased in lymph node; notably decreased CD21hiCD23med B cells in spleen; decrease in Peyer's patch B220+ cells; decreased mean percentages of CD8 and natural killer cells with increased mean percentage of B cells; reduced number of TCRB+ CD38+ activated T cells in Peyer's patches; decreased mean percentage of CD4 cells with increased mean percentage of B cells; decreased B220+ CD38low and IgM in Payer's patches; increased mean platelet count; decreased mean platelet count; widespread apoptosis and loss of T lymphocytes in the thymic cortex and depletion of T cells in spleen; increased mean serum IgG2a response to an ovalbumin challenge; decreased to no serum IgG1 and IgG2a response to ovalbumin challenge; increased mean serum IgG1 response to an ovalbumin challenge; decreased mean serum TNF-alpha, MCP-1 and IL-6 responses to LPS challenge; increased mean serum MCP-1 response to a LPS challenge; increased mean serum TNF-alpha response to a LPS challenge; increased mean serum IL-6 response to a LPS challenge; increased skin fibroblast proliferation; decreased skin fibroblast proliferation; increased mean percent of total body fat and total fat mass; increased mean body weight; increased mean body length; increased total tissue mass (TTM); increased lean body mass (LBM); increased femoral bone mineral density (BMD); increased vertebral bone mineral density (BMD); increased bone mineral density (BMD); increased total body volumetric bone mineral density (vBMD); increased bone mineral content (BMC); increased mean femoral midshaft cortical thickness and cross-sectional area; increased mean vertebral trabecular bone volume, number and connectivity density; decreased mean percent of total body fat and total fat mass; decreased mean body weight; decreased mean body length; decreased total tissue mass (TTM); decreased lean body mass (LBM); decreased femoral bone mineral density (BMD); decreased vertebral bone mineral density (BMD); decreased bone mineral density (BMD); decreased bone mineral content (BMC); decreased bone mineral density index; decreased volumetric bone mineral density (vBMD); decreased mean femoral midshaft cortical thickness and cross-sectional area; decreased mean vertebral trabecular bone volume, number and connectivity density; marked osteopetrosis with increased bone mineralization; chronic inflammation in various tissues; thymic atrophy; systemic histiocytic storage disease affecting macrophages in liver, spleen and mesenteric lymph nodes; reduced liver size; chronic active hepatitis with focal hepatocyte necrosis; fatty changes in the liver; increased intracytoplasmic vacuolization of glycogen in hepatocytes; pancreatic dyserythropoietic anemia (type 1); multifocal neuronal necrosis; diffuse abiotrophy of the cerebellum granule cell layer; multifocal developmental malformation of the brain; hydronephosis; diffuse alopecia; epidermal hyperkeratosis; hypochromasia and anisocytosis characterized by abnormal erythrocytes (abnormally low hemoglobin and decreased erythropoiesis); growth retardation; development abnormalities; granulocytic hypoplasia of bone marrow; decreased numbers of myeloid granulocytic cell precursors; decreased granulocytopoiesis; no teeth; stunted growth with general reduction in all organ size; myocardial defects with defective structure and arrangement of the cardiac myocytes; cardiomyopathy with condensed eosinophilic sarcoplasm; congestive heart failure; pancreatic islets of Langerhans smaller and distribution of alpha (glycogen) and beta (insulin) cells altered; notable histopathologic alteration in cytoplasm of all cells in the zona fasciculata of the adrenal gland consistent with altered lipid/cholesterol uptake or metabolism (elevated cholesterol and triglycerides); infertility; testicular degeneration; vacuolar degeneration of seminiferous tubules; hypospermia; atrophic testes; ovarian and uterine hypoplasia; mammary gland was represented with just a few ducts; growth retardation with reduced viability; and embryonic lethality. 86. An agent identified by the method of Claim 67. 87. The agent of Claim 86 which is an agonist or antagonist of a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide. 88. The agent of Claim 87, wherein the agonist is an anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibody. 89. The agent of Claim 87, wherein the antagonist is an anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316,

anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibody. 90. A therapeutic agent identified by the method of Claim 67. 91. A method of identifying an agent that modulates the expression of a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, the method comprising:

[0154] (a) contacting a test agent with a host cell expressing a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide; and

[0155] (b) determining whether the test agent modulates the expression of the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide by the host cell.

92. An agent identified by the method of Claim 91. 93. The agent of Claim 92 which is an agonist or antagonist of a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide. 94. The agent of Claim 93, wherein the agonist is an anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibody. 95. The agent of Claim 93, wherein the antagonist is an anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibody. 96. A method of evaluating a therapeutic agent capable of affecting a condition associated with a disruption of a gene which encodes for a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, the method comprising:

[0156] (a) providing a non-human transgenic animal whose genome comprises a disruption of the gene which encodes for the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide;

[0157] (b) measuring a physiological characteristic of the non-human transgenic animal of (a);

[0158] (c) comparing the measured physiological characteristic of (b) with that of a gender matched wild-type animal, wherein the physiological characteristic of the non-human transgenic animal that differs from the physiological characteristic of the wild-type animal is identified as a condition resulting from the gene disruption in the non-human transgenic animal;

[0159] (d) administering a test agent to the non-human transgenic animal of (a); and

[0160] (e) evaluating the effects of the test agent on the identified condition associated with gene disruption in the non-human transgenic animal.

97. The method of Claim 96, wherein the condition is a neurological disorder; a cardiovascular, endothelial or angiogenic disorder; an eye abnormality; an immunological disorder; an oncological disorder; a bone metabolic abnormality or disorder; a lipid metabolic disorder; or a developmental abnormality. 98. A therapeutic agent identified by the method of Claim 96. 99. The therapeutic agent of Claim 98 which is an agonist or antagonist of a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide. 100. The therapeutic agent of Claim 99, wherein the agonist is an anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibody. 101. The therapeutic agent of Claim 99, wherein the antagonist is an anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234; anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibody. 102. A pharmaceutical composition comprising the therapeutic agent of Claim 98. 103. A method of treating or preventing or ameliorating a neurological disorder; cardiovascular, endothelial or angiogenic disorder; immunological disorder; oncological disorder; bone metabolic abnormality or disorder, or embryonic lethality associated with the disruption of a gene which encodes for a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, the method comprising administering to a subject in need of such treatment whom may already have the disorder, or may be prone to have the disorder or may be in whom the disorder is to be prevented, a therapeutically effective amount of the therapeutic agent of Claim 94, or agonists or antagonists thereof, thereby effectively treating or preventing or ameliorating said disorder. 104. The method of Claim 103, wherein the neurological disorder is an increased anxiety-like response during open field activity testing. 105. The method of Claim 103, wherein the neurological disorder is a decreased anxiety-like response during open field activity testing. 106. The method of Claim 103, wherein the neurological disorder is an abnormal circadian rhythm during home-cage activity testing. 107. The method of Claim 103, wherein the neurological disorder is an enhanced motor coordination during inverted screen testing. 108. The method of Claim 103, wherein the neurological disorder is an impaired motor coordination during inverted screen testing. 109. The method of Claim 103, wherein the neurological disorder is depression, generalized anxiety disorders, attention deficit disorder, sleep disorder, hyperactivity disorder, obsessive compulsive disorder, schizophrenia, cognitive disorders, hyperalgesia or sensory disorders. 110. The method of Claim 103, wherein the eye abnormality is a retinal abnormality. 111. The method of Claim 103, wherein the eye abnormality is consistent with vision problems or blindness. 112. The method of Claim 110, wherein the retinal abnormality is consistent with retinitis pigmentosa. 113. The method of Claim 110, wherein the retinal abnormality is characterized by retinal degeneration or retinal dysplasia. 114. The method of Claim 110, wherein the retinal abnormality is consistent with retinal dysplasia, various retinopathies, including retinopathy of prematurity, retrolental fibroplasia, neovascular glaucoma, age-related macular degeneration, diabetic macular edema, corneal neovascularization, corneal graft neovascularization, corneal graft rejection, retinal/choroidal neovascularization, neovascularization of the angle (rubeosis), ocular neovascular disease, vascular restenosis, arteriovenous malformations (AVM), meningioma, hemangioma, angiofibroma, thyroid hyperplasias (including Grave's disease), corneal and other tissue transplantation, retinal artery obstruction or occlusion; retinal degeneration causing secondary atrophy of the retinal vasculature, retinitis pigmentosa, macular dystrophies, Stargardt's disease, congenital stationary night blindness, choroideremia, gyrate atrophy, Leber's congenital amaurosis, retinoschisis disorders, Wagner's syndrome, Usher syndromes, Zellweger syndrome, Saldino-Mainzer syndrome, Senior-Loken syndrome, Bardet-Biedl syndrome, Alport's syndrome, Alstrom's syndrome, Cockayne's syndrome, dysplaisa spondyloepiphysaria congentia, Flynn-Aird syndrome, Friedreich ataxia, Hallgren syndrome, Marshall syndrome, Albers-Schnoberg disease, Refsum's disease, Kearns-Sayre syndrome, Waardenburg's syndrome, Alagile syndrome, myotonic dystrophy, olivopontocerebellar atrophy, Pierre-Marie dunsdrome, Stickler syndrome, carotinemeia, cystinosis, Wolfram syndrome, Bassen-Kornzweig syndrome, abetalipoproteinemia, incontinentia pigmenti, Batten's disease, mucopolysaccharidoses, homocystinuria, or mannosidosis. 115. The method of Claim 103, wherein the eye abnormality is a cataract. 116. The method of Claim 115, wherein the cataract is a systemic disease such as human Down's syndrome, Hallerman-Streiff syndrome, Lowe syndrome, galactosemia, Marfan syndrome, Trismoy 13-15, Alport syndrome, myotonic dystrophy, Fabry disease, hypoparathroidism or Conradi syndrome. 117. The method of Claim 103, wherein the developmental abnormality comprises embryonic lethality or reduced viability. 118. The method of Claim 103, wherein the cardiovascular, endothelial or angiogenic disorders are arterial diseases, such as diabetes mellitus; papilledema; optic atrophy; atherosclerosis; angina; myocardial infarctions such as acute myocardial infarctions, cardiac hypertrophy, and heart failure such as congestive heart failure; hypertension; inflammatory vasculitides; Reynaud's disease and Reynaud's phenomenon; aneurysms and arterial restenosis; venous and lymphatic disorders such as thrombophlebitis, lymphangitis, and lymphedema; peripheral vascular disease; cancer such as vascular tumors, e.g., hemangioma (capillary and cavernous), glomus tumors, telangiectasia, bacillary angiomatosis, hemangioendothelioma, angiosarcoma, haemangiopericytoma, Kaposi's sarcoma, lymphangioma, and lymphangiosarcoma; tumor angiogenesis; trauma such as wounds, burns, and other injured tissue, implant fixation, scarring; ischemia reperfusion injury; rheumatoid arthritis; cerebrovascular disease; renal diseases such as acute renal failure, or osteoporosis. 119. The method of Claim 103, wherein the immunological disorders are systemic lupus erythematosis; rheumatoid arthritis; juvenile chronic arthritis; spondyloarthropathies; systemic sclerosis (scleroderma); idiopathic inflammatory myopathies (dermatomyositis, polymyositis); Sjogren's syndrome; systemic vasculitis; sarcoidosis; autoimmune hemolytic anemia (immune pancytopenia, paroxysmal nocturnal hemoglobinuria); autoimmune thrombocytopenia (idiopathic thrombocytopenic purpura, immune-mediated thrombocytopenia); thyroiditis (Grave's disease, Hashimoto's thyroiditis, juvenile lymphocytic thyroiditis, atrophic thyroiditis); diabetes mellitus; immune-mediated renal disease (glomerulonephritis, tubulointerstitial nephritis); demyelinating diseases of the central and peripheral nervous systems such as multiple sclerosis, idiopathic demyelinating polyneuropathy or Guillain-Barre syndrome, and chronic inflammatory demyelinating polyneuropathy; hepatobiliary diseases such as infectious hepatitis (hepatitis A, B, C, D, E and other non-hepatotropic viruses), autoimmune chronic active hepatitis, primary biliary cirrhosis, granulomatous hepatitis, and sclerosing cholangitis; inflammatory bowel disease (ulcerative colitis: Crohn's disease); gluten-sensitive enteropathy, and Whipple's disease; autoimmune or immune-mediated skin diseases including bullous skin diseases, erythema multiforme and contact dermatitis, psoriasis; allergic diseases such as asthma, allergic rhinitis, atopic dermatitis, food hypersensitivity and urticaria; immunologic diseases of the lung such as eosinophilic pneumonia, idiopathic pulmonary fibrosis and hypersensitivity pneumonitis; or transplantation associated diseases including graft rejection and graft-versus-host disease. 120. The method of Claim 103, wherein said bone metabolic abnormality or disorder is arthritis, osteoporosis or osteopetrosis. 121. A method of identifying an agent that ameliorates or modulates a neurological disorder; a cardiovascular, endothelial or angiogenic disorder; an eye abnormality; an immunological disorder; an oncological disorder; a bone metabolic abnormality or disorder; a lipid metabolic disorder; or a developmental abnormality associated with a disruption in the gene which encodes for a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, the method comprising:

[0161] (a) providing a non-human transgenic animal cell culture, each cell of said culture comprising a disruption of the gene which encodes for a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide;

[0162] (b) administering a test agent to said cell culture; and

[0163] (c) determining whether said test agent ameliorates or modulates the neurological disorder; cardiovascular, endothelial or angiogenic disorder; eye abnormality; immunological disorder; oncological disorder; bone metabolic abnormality or disorder; lipid metabolic disorder; or developmental abnormality in said cell culture.

122. The method of Claim 121, wherein the neurological disorder is an increased anxiety-like response during open field activity testing. 123. The method of Claim 121, wherein the neurological disorder is a decreased anxiety-like response during open field activity testing. 124. The method of Claim 121, wherein the neurological disorder is an abnormal circadian rhythm during home-cage activity testing. 125. The method of Claim 121, wherein the neurological disorder is an enhanced motor coordination during inverted screen testing. 126. The method of Claim 121, wherein the neurological disorder is an impaired motor coordination during inverted screen testing. 127. The method of Claim 121, wherein the neurological disorder is depression, generalized anxiety disorders, attention deficit disorder, sleep disorder, hyperactivity disorder, obsessive compulsive disorder, schizophrenia, cognitive disorders, hyperalgesia or sensory disorders. 128. The method of Claim 121, wherein the eye abnormality is a retinal abnormality. 129. The method of Claim 121, wherein the eye abnormality is consistent with vision problems or blindness. 130. The method of Claim 128, wherein the retinal abnormality is consistent with retinitis pigmentosa. 131. The method of Claim 128, wherein the retinal abnormality is characterized by retinal degeneration or retinal dysplasia. 132. The method of Claim 128, wherein the retinal abnormality is consistent with retinal dysplasia, various retinopathies, including retinopathy of prematurity, retrolental fibroplasia, neovascular glaucoma, age-related macular degeneration, diabetic macular edema, corneal neovascularization, corneal graft neovascularization, corneal graft rejection, retinal/choroidal neovascularization, neovascularization of the angle (rubeosis), ocular neovascular disease, vascular restenosis, arteriovenous malformations (AVM), meningioma, hemangioma, angiofibroma, thyroid hyperplasias (including Grave's disease), corneal and other tissue transplantation, retinal artery obstruction or occlusion; retinal degeneration causing secondary atrophy of the retinal vasculature, retinitis pigmentosa, macular dystrophies, Stargardt's disease, congenital stationary night blindness, choroideremia, gyrate atrophy, Leber's congenital amaurosis, retinoschisis disorders, Wagner's syndrome, Usher syndromes, Zellweger syndrome, Saldino-Mainzer syndrome, Senior-Loken syndrome, Bardet-Biedl syndrome, Alport's syndrome, Alstrom's syndrome, Cockayne's syndrome, dysplaisa spondyloepiphysaria congentia, Flynn-Aird syndrome, Friedreich ataxia, Hallgren syndrome, Marshall syndrome, Albers-Schnoberg disease, Refsum's disease, Kearns-Sayre syndrome, Waardenburg's syndrome, Alagile syndrome, myotonic dystrophy, olivopontocerebellar atrophy, Pierre-Marie dunsdrome, Stickler syndrome, carotinemeia, cystinosis, Wolfram syndrome, Bassen-Kornzweig syndrome, abetalipoproteinemia, incontinentia pigmenti, Batten's disease, mucopolysaccharidoses, homocystinuria, or mannosidosis. 133. The method of Claim 121, wherein the eye abnormality is a cataract. 134. The method of Claim 133, wherein the cataract is a systemic disease such as human Down's syndrome, Hallerman-Streiff syndrome, Lowe syndrome, galactosemia, Marfan syndrome, Trismoy 13-15, Alport syndrome, myotonic dystrophy, Fabry disease, hypoparathroidism or Conradi syndrome. 135. The method of Claim 121, wherein the developmental abnormality comprises embryonic lethality or reduced viability. 136. The method of Claim 121, wherein the cardiovascular, endothelial or angiogenic disorders are arterial diseases, such as diabetes mellitus; papilledema; optic atrophy; atherosclerosis; angina; myocardial infarctions such as acute myocardial infarctions, cardiac hypertrophy, and heart failure such as congestive heart failure; hypertension; inflammatory vasculitides; Reynaud's disease and Reynaud's phenomenon; aneurysms and arterial restenosis; venous and lymphatic disorders such as thrombophlebitis, lymphangitis, and lymphedema; peripheral vascular disease; cancer such as vascular tumors, e.g., hemangioma (capillary and cavernous), glomus tumors, telangiectasia, bacillary angiomatosis, hemangioendothelioma, angiosarcoma, haemangiopericytoma, Kaposi's sarcoma, lymphangioma, and lymphangiosarcoma; tumor angiogenesis; trauma such as wounds, burns, and other injured tissue, implant fixation, scarring; ischemia reperfusion injury; rheumatoid arthritis; cerebrovascular disease; renal diseases such as acute renal failure, or osteoporosis. 137. The method of Claim 121, wherein the immunological disorders are systemic lupus erythematosis; rheumatoid arthritis; juvenile chronic arthritis; spondyloarthropathies; systemic sclerosis (scleroderma); idiopathic inflammatory myopathies (dermatomyositis, polymyositis); Sjogren's syndrome; systemic vasculitis; sarcoidosis; autoimmune hemolytic anemia (immune pancytopenia, paroxysmal nocturnal hemoglobinuria); autoimmune thrombocytopenia (idiopathic thrombocytopenic purpura, immune-mediated thrombocytopenia); thyroiditis (Grave's disease, Hashimoto's thyroiditis, juvenile lymphocytic thyroiditis, atrophic thyroiditis); diabetes mellitus; immune-mediated renal disease (glomerulonephritis, tubulointerstitial nephritis); demyelinating diseases of the central and peripheral nervous systems such as multiple sclerosis, idiopathic demyelinating polyneuropathy or Guillain-Barre syndrome, and chronic inflammatory demyelinating polyneuropathy; hepatobiliary diseases such as infectious hepatitis (hepatitis A, B, C, D, E and other non-hepatotropic viruses), autoimmune chronic active hepatitis, primary biliary cirrhosis, granulomatous hepatitis, and sclerosing cholangitis; inflammatory bowel disease (ulcerative colitis: Crohn's disease); gluten-sensitive enteropathy, and Whipple's disease; autoimmune or immune-mediated skin diseases including bullous skin diseases, erythema multiforme and contact dermatitis, psoriasis; allergic diseases such as asthma, allergic rhinitis, atopic dermatitis, food hypersensitivity and urticaria; immunologic diseases of the lung such as eosinophilic pneumonia, idiopathic pulmonary fibrosis and hypersensitivity pneumonitis; or transplantation associated diseases including graft rejection and graft-versus-host disease. 138. The method of Claim 121, wherein said bone metabolic abnormality or disorder is arthritis, osteoporosis or osteopetrosis. 139. An agent identified by the method of Claim 121. 140. The agent of Claim 139 which is an agonist or antagonist of a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide. 141. The agent of Claim 140, wherein the agonist is an anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibody. 142. The agent of Claim 140, wherein the antagonist is an anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibody. 143. A therapeutic agent identified by the method of Claim 121. 144. A method of modulating a phenotype associated with a disruption of a gene which encodes for a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, the method comprising administering to a subject whom may already have the phenotype, or may be prone to have the phenotype or may be in whom the phenotype is to be prevented, an effective amount of the agent of Claim 46, or agonists or antagonists thereof, thereby effectively modulating the phenotype. 145. A method of modulating a physiological characteristic associated with a disruption of a gene which encodes for a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, the method comprising administering to a subject whom may already exhibit the physiological characteristic, or may be prone to exhibit the physiological characteristic or may be in whom the physiological characteristic is to be prevented, an effective amount of the agent of Claim 52, or agonists or antagonists thereof, thereby effectively modulating the physiological characteristic. 146. A method of modulating a behavior associated with a disruption of a gene which encodes for a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, the method comprising administering to a subject whom may already exhibit the behavior, or may be prone to exhibit the behavior or may be in whom the exhibited behavior is to be prevented, an effective amount of the agent of Claim 63, or agonists or antagonists thereof, thereby effectively modulating the behavior. 147. A method of modulating the expression of a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO285, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, the method comprising administering to a host cell expressing said PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, an effective amount of the agent of Claim 92, or agonists or antagonists thereof, thereby effectively modulating the expression of said polypeptide. 148. A method of modulating a condition associated with a disruption of a gene which encodes for a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, the method comprising administering to a subject whom may have the condition, or may be prone to have the condition or may be in whom the condition is to be prevented, a therapeutically effective amount of the therapeutic agent of Claim 98, or agonists or antagonists thereof, thereby effectively modulating the condition. 149. A method of treating or preventing or ameliorating a neurological disorder; cardiovascular, endothelial or angiogenic disorder; immunological disorder; oncological disorder; bone metabolic abnormality or disorder, or embryonic lethality associated with the disruption of a gene which encodes for a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, the method comprising administering to a non-human transgenic animal cell culture, each cell of said culture comprising a disruption of the gene which encodes for a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, a therapeutically effective amount of the agent of Claim 139, or agonists or antagonists thereof, thereby effectively treating or preventing or ameliorating said disorder.

BRIEF DESCRIPTION OF THE DRAWINGS

[0164] FIG. 1 shows a nucleotide sequence (SEQ ID NO:1) of a native sequence PRO69122 cDNA, wherein SEQ ID NO:1 is a clone designated herein as "DNA284870" (UNQ128).

[0165] FIG. 2 shows the amino acid sequence (SEQ ID NO:2) derived from the coding sequence of SEQ ID NO:1 shown in FIG. 1.

[0166] FIG. 3 shows a nucleotide sequence (SEQ ID NO:3) of a native sequence PRO204 cDNA, wherein SEQ ID NO:3 is a clone designated herein as "DNA30871-1157" (UNQ178).

[0167] FIG. 4 shows the amino acid sequence (SEQ ID NO:4) derived from the coding sequence of SEQ ID NO:3 shown in FIG. 3.

[0168] FIG. 5 shows a nucleotide sequence (SEQ ID NO:5) of a native sequence PRO214 cDNA, wherein SEQ ID NO:5 is a clone designated herein as "DNA32286-1191" (UNQ188).

[0169] FIG. 6 shows the amino acid sequence (SEQ ID NO:6) derived from the coding sequence of SEQ ID NO:5 shown in FIG. 5.

[0170] FIG. 7 shows a nucleotide sequence (SEQ ID NO:7) of a native sequence PRO222 cDNA, wherein SEQ ID NO:7 is a clone designated herein as "DNA33107-1135" (UNQ196).

[0171] FIG. 8 shows the amino acid sequence (SEQ ID NO:8) derived from the coding sequence of SEQ ID NO:7 shown in FIG. 7.

[0172] FIG. 9 shows a nucleotide sequence (SEQ ID NO:9) of a native sequence PRO234 cDNA, wherein SEQ ID NO:9 is a clone designated herein as "DNA35557-1137" (UNQ208).

[0173] FIG. 10 shows the amino acid sequence (SEQ ID NO:10) derived from the coding sequence of SEQ ID NO:9 shown in FIG. 9.

[0174] FIG. 11 shows a nucleotide sequence (SEQ ID NO:11) of a native sequence PRO265 cDNA, wherein SEQ ID NO:11 is a clone designated herein as "DNA36350-1158" (UNQ232).

[0175] FIG. 12 shows the amino acid sequence (SEQ ID NO:12) derived from the coding sequence of SEQ ID NO:11 shown in FIG. 11.

[0176] FIG. 13 shows a nucleotide sequence (SEQ ID NO:13) of a native sequence PRO309 cDNA, wherein SEQ ID NO:13 is a clone designated herein as "DNA61601-1223" (UNQ272).

[0177] FIG. 14 shows the amino acid sequence (SEQ ID NO:14) derived from the coding sequence of SEQ ID NO:13 shown in FIG. 13.

[0178] FIG. 15 shows a nucleotide sequence (SEQ ID NO:15) of a native sequence PRO332 cDNA, wherein SEQ ID NO:15 is a clone designated herein as "DNA40982-1235" (UNQ293).

[0179] FIG. 16 shows the amino acid sequence (SEQ ID NO:16) derived from the coding sequence of SEQ ID NO:15 shown in FIG. 15.

[0180] FIG. 17 shows a nucleotide sequence (SEQ ID NO:17) of a native sequence PRO342 cDNA, wherein SEQ ID NO:17 is a clone designated herein as "DNA38649" (UNQ301).

[0181] FIG. 18 shows the amino acid sequence (SEQ ID NO:18) derived from the coding sequence of SEQ ID NO:17 shown in FIG. 17.

[0182] FIG. 19 shows a nucleotide sequence (SEQ ID NO:19) of a native sequence PRO356 cDNA, wherein SEQ ID NO:19 is a clone designated herein as "DNA47470-1130P1" (UNQ313).

[0183] FIG. 20 shows the amino acid sequence (SEQ ID NO:20) derived from the coding sequence of SEQ ID NO:19 shown in FIG. 19.

[0184] FIG. 21 shows a nucleotide sequence (SEQ ID NO:21) of a native sequence PRO540 cDNA, wherein SEQ ID NO:21 is a clone designated herein as "DNA44189-1322" (UNQ341).

[0185] FIG. 22 shows the amino acid sequence (SEQ ID NO:22) derived from the coding sequence of SEQ ID NO:21 shown in FIG. 21.

[0186] FIG. 23 shows a nucleotide sequence (SEQ ID NO:23) of a native sequence PRO618 cDNA, wherein SEQ ID NO:23 is a clone designated herein as "DNA49152-1324" (UNQ354).

[0187] FIG. 24 shows the amino acid sequence (SEQ ID NO:24) derived from the coding sequence of SEQ ID NO:23 shown in FIG. 23.

[0188] FIG. 25 shows a nucleotide sequence (SEQ ID NO:25) of a native sequence PRO944 cDNA, wherein SEQ ID NO:25 is a clone designated herein as "DNA52185-1370" (UNQ481).

[0189] FIG. 26 shows the amino acid sequence (SEQ ID NO:26) derived from the coding sequence of SEQ ID NO:25 shown in FIG. 25.

[0190] FIG. 27 shows a nucleotide sequence (SEQ ID NO:27) of a native sequence PRO994 cDNA, wherein SEQ ID NO:27 is a clone designated herein as "DNA58855-1422" (UNQ518).

[0191] FIG. 28 shows the amino acid sequence (SEQ ID NO:28) derived from the coding sequence of SEQ ID NO:27 shown in FIG. 27.

[0192] FIG. 29 shows a nucleotide sequence (SEQ ID NO:29) of a native sequence PRO1079 cDNA, wherein SEQ ID NO:29 is a clone designated herein as "DNA56050-1455" (UNQ536).

[0193] FIG. 30 shows the amino acid sequence (SEQ ID NO:30) derived from the coding sequence of SEQ ID NO:29 shown in FIG. 29.

[0194] FIG. 31 shows a nucleotide sequence (SEQ ID NO:31) of a native sequence PRO1110 cDNA, wherein SEQ ID NO:31 is a clone designated herein as "DNA58727-1474" (UNQ553).

[0195] FIG. 32 shows the amino acid sequence (SEQ ID NO:32) derived from the coding sequence of SEQ ID NO:31 shown in FIG. 31.

[0196] FIG. 33 shows a nucleotide sequence (SEQ ID NO:33) of a native sequence PRO1122 cDNA, wherein SEQ ID NO:33 is a clone designated herein as "DNA62377-1381-1" (UNQ561).

[0197] FIG. 34 shows the amino acid sequence (SEQ ID NO:34) derived from the coding sequence of SEQ ID NO:33 shown in FIG. 33.

[0198] FIG. 35 shows a nucleotide sequence (SEQ ID NO:35) of a native sequence PRO1138 cDNA, wherein SEQ ID NO:35 is a clone designated herein as "DNA58850-1495" (UNQ576).

[0199] FIG. 36 shows the amino acid sequence (SEQ ID NO:36) derived from the coding sequence of SEQ ID NO:35 shown in FIG. 35.

[0200] FIG. 37 shows a nucleotide sequence (SEQ ID NO:37) of a native sequence PRO1190 cDNA, wherein SEQ ID NO:37 is a clone designated herein as "DNA59586-1520" (UNQ604).

[0201] FIG. 38 shows the amino acid sequence (SEQ ID NO:38) derived from the coding sequence of SEQ ID NO:37 shown in FIG. 37.

[0202] FIG. 39 shows a nucleotide sequence (SEQ ID NO:39) of a native sequence PRO1272 cDNA, wherein SEQ ID NO:39 is a clone designated herein as "DNA64896-1539" (UNQ642).

[0203] FIG. 40 shows the amino acid sequence (SEQ ID NO:40) derived from the coding sequence of SEQ ID NO:39 shown in FIG. 39.

[0204] FIG. 41 shows a nucleotide sequence (SEQ ID NO:41) of a native sequence PRO1286 cDNA, wherein SEQ ID NO:41 is a clone designated herein as "DNA64903-1553" (UNQ655).

[0205] FIG. 42 shows the amino acid sequence (SEQ ID NO:42) derived from the coding sequence of SEQ ID NO:41 shown in FIG. 41.

[0206] FIG. 43 shows a nucleotide sequence (SEQ ID NO:43) of a native sequence PRO1295 cDNA, wherein SEQ ID NO:43 is a clone designated herein as "DNA59218-1559" (UNQ664).

[0207] FIG. 44 shows the amino acid sequence (SEQ ID NO:44) derived from the coding sequence of SEQ ID NO:43 shown in FIG. 43.

[0208] FIG. 45 shows a nucleotide sequence (SEQ ID NO:45) of a native sequence PRO1309 cDNA, wherein SEQ ID NO:45 is a clone designated herein as "DNA59588-1571" (UNQ675).

[0209] FIG. 46 shows the amino acid sequence (SEQ ID NO:46) derived from the coding sequence of SEQ ID NO:45 shown in FIG. 45.

[0210] FIG. 47 shows a nucleotide sequence (SEQ ID NO:47) of a native sequence PRO1316 cDNA, wherein SEQ ID NO:47 is a clone designated herein as "DNA60608-1577" (UNQ682).

[0211] FIG. 48 shows the amino acid sequence (SEQ ID NO:48) derived from the coding sequence of SEQ ID NO:47 shown in FIG. 47.

[0212] FIG. 49 shows a nucleotide sequence (SEQ ID NO:49) of a native sequence PRO1383 cDNA, wherein SEQ ID NO:49 is a clone designated herein as "DNA58743-1609" (UNQ719).

[0213] FIG. 50 shows the amino acid sequence (SEQ ID NO:50) derived from the coding sequence of SEQ ID NO:49 shown in FIG. 49.

[0214] FIG. 51 shows a nucleotide sequence (SEQ ID NO:51) of a native sequence PRO1384 cDNA, wherein SEQ ID NO:51 is a clone designated herein as "DNA71159-1617" (UNQ721).

[0215] FIG. 52 shows the amino acid sequence (SEQ ID NO:52) derived from the coding sequence of SEQ ID NO:51 shown in FIG. 51.

[0216] FIG. 53 shows a nucleotide sequence (SEQ ID NO:53) of a native sequence PRO1431 cDNA, wherein SEQ ID NO:53 is a clone designated herein as "DNA73401-1633" (UNQ737).

[0217] FIG. 54 shows the amino acid sequence (SEQ ID NO:54) derived from the coding sequence of SEQ ID NO:53 shown in FIG. 53.

[0218] FIG. 55 shows a nucleotide sequence (SEQ ID NO:55) of a native sequence PRO1434 cDNA, wherein SEQ ID NO:55 is a clone designated herein as "DNA68818-2536" (UNQ739).

[0219] FIG. 56 shows the amino acid sequence (SEQ ID NO:56) derived from the coding sequence of SEQ ID NO:55 shown in FIG. 55.

[0220] FIG. 57 shows a nucleotide sequence (SEQ ID NO:57) of a native sequence PRO1475 cDNA, wherein SEQ ID NO:57 is a clone designated herein as "DNA61185-1646" (UNQ746).

[0221] FIG. 58 shows the amino acid sequence (SEQ ID NO:58) derived from the coding sequence of SEQ ID NO:57 shown in FIG. 57.

[0222] FIG. 59 shows a nucleotide sequence (SEQ ID NO:59) of a native sequence PRO1481 cDNA, wherein SEQ ID NO:59 is a clone designated herein as "DNA58732-1650" (UNQ750).

[0223] FIG. 60 shows the amino acid sequence (SEQ ID NO:60) derived from the coding sequence of SEQ ID NO:59 shown in FIG. 59.

[0224] FIG. 61 shows a nucleotide sequence (SEQ ID NO:61) of a native sequence PRO1568 cDNA, wherein SEQ ID NO:61 is a clone designated herein as "DNA68880-1676" (UNQ774).

[0225] FIG. 62 shows the amino acid sequence (SEQ ID NO:62) derived from the coding sequence of SEQ ID NO:61 shown in FIG. 61.

[0226] FIG. 63 shows a nucleotide sequence (SEQ ID NO:63) of a native sequence PRO1573 cDNA, wherein SEQ ID NO:63 is a clone designated herein as "DNA73735-1681" (UNQ779).

[0227] FIG. 64 shows the amino acid sequence (SEQ ID NO:64) derived from the coding sequence of SEQ ID NO:63 shown in FIG. 63.

[0228] FIG. 65 shows a nucleotide sequence (SEQ ID NO:65) of a native sequence PRO1599 cDNA, wherein SEQ ID NO:65 is a clone designated herein as "DNA62845-1684" (UNQ782).

[0229] FIG. 66 shows the amino acid sequence (SEQ ID NO:66) derived from the coding sequence of SEQ ID NO:65 shown in FIG. 65.

[0230] FIG. 67 shows a nucleotide sequence (SEQ ID NO:67) of a native sequence PRO1604 cDNA, wherein SEQ ID NO:67 is a clone designated herein as "DNA71286-1687" (UNQ785).

[0231] FIG. 68 shows the amino acid sequence (SEQ ID NO:68) derived from the coding sequence of SEQ ID NO:67 shown in FIG. 67.

[0232] FIG. 69 shows a nucleotide sequence (SEQ ID NO:69) of a native sequence PRO1605 cDNA, wherein SEQ ID NO:69 is a clone designated herein as "DNA77648-1688" (UNQ786).

[0233] FIG. 70 shows the amino acid sequence (SEQ ID NO:70) derived from the coding sequence of SEQ ID NO:69 shown in FIG. 69.

[0234] FIG. 71 shows a nucleotide sequence (SEQ ID NO:71) of a native sequence PRO1693 cDNA, wherein SEQ ID NO:71 is a clone designated herein as "DNA77301-1708" (UNQ803).

[0235] FIG. 72 shows the amino acid sequence (SEQ ID NO:72) derived from the coding sequence of SEQ ID NO:71 shown in FIG. 71.

[0236] FIG. 73 shows a nucleotide sequence (SEQ ID NO:73) of a native sequence PRO1753 cDNA, wherein SEQ ID NO:73 is a clone designated herein as "DNA68883-1691" (UNQ826).

[0237] FIG. 74 shows the amino acid sequence (SEQ ID NO:74) derived from the coding sequence of SEQ ID NO:73 shown in FIG. 73.

[0238] FIG. 75 shows a nucleotide sequence (SEQ ID NO:75) of a native sequence PRO1755 cDNA, wherein SEQ ID NO:75 is a clone designated herein as "DNA76396-1698" (UNQ828).

[0239] FIG. 76 shows the amino acid sequence (SEQ ID NO:76) derived from the coding sequence of SEQ ID NO:75 shown in FIG. 75.

[0240] FIG. 77 shows a nucleotide sequence (SEQ ID NO:77) of a native sequence PRO1777 cDNA, wherein SEQ ID NO:77 is a clone designated herein as "DNA71235-1706" (UNQ839).

[0241] FIG. 78 shows the amino acid sequence (SEQ ID NO:78) derived from the coding sequence of SEQ ID NO:77 shown in FIG. 77.

[0242] FIG. 79 shows a nucleotide sequence (SEQ ID NO:79) of a native sequence PRO1788 cDNA, wherein SEQ ID NO:79 is a clone designated herein as "DNA77652-2505" (UNQ850).

[0243] FIG. 80 shows the amino acid sequence (SEQ ID NO:80) derived from the coding sequence of SEQ ID NO:79 shown in FIG. 79.

[0244] FIG. 81 shows a nucleotide sequence (SEQ ID NO:81) of a native sequence PRO1864 cDNA, wherein SEQ ID NO:81 is a clone designated herein as "DNA45409-2511" (UNQ855).

[0245] FIG. 82 shows the amino acid sequence (SEQ ID NO:82) derived from the coding sequence of SEQ ID NO:81 shown in FIG. 81.

[0246] FIG. 83 shows a nucleotide sequence (SEQ ID NO:83) of a native sequence PRO1925 cDNA, wherein SEQ ID NO:83 is a clone designated herein as "DNA82302-2529" (UNQ904).

[0247] FIG. 84 shows the amino acid sequence (SEQ ID NO:84) derived from the coding sequence of SEQ ID NO:83 shown in FIG. 83.

[0248] FIG. 85 shows a nucleotide sequence (SEQ ID NO:85) of a native sequence PRO1926 cDNA, wherein SEQ ID NO:85 is a clone designated herein as "DNA82340-2530" (UNQ905).

[0249] FIG. 86 shows the amino acid sequence (SEQ ID NO:86) derived from the coding sequence of SEQ ID NO:85 shown in FIG. 85.

[0250] FIG. 87 shows a nucleotide sequence (SEQ ID NO:87) of a native sequence PRO3566 cDNA, wherein SEQ ID NO:87 is a clone designated herein as "DNA59844-2542" (UNQ1840).

[0251] FIG. 88 shows the amino acid sequence (SEQ ID NO:88) derived from the coding sequence of SEQ ID NO:87 shown in FIG. 87.

[0252] FIG. 89 shows a nucleotide sequence (SEQ ID NO:89) of a native sequence PRO4330 cDNA, wherein SEQ ID NO:89 is a clone designated herein as "DNA90842-2574" (UNQ1886).

[0253] FIG. 90 shows the amino acid sequence (SEQ ID NO:90) derived from the coding sequence of SEQ ID NO:89 shown in FIG. 89.

[0254] FIG. 91 shows a nucleotide sequence (SEQ ID NO:91) of a native sequence PRO4423 cDNA, wherein SEQ ID NO:91 is a clone designated herein as "DNA96893-2621" (UNQ1940).

[0255] FIG. 92 shows the amino acid sequence (SEQ ID NO:92) derived from the coding sequence of SEQ ID NO:91 shown in FIG. 91.

[0256] FIG. 93 shows a nucleotide sequence (SEQ ID NO:93) of a native sequence PRO36935 cDNA, wherein SEQ ID NO:93 is a clone designated herein as "DNA336539" (UNQ2257).

[0257] FIG. 94 shows the amino acid sequence (SEQ ID NO:94) derived from the coding sequence of SEQ ID NO:93 shown in FIG. 93.

[0258] FIG. 95 shows a nucleotide sequence (SEQ ID NO:95) of a native sequence PRO4977 cDNA, wherein SEQ ID NO:95 is a clone designated herein as "DNA62849-2647" (UNQ2420).

[0259] FIG. 96 shows the amino acid sequence (SEQ ID NO:96) derived from the coding sequence of SEQ ID NO:95 shown in FIG. 95.

[0260] FIG. 97 shows a nucleotide sequence (SEQ ID NO:97) of a native sequence PRO4979 cDNA, wherein SEQ ID NO:97 is a clone designated herein as "DNA222844" (UNQ2421).

[0261] FIG. 98 shows the amino acid sequence (SEQ ID NO:98) derived from the coding sequence of SEQ ID NO:97 shown in FIG. 97.

[0262] FIG. 99 shows a nucleotide sequence (SEQ ID NO:99) of a native sequence PRO4980 cDNA, wherein SEQ ID NO:99 is a clone designated herein as "DNA97003-2649" (UNQ2422).

[0263] FIG. 100 shows the amino acid sequence (SEQ ID NO:100) derived from the coding sequence of SEQ ID NO:99 shown in FIG. 99.

[0264] FIG. 101 shows a nucleotide sequence (SEQ ID NO:101) of a native sequence PRO4981 cDNA, wherein SEQ ID NO:101 is a clone designated herein as "DNA94849-2960" (UNQ2423).

[0265] FIG. 102 shows the amino acid sequence (SEQ ID NO:102) derived from the coding sequence of SEQ ID NO:101 shown in FIG. 101.

[0266] FIG. 103 shows a nucleotide sequence (SEQ ID NO:103) of a native sequence PRO5801 cDNA, wherein SEQ ID NO:103 is a clone designated herein as "DNA115291-2681" (UNQ2501).

[0267] FIG. 104 shows the amino acid sequence (SEQ ID NO:104) derived from the coding sequence of SEQ ID NO:103 shown in FIG. 103.

[0268] FIG. 105 shows a nucleotide sequence (SEQ ID NO:105) of a native sequence PRO5995 cDNA, wherein SEQ ID NO:105 is a clone designated herein as "DNA96988-2685" (UNQ2507).

[0269] FIG. 106 shows the amino acid sequence (SEQ ID NO:106) derived from the coding sequence of SEQ ID NO:105 shown in FIG. 105.

[0270] FIG. 107 shows a nucleotide sequence (SEQ ID NO:107) of a native sequence PRO6001 cDNA, wherein SEQ ID NO:107 is a clone designated herein as "DNA98380" (UNQ2512).

[0271] FIG. 108 shows the amino acid sequence (SEQ ID NO:108) derived from the coding sequence of SEQ ID NO:107 shown in FIG. 107.

[0272] FIG. 109 shows a nucleotide sequence (SEQ ID NO:109) of a native sequence PRO6095cDNA, wherein SEQ ID NO:109 is a clone designated herein as "DNA105680-2710" (UNQ2543).

[0273] FIG. 110 shows the amino acid sequence (SEQ ID NO:110) derived from the coding sequence of SEQ ID NO:109 shown in FIG. 109.

[0274] FIG. 111 shows a nucleotide sequence (SEQ ID NO:111) of a native sequence PRO6182 cDNA, wherein SEQ ID NO:111 is a clone designated herein as "DNA110700-2716" (UNQ2553).

[0275] FIG. 112 shows the amino acid sequence (SEQ ID NO:112) derived from the coding sequence of SEQ ID NO:111 shown in FIG. 111.

[0276] FIG. 113 shows a nucleotide sequence (SEQ ID NO:113) of a native sequence PRO7170 cDNA, wherein SEQ ID NO:113 is a clone designated herein as "DNA108722-2743" (UNQ2782).

[0277] FIG. 114 shows the amino acid sequence (SEQ ID NO:114) derived from the coding sequence of SEQ ID NO:113 shown in FIG. 113.

[0278] FIG. 115 shows a nucleotide sequence (SEQ ID NO:115) of a native sequence PRO7171 cDNA, wherein SEQ ID NO:115 is a clone designated herein as "DNA108670-2744" (UNQ2783).

[0279] FIG. 116 shows the amino acid sequence (SEQ ID NO:116) derived from the coding sequence of SEQ ID NO:115 shown in FIG. 115.

[0280] FIG. 117 shows a nucleotide sequence (SEQ ID NO:117) of a native sequence PRO7436 cDNA, wherein SEQ ID NO:117 is a clone designated herein as "DNA119535-2756" (UNQ2973).

[0281] FIG. 118 shows the amino acid sequence (SEQ ID NO:118) derived from the coding sequence of SEQ ID NO:117 shown in FIG. 117.

[0282] FIG. 119 shows a nucleotide sequence (SEQ ID NO:119) of a native sequence PRO9912 cDNA, wherein SEQ ID NO:119 is a clone designated herein as "DNA108700-2802" (UNQ3077).

[0283] FIG. 120 shows the amino acid sequence (SEQ ID NO:120) derived from the coding sequence of SEQ ID NO:119 shown in FIG. 119.

[0284] FIG. 121 shows a nucleotide sequence (SEQ ID NO:121) of a native sequence PRO9917 cDNA, wherein SEQ ID NO:121 is a clone designated herein as "DNA119474-2803" (UNQ3079).

[0285] FIG. 122 shows the amino acid sequence (SEQ ID NO:122) derived from the coding sequence of SEQ ID NO:121 shown in FIG. 121.

[0286] FIG. 123 shows a nucleotide sequence (SEQ ID NO:123) of a native sequence PRO37337 cDNA, wherein SEQ ID NO:123 is a clone designated herein as "DNA226874" (UNQ5291).

[0287] FIG. 124 shows the amino acid sequence (SEQ ID NO:124) derived from the coding sequence of SEQ ID NO:123 shown in FIG. 123.

[0288] FIG. 125 shows a nucleotide sequence (SEQ ID NO:125) of a native sequence PRO37496 cDNA, wherein SEQ ID NO:125 is a clone designated herein as "DNA227033" (UNQ5407).

[0289] FIG. 126 shows the amino acid sequence (SEQ ID NO:126) derived from the coding sequence of SEQ ID NO:125 shown in FIG. 125.

[0290] FIG. 127 shows a nucleotide sequence (SEQ ID NO:127) of a native sequence PRO19646 cDNA, wherein SEQ ID NO:127 is a clone designated herein as "DNA145841-2868" (UNQ5827).

[0291] FIG. 128 shows the amino acid sequence (SEQ ID NO:128) derived from the coding sequence of SEQ ID NO:127 shown in FIG. 127.

[0292] FIG. 129 shows a nucleotide sequence (SEQ ID NO:129) of a native sequence PRO21718 cDNA, wherein SEQ ID NO:129 is a clone designated herein as "DNA188342" (UNQ5893).

[0293] FIG. 130 shows the amino acid sequence (SEQ ID NO:130) derived from the coding sequence of SEQ ID NO:129 shown in FIG. 129.

[0294] FIG. 131 shows a nucleotide sequence (SEQ ID NO:131) of a native sequence PRO19820 cDNA, wherein SEQ ID NO:131 is a clone designated herein as "DNA149911-2885" (UNQ5926).

[0295] FIG. 132 shows the amino acid sequence (SEQ ID NO:132) derived from the coding sequence of SEQ ID NO:131 shown in FIG. 131.

[0296] FIG. 133 shows a nucleotide sequence (SEQ ID NO:133) of a native sequence PRO21201 cDNA, wherein SEQ ID NO:133 is a clone designated herein as "DNA168028-2956" (UNQ6098).

[0297] FIG. 134 shows the amino acid sequence (SEQ ID NO:134) derived from the coding sequence of SEQ ID NO:133 shown in FIG. 133.

[0298] FIG. 135 shows a nucleotide sequence (SEQ ID NO:135) of a native sequence PRO20026 cDNA, wherein SEQ ID NO:135 is a clone designated herein as "DNA154095-2998" (UNQ6115).

[0299] FIG. 136 shows the amino acid sequence (SEQ ID NO:136) derived from the coding sequence of SEQ ID NO:135 shown in FIG. 135.

[0300] FIG. 137 shows a nucleotide sequence (SEQ ID NO:137) of a native sequence PRO20110 cDNA, wherein SEQ ID NO:137 is a clone designated herein as "DNA166819-1381R1P1" (UNQ6129).

[0301] FIG. 138 shows the amino acid sequence (SEQ ID NO:138) derived from the coding sequence of SEQ ID NO:137 shown in FIG. 137.

[0302] FIG. 139 shows a nucleotide sequence (SEQ ID NO:139) of a native sequence PRO23203 cDNA, wherein SEQ ID NO:139 is a clone designated herein as "DNA185171-2994" (UNQ6507).

[0303] FIG. 140 shows the amino acid sequence (SEQ ID NO:140) derived from the coding sequence of SEQ ID NO:139 shown in FIG. 139.

[0304] FIG. 141 shows a nucleotide sequence (SEQ ID NO:141) of a native sequence PRO35250 cDNA, wherein SEQ ID NO:141 is a clone designated herein as "DNA171732-3100" (UNQ9574).

[0305] FIG. 142 shows the amino acid sequence (SEQ ID NO:142) derived from the coding sequence of SEQ ID NO:141 shown in FIG. 141.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

I. Definitions

[0306] The terms "PRO polypeptide" and "PRO" as used herein and when immediately followed by a numerical designation refer to various polypeptides, wherein the complete designation (i.e., PRO/number) refers to specific polypeptide sequences as described herein. The terms "PRO/number polypeptide" and "PRO/number" wherein the term "number" is provided as an actual numerical designation as used herein encompass native sequence polypeptides and polypeptide variants (which are further defined herein). The PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides described herein may be isolated from a variety of sources, such as from human tissue types or from another source, or prepared by recombinant or synthetic methods. The term "PRO polypeptide" refers to each individual PRO/number polypeptide disclosed herein. All disclosures in this specification which refer to the "PRO polypeptide" refer to each of the polypeptides individually as well as jointly. For example, descriptions of the preparation of, purification of, derivation of, formation of antibodies to or against, administration of, compositions containing, treatment of a disease with, etc., pertain to each polypeptide of the invention individually. The term "PRO polypeptide" also includes variants of the PRO/number polypeptides disclosed herein.

[0307] A "native sequence PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO1110, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide" comprises a polypeptide having the same amino acid sequence as the corresponding PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO1110, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272; PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide derived from nature. Such native sequence PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides can be isolated from nature or can be produced by recombinant or synthetic means. The term "native sequence PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide" specifically encompasses naturally-occurring truncated or secreted forms of the specific PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide (e.g., an extracellular domain sequence), naturally-occurring variant forms (e.g., alternatively spliced forms) and naturally-occurring allelic variants of the polypeptide. The invention provides native sequence PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides disclosed herein which are mature or full-length native sequence polypeptides comprising the full-length amino acids sequences shown in the accompanying figures. Start and stop codons are shown in bold font and underlined in the figures. However, while the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide disclosed in the accompanying figures are shown to begin with methionine residues designated herein as amino acid position 1 in the figures, it is conceivable and possible that other methionine residues located either upstream or downstream from the amino acid position 1 in the figures may be employed as the starting amino acid residue for the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides.

[0308] The PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide "extracellular domain" or "ECD" refers to a form of the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide which is essentially free of the transmembrane and cytoplasmic domains. Ordinarily, a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide ECD will have less than 1% of such transmembrane and/or cytoplasmic domains and preferably, will have less than 0.5% of such domains. It will be understood that any transmembrane domains identified for the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981; PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides of the present invention are identified pursuant to criteria routinely employed in the art for identifying that type of hydrophobic domain. The exact boundaries of a transmembrane domain may vary but most likely by no more than about 5 amino acids at either end of the domain as initially identified herein. Optionally, therefore, an extracellular domain of a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide may contain from about 5 or fewer amino acids on either side of the transmembrane domain/extracellular domain boundary as identified in the Examples or specification and such polypeptides, with or without the associated signal peptide, and nucleic acid encoding them, are contemplated by the present invention.

[0309] The approximate location of the "signal peptides" of the various PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides disclosed herein are shown in the present specification and/or the accompanying figures. It is noted, however, that the C-terminal boundary of a signal peptide may vary, but most likely by no more than about 5 amino acids on either side of the signal peptide C-terminal boundary as initially identified herein, wherein the C-terminal boundary of the signal peptide may be identified pursuant to criteria routinely employed in the art for identifying that type of amino acid sequence element (e.g., Nielsen et al., Prot. Eng. 10:1-6 (1997) and von Heinje et al., Nucl. Acids. Res. 14:4683-4690 (1986)). Moreover, it is also recognized that, in some cases, cleavage of a signal sequence from a secreted polypeptide is not entirely uniform, resulting in more than one secreted species. These mature polypeptides, where the signal peptide is cleaved within no more than about 5 amino acids on either side of the C-terminal boundary of the signal peptide as identified herein, and the polynucleotides encoding them, are contemplated by the present invention.

[0310] "PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide variant" means a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, preferably an active PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO13$4, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718; PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, as defined herein having at least about 80% amino acid sequence identity with a full-length native sequence PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide sequence as disclosed herein, a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide sequence lacking the signal peptide as disclosed herein, an extracellular domain of a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, with or without the signal peptide, as disclosed herein or any other fragment of a full-length PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide sequence as disclosed herein (such as those encoded by a nucleic acid that represents only a portion of the complete coding sequence for a full-length PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide). Such PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide variants include, for instance, PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides wherein one or more amino acid residues are added, or deleted, at the N- or C-terminus of the full-length native amino acid sequence. Ordinarily, a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide variant will have or will have at least about 80% amino acid sequence identity, alternatively will have or will have at least about 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity, to a full-length native sequence PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide sequence as disclosed herein, a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide sequence lacking the signal peptide as disclosed herein, an extracellular domain of a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, with or without the signal peptide, as disclosed herein or any other specifically defined fragment of a full-length PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide sequence as disclosed herein. Ordinarily, PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 variant polypeptides are or are at least about 10 amino acids in length, alternatively are or are at least about 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600 amino acids in length, or more. Optionally, PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 variant polypeptides will have no more than one conservative amino acid substitution as compared to the native PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide sequence, alternatively will have or will have no more than 2, 3, 4, 5, 6, 7, 8, 9, or 10 conservative amino acid substitution as compared to the native PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide sequence.

[0311] "Percent (%) amino acid sequence identity" with respect to the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide sequences identified herein is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the specific PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. For purposes herein, however, % amino acid sequence identity values are generated using the sequence comparison computer program ALIGN-2, wherein the complete source code for the ALIGN-2 program is provided in Table 1 below. The ALIGN-2 sequence comparison computer program was authored by Genentech, Inc. and the source code shown in Table 1 below has been filed with user documentation in the U.S. Copyright Office, Washington D.C., 20559, where it is registered under U.S. Copyright Registration No. TXU510087. The ALIGN-2 program is publicly available through Genentech, Inc., South San Francisco, Calif. or may be compiled from the source code provided in Table 1 below. The ALIGN-2 program should be compiled for use on a UNIX operating system, preferably digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary.

[0312] In situations where ALIGN-2 is employed for amino acid sequence comparisons, the % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B (which can alternatively be phrased as a given amino acid sequence A that has or comprises a certain % amino acid sequence identity to, with, or against a given amino acid sequence B) is calculated as follows:

100 times the fraction X/Y

where X is the number of amino acid residues scored as identical matches by the sequence alignment program ALIGN-2 in that program's alignment of A and B, and where Y is the total number of amino acid residues in B. It will be appreciated that where the length of amino acid sequence A is not equal to the length of amino acid sequence B, the % amino acid sequence identity of A to B will not equal the % amino acid sequence identity of B to A. As examples of % amino acid sequence identity calculations using this method, Tables 2 and 3 demonstrate how to calculate the % amino acid sequence identity of the amino acid sequence designated "Comparison Protein" to the amino acid sequence designated "PRO", wherein "PRO" represents the amino acid sequence of a hypothetical PRO polypeptide of interest, "Comparison Protein" represents the amino acid sequence of a polypeptide against which the "PRO" polypeptide of interest is being compared, and "X," "Y" and "Z" each represent different hypothetical amino acid residues. Unless specifically stated otherwise, all % amino acid sequence identity values used herein are obtained as described in the immediately preceding paragraph using the ALIGN-2 computer program.

[0313] "PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 variant polynucleotide" or "PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 variant nucleic acid sequence" means a nucleic acid molecule which encodes a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, preferably an active PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, as defined herein and which has at least about 80% nucleic acid sequence identity with a nucleotide acid sequence encoding a full-length native sequence PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide sequence as disclosed herein, a full-length native sequence PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide sequence lacking the signal peptide as disclosed herein, an extracellular domain of a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, with or without the signal peptide, as disclosed herein or any other fragment of a full-length PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide sequence as disclosed herein (such as those encoded by a nucleic acid that represents only a portion of the complete coding sequence for a full-length PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122; PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide). Ordinarily, a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 variant polynucleotide will have or will have at least about 80% nucleic acid sequence identity, alternatively will have or will have at least about 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% nucleic acid sequence identity with a nucleic acid sequence encoding a full-length native sequence PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide sequence as disclosed herein, a full-length native sequence PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide sequence lacking the signal peptide as disclosed herein, an extracellular domain of a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, with or without the signal sequence, as disclosed herein or any other fragment of a full-length PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide sequence as disclosed herein. Variants do not encompass the native nucleotide sequence.

[0314] Ordinarily, PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 variant polynucleotides are or are at least about 5 nucleotides in length, alternatively are or are at least about 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, or 1000 nucleotides in length, wherein in this context the term "about" means the referenced nucleotide sequence length plus or minus 10% of that referenced length.

[0315] "Percent (%) nucleic acid sequence identity" with respect to PRO69122-, PRO204-, PRO214-, PRO222-, PRO234-, PRO265-, PRO309-, PRO332-, PRO342-, PRO356-, PRO540-, PRO618-, PRO944-, PRO994-, PRO1079, PRO1110-, PRO1122-, PRO1138-, PRO1190-, PRO1272-, PRO1286-, PRO1295-, PRO1309-, PRO1316-, PRO1383-, PRO1384-, PRO1431-, PRO1434-, PRO1475-, PRO1481-, PRO1568-, PRO1573-, PRO1599-, PRO1604-, PRO1605-, PRO1693-, PRO1753-, PRO1755-, PRO1777-, PRO1788-, PRO1864-, PRO1925-, PRO1926-, PRO3566-, PRO4330-, PRO4423-, PRO36935-, PRO4977-, PRO4979-, PRO4980-, PRO4981-, PRO5801-, PRO5995-, PRO6001-, PRO6095-, PRO6182-, PRO7170-, PRO7171-, PRO7436-, PRO9912-, PRO9917-, PRO37337-, PRO37496-, PRO19646-, PRO21718-, PRO19820-, PRO21201-, PRO20026-, PRO20110-, PRO23203- or PRO35250-encoding nucleic acid sequences identified herein is defined as the percentage of nucleotides in a candidate sequence that are identical with the nucleotides in the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 nucleic acid sequence of interest, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity. Alignment for purposes of determining percent nucleic acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. For purposes herein, however, % nucleic acid sequence identity values are generated using the sequence comparison computer program ALIGN-2, wherein the complete source code for the ALIGN-2 program is provided in Table 1 below. The ALIGN-2 sequence comparison computer program was authored by Genentech, Inc. and the source code shown in Table 1 below has been filed with user documentation in the U.S. Copyright Office, Washington D.C., 20559, where it is registered under U.S. Copyright Registration No. TXU510087. The ALIGN-2 program is publicly available through Genentech, Inc., South San Francisco, Calif. or may be compiled from the source code provided in Table 1 below. The ALIGN-2 program should be compiled for use on a UNIX operating system, preferably digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary.

[0316] In situations where ALIGN-2 is employed for nucleic acid sequence comparisons, the % nucleic acid sequence identity of a given nucleic acid sequence C to, with, or against a given nucleic acid sequence D (which can alternatively be phrased as a given nucleic acid sequence C that has or comprises a certain % nucleic acid sequence identity to, with, or against a given nucleic acid sequence D) is calculated as follows:

100 times the fraction W/Z

where W is the number of nucleotides scored as identical matches by the sequence alignment program ALIGN-2 in that program's alignment of C and D, and where Z is the total number of nucleotides in D. It will be appreciated that where the length of nucleic acid sequence C is not equal to the length of nucleic acid sequence D, the % nucleic acid sequence identity of C to D will not equal the % nucleic acid sequence identity of D to C. As examples of % nucleic acid sequence identity calculations, Tables 4 and 5, demonstrate how to calculate the % nucleic acid sequence identity of the nucleic acid sequence designated "Comparison DNA" to the nucleic acid sequence designated "PRO-DNA", wherein "PRO-DNA" represents a hypothetical PRO-encoding nucleic acid sequence of interest, "Comparison DNA" represents the nucleotide sequence of a nucleic acid molecule against which the "PRO-DNA" nucleic acid molecule of interest is being compared, and "N", "L" and "V" each represent different hypothetical nucleotides. Unless specifically stated otherwise, all % nucleic acid sequence identity values used herein are obtained as described in the immediately preceding paragraph using the ALIGN-2 computer program.

[0317] The invention also provides PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 variant polynucleotides which are nucleic acid molecules that encode a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide and which are capable of hybridizing, preferably under stringent hybridization and wash conditions, to nucleotide sequences encoding a full-length PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide as disclosed herein. PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO148-1, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 variant polypeptides may be those that are encoded by a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 variant polynucleotide.

[0318] The term "full-length coding region" when used in reference to a nucleic acid encoding a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide refers to the sequence of nucleotides which encode the full-length PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide of the invention (which is often shown between start and stop codons, inclusive thereof, in the accompanying figures). The term "full-length coding region" when used in reference to an ATCC deposited nucleic acid refers to the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide-encoding portion of the cDNA that is inserted into the vector deposited with the ATCC (which is often shown between start and stop codons, inclusive thereof, in the accompanying figures).

[0319] "Isolated," when used to describe the various polypeptides disclosed herein, means polypeptide that has been identified and separated and/or recovered from a component of its natural environment. Contaminant components of its natural environment are materials that would typically interfere with diagnostic or therapeutic uses for the polypeptide, and may include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes. The invention provides that the polypeptide will be purified (1) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use of a spinning cup sequenator, or (2) to homogeneity by SDS-PAGE under non-reducing or reducing conditions using Coomassie blue or, preferably, silver stain. Isolated polypeptide includes polypeptide in situ within recombinant cells, since at least one component of the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide natural environment will not be present. Ordinarily, however, isolated polypeptide will be prepared by at least one purification step.

[0320] An "isolated" PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide-encoding nucleic acid or other polypeptide-encoding nucleic acid is a nucleic acid molecule that is identified and separated from at least one contaminant nucleic acid molecule with which it is ordinarily associated in the natural source of the polypeptide-encoding nucleic acid. An isolated polypeptide-encoding nucleic acid molecule is other than in the forth or setting in which it is found in nature. Isolated polypeptide-encoding nucleic acid molecules therefore are distinguished from the specific polypeptide-encoding nucleic acid molecule as it exists in natural cells. However, an isolated polypeptide-encoding nucleic acid molecule includes polypeptide-encoding nucleic acid molecules contained in cells that ordinarily express the polypeptide where, for example, the nucleic acid molecule is in a chromosomal location different from that of natural cells.

[0321] The term "control sequences" refers to DNA sequences necessary for the expression of an operably linked coding sequence in a particular host organism. The control sequences that are suitable for prokaryotes, for example, include a promoter, optionally an operator sequence, and a ribosome binding site. Eukaryotic cells are known to utilize promoters, polyadenylation signals, and enhancers.

[0322] Nucleic acid is "operably linked" when it is placed into a functional relationship with another nucleic acid sequence. For example, DNA for a presequence or secretory leader is operably linked to DNA for a polypeptide if it is expressed as a preprotein that participates in the secretion of the polypeptide; a promoter or enhancer is operably linked to a coding sequence if it affects the transcription of the sequence; or a ribosome binding site is operably linked to a coding sequence if it is positioned so as to facilitate translation. Generally, "operably linked" means that the DNA sequences being linked are contiguous, and, in the case of a secretory leader, contiguous and in reading phase. However, enhancers do not have to be contiguous. Linking is accomplished by ligation at convenient restriction sites. If such sites do not exist, the synthetic oligonucleotide adaptors or linkers are used in accordance with conventional practice.

[0323] "Stringency" of hybridization reactions is readily determinable by one of ordinary skill in the art, and generally is an empirical calculation dependent upon probe length, washing temperature, and salt concentration. In general, longer probes require higher temperatures for proper annealing, while shorter probes need lower temperatures. Hybridization generally depends on the ability of denatured DNA to reanneal when complementary strands are present in an environment below their melting temperature. The higher the degree of desired homology between the probe and hybridizable sequence, the higher the relative temperature which can be used. As a result, it follows that higher relative temperatures would tend to make the reaction conditions more stringent, while lower temperatures less so. For additional details and explanation of stringency of hybridization reactions, see Ausubel et al., Current Protocols in Molecular Biology, Wiley Interscience Publishers, (1995).

[0324] "Stringent conditions" or "high stringency conditions", as defined herein, may be identified by those that: (1) employ low ionic strength and high temperature for washing, for example 0.015 M sodium chloride/0.0015 M sodium citrate/0.1% sodium dodecyl sulfate at 50.degree. C.; (2) employ during hybridization a denaturing agent, such as formamide, for example, 50% (v/v) formamide with 0.1% bovine serum albumin/0.1% Ficoll/0.1% polyvinylpyrrolidone/50 mM sodium phosphate buffer at pH 6.5 with 750 mM sodium chloride, 75 mM sodium citrate at 42.degree. C.; or (3) employ 50% formamide, 5.times.SSC (0.75 M NaCl, 0.075 M sodium citrate), 50 mM sodium phosphate (pH 6.8), 0.1% sodium pyrophosphate, 5.times.Denhardt's solution, sonicated salmon sperm DNA (50 .mu.g/ml), 0.1% SDS, and 10% dextran sulfate at 42.degree. C., with washes at 42.degree. C. in 0.2.times.SSC (sodium chloride/sodium citrate) and 50% formamide at 55.degree. C., followed by a high-stringency wash consisting of 0.1.times.SSC containing EDTA at 55.degree. C.

[0325] "Moderately stringent conditions" may be identified as described by Sambrook et al., Molecular Cloning: A Laboratory Manual, New York: Cold Spring Harbor Press, 1989, and include the use of washing solution and hybridization conditions (e.g., temperature, ionic strength and % SDS) less stringent that those described above. An example of moderately stringent conditions is overnight incubation at 37.degree. C. in a solution comprising: 20% formamide, 5.times.SSC (150 mM NaCl, 15 mM trisodium citrate), 50 mM sodium phosphate (pH 7.6), 5.times.Denhardt's solution, 10% dextran sulfate, and 20 mg/ml denatured sheared salmon sperm DNA, followed by washing the filters in 1.times.SSC at about 37-50.degree. C. The skilled artisan will recognize how to adjust the temperature, ionic strength, etc. as necessary to accommodate factors such as probe length and the like.

[0326] The term "epitope tagged" when used herein refers to a chimeric polypeptide comprising a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide fused to a "tag polypeptide". The tag polypeptide has enough residues to provide an epitope against which an antibody can be made, yet is short enough such that it does not interfere with activity of the polypeptide to which it is fused. The tag polypeptide preferably also is fairly unique so that the antibody does not substantially cross-react with other epitopes. Suitable tag polypeptides generally have at least six amino acid residues and usually between about 8 and 50 amino acid residues (preferably, between about 10 and 20 amino acid residues).

[0327] "Active" or "activity" for the purposes herein refers to form(s) of a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide which retain a biological and/or an immunological activity of native or naturally-occurring PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, wherein "biological" activity refers to a biological function (either inhibitory or stimulatory) caused by a native or naturally-occurring PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide other than the ability to induce the production of an antibody against an antigenic epitope possessed by a native or naturally-occurring PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide and an "immunological" activity refers to the ability to induce the production of an antibody against an antigenic epitope possessed by a native or naturally-occurring PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide.

[0328] The term "antagonist" is used in the broadest sense [unless otherwise qualified], and includes any molecule that partially or fully blocks, inhibits, or neutralizes a biological activity of a native PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide disclosed herein. In a similar manner, the term "agonist" is used in the broadest sense [unless otherwise qualified] and includes any molecule that mimics a biological activity of a native PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide disclosed herein. Suitable agonist or antagonist molecules specifically include agonist or antagonist antibodies or antibody fragments, fragments or amino acid sequence variants of native PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides, peptides, antisense oligonucleotides, small organic molecules, etc. Methods for identifying agonists or antagonists of a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide may comprise contacting a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO 1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide with a candidate agonist or antagonist molecule and measuring a detectable change in one or more biological activities normally associated with the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide.

[0329] "Treating" or "treatment" or "alleviation" refers to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) the targeted pathologic condition or disorder. A subject in need of treatment may already have the disorder, or may be prone to have the disorder or may be in whom the disorder is to be prevented.

[0330] "Chronic" administration refers to administration of the agent(s) in a continuous mode as opposed to an acute mode, so as to maintain the initial therapeutic effect (activity) for an extended period of time. "Intermittent" administration is treatment that is not consecutively done without interruption, but rather is cyclic in nature.

[0331] "Mammal" for purposes of treatment refers to any animal classified as a mammal, including humans, rodents such as rats or mice, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, cats, cattle, horses, sheep, pigs, goats, rabbits, etc. Preferably, the mammal is human.

[0332] Administration "in combination with" one or more further therapeutic agents includes simultaneous (concurrent) and consecutive administration in any order.

[0333] "Carriers" as used herein include pharmaceutically acceptable carriers, excipients, or stabilizers which are nontoxic to the cell or mammal being exposed thereto at the dosages and concentrations employed. Often the physiologically acceptable carrier is an aqueous pH buffered solution. Examples of physiologically acceptable carriers include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptide; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and/or nonionic surfactants such as TWEEN.TM., polyethylene glycol (PEG), and PLURONICS.TM..

[0334] By "solid phase" is meant a non-aqueous matrix to which the antibody of the present invention can adhere. Examples of solid phases encompassed herein include those formed partially or entirely of glass (e.g., controlled pore glass), polysaccharides (e.g., agarose), polyacrylamides, polystyrene, polyvinyl alcohol and silicones. Depending on the context, the solid phase can comprise the well of an assay plate; in others it is a purification column (e.g., an affinity chromatography column). This term also includes a discontinuous solid phase of discrete particles, such as those described in U.S. Pat. No. 4,275,149.

[0335] A "liposome" is a small vesicle composed of various types of lipids, phospholipids and/or surfactant which is useful for delivery of a drug (such as a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, P1201693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide or antibody thereto) to a mammal. The components of the liposome are commonly arranged in a bilayer formation, similar to the lipid arrangement of biological membranes.

[0336] A "small molecule" is defined herein to have a molecular weight below about 500 Daltons.

[0337] An "effective amount" of a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, an anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-1-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibody, a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 binding oligopeptide, a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 binding organic molecule or an agonist or antagonist thereof as disclosed herein is an amount sufficient to carry out a specifically stated purpose. An "effective amount" may be determined empirically and in a routine manner, in relation to the stated purpose.

[0338] The term "therapeutically effective amount" refers to an amount of an anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibody, a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 binding oligopeptide, a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 binding organic molecule or other drug effective to "treat" a disease or disorder in a subject or mammal. In the case of cancer, the therapeutically effective amount of the drug may reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; and/or relieve to some extent one or more of the symptoms associated with the cancer. See the definition herein of "treating". To the extent the drug may prevent growth and/or kill existing cancer cells, it may be cytostatic and/or cytotoxic.

[0339] The phrases "cardiovascular, endothelial and angiogenic disorder", "cardiovascular, endothelial and angiogenic dysfunction", "cardiovascular, endothelial or angiogenic disorder" and "cardiovascular, endothelial or angiogenic dysfunction" are used interchangeably and refer in part to systemic disorders that affect vessels, such as diabetes mellitus, as well as diseases of the vessels themselves, such as of the arteries, capillaries, veins, and/or lymphatics. This would include indications that stimulate angiogenesis and/or cardiovascularization, and those that inhibit angiogenesis and/or cardiovascularization. Such disorders include, for example, arterial disease, such as atherosclerosis, hypertension, inflammatory vasculitides, Reynaud's disease and Reynaud's phenomenon, aneurysms, and arterial restenosis; venous and lymphatic disorders such as thrombophlebitis, lymphangitis, and lymphedema; and other vascular disorders such as peripheral vascular disease, cancer such as vascular tumors, e.g., hemangioma (capillary and cavernous), glomus tumors, telangiectasia, bacillary angiomatosis, hemangioendothelioma, angiosarcoma, haemangiopericytoma, Kaposi's sarcoma, lymphangioma, and lymphangiosarcoma, tumor angiogenesis, trauma such as wounds, burns, and other injured tissue, implant fixation, scarring, ischemia reperfusion injury, rheumatoid arthritis, cerebrovascular disease, renal diseases such as acute renal failure, or osteoporosis. This would also include angina, myocardial infarctions such as acute myocardial infarctions, cardiac hypertrophy, and heart failure such as CHF.

[0340] "Hypertrophy", as used herein, is defined as an increase in mass of an organ or structure independent of natural growth that does not involve tumor formation. Hypertrophy of an organ or tissue is due either to an increase in the mass of the individual cells (true hypertrophy), or to an increase in the number of cells making up the tissue (hyperplasia), or both. Certain organs, such as the heart, lose the ability to divide shortly after birth. Accordingly, "cardiac hypertrophy" is defined as an increase in mass of the heart, which, in adults, is characterized by an increase in myocyte cell size and contractile protein content without concomitant cell division. The character of the stress responsible for inciting the hypertrophy, (e.g., increased preload, increased afterload, loss of myocytes, as in myocardial infarction, or primary depression of contractility), appears to play a critical role in determining the nature of the response. The early stage of cardiac hypertrophy is usually characterized morphologically by increases in the size of myofibrils and mitochondria, as well as by enlargement of mitochondria and nuclei. At this stage, while muscle cells are larger than normal, cellular organization is largely preserved. At a more advanced stage of cardiac hypertrophy, there are preferential increases in the size or number of specific organelles, such as mitochondria, and new contractile elements are added in localized areas of the cells, in an irregular manner. Cells subjected to long-standing hypertrophy show more obvious disruptions in cellular organization, including markedly enlarged nuclei with highly lobulated membranes, which displace adjacent myofibrils and cause breakdown of normal Z-band registration. The phrase "cardiac hypertrophy" is used to include all stages of the progression of this condition, characterized by various degrees of structural damage of the heart muscle, regardless of the underlying cardiac disorder. Hence, the term also includes physiological conditions instrumental in the development of cardiac hypertrophy, such as elevated blood pressure, aortic stenosis, or myocardial infarction.

[0341] "Heart failure" refers to an abnormality of cardiac function where the heart does not pump blood at the rate needed for the requirements of metabolizing tissues. The heart failure can be caused by a number of factors, including ischemic, congenital, rheumatic, or idiopathic forms.

[0342] "Congestive heart failure" (CHF) is a progressive pathologic state where the heart is increasingly unable to supply adequate cardiac output (the volume of blood pumped by the heart over time) to deliver the oxygenated blood to peripheral tissues. As CHF progresses, structural and hemodynamic damages occur. While these damages have a variety of manifestations, one characteristic symptom is ventricular hypertrophy. CHF is a common end result of a number of various cardiac disorders.

[0343] "Myocardial infarction" generally results from atherosclerosis of the coronary arteries, often with superimposed coronary thrombosis. It may be divided into two major types: transmural infarcts, in which myocardial necrosis involves the full thickness of the ventricular wall, and subendocardial (nontransmural) infarcts, in which the necrosis involves the subendocardium, the intramural myocardium, or both, without extending all the way through the ventricular wall to the epicardium. Myocardial infarction is known to cause both a change in hemodynamic effects and an alteration in structure in the damaged and healthy zones of the heart. Thus, for example, myocardial infarction reduces the maximum cardiac output and the stroke volume of the heart. Also associated with myocardial infarction is a stimulation of the DNA synthesis occurring in the interstice as well as an increase in the formation of collagen in the areas of the heart not affected.

[0344] As a result of the increased stress or strain placed on the heart in prolonged hypertension due, for example, to the increased total peripheral resistance, cardiac hypertrophy has long been associated with "hypertension". A characteristic of the ventricle that becomes hypertrophic as a result of chronic pressure overload is an impaired diastolic performance. Fouad et al., J. Am. Coll. Cardiol., 4: 1500-1506 (1984); Smith et al., J. Am. Coll. Cardiol., 5: 869-874 (1985). A prolonged left ventricular relaxation has been detected in early essential hypertension, in spite of normal or supranormal systolic function. Hartford et al., Hypertension, 6: 329-338 (1984). However, there is no close parallelism between blood pressure levels and cardiac hypertrophy. Although improvement in left ventricular function in response to antihypertensive therapy has been reported in humans, patients variously treated with a diuretic (hydrochlorothiazide), a .beta.-blocker (propranolol), or a calcium channel blocker (diltiazem), have shown reversal of left ventricular hypertrophy, without improvement in diastolic function. Inouye et al., Am. J. Cardiol., 53: 1583-7 (1984).

[0345] Another complex cardiac disease associated with cardiac hypertrophy is "hypertrophic cardiomyopathy". This condition is characterized by a great diversity of morphologic, functional, and clinical features (Maron et al., N. Engl. J. Med., 316: 780-789 (1987); Spirito et al., N. Engl. J. Med., 320: 749-755 (1989); Louie and Edwards, Prog. Cardiovasc. Dis., 36: 275-308 (1994); Wigle et al., Circulation, 92: 1680-1692 (1995)), the heterogeneity of which is accentuated by the fact that it afflicts patients of all ages. Spirito et al., N. Engl. J. Med., 336: 775-785 (1997). The causative factors of hypertrophic cardiomyopathy are also diverse and little understood. In general, mutations in genes encoding sarcomeric proteins are associated with hypertrophic cardiomyopathy. Recent data suggest that .beta.-myosin heavy chain mutations may account for approximately 30 to 40 percent of cases of familial hypertrophic cardiomyopathy. Watkins et al., N. Engl. J. Med., 326: 1108-1114 (1992); Schwartz et al, Circulation, 91: 532-540 (1995); Marian and Roberts, Circulation, 92: 1336-1347 (1995); Thierfelder et al., Cell, 77: 701-712 (1994); Watkins et al., Nat. Gen., 11: 434-437 (1995). Besides .beta.-myosin heavy chain, other locations of genetic mutations include cardiac troponin T, alpha topomyosin, cardiac myosin binding protein C, essential myosin light chain, and regulatory myosin light chain. See, Malik and Watkins, Curr. Opin. Cardiol., 12: 295-302 (1997).

[0346] Supravalvular "aortic stenosis" is an inherited vascular disorder characterized by narrowing of the ascending aorta, but other arteries, including the pulmonary arteries, may also be affected. Untreated aortic stenosis may lead to increased intracardiac pressure resulting in myocardial hypertrophy and eventually heart failure and death. The pathogenesis of this disorder is not fully understood, but hypertrophy and possibly hyperplasia of medial smooth muscle are prominent features of this disorder. It has been reported that molecular variants of the elastin gene are involved in the development and pathogenesis of aortic stenosis. U.S. Pat. No. 5,650,282 issued Jul. 22, 1997.

[0347] "Valvular regurgitation" occurs as a result of heart diseases resulting in disorders of the cardiac valves. Various diseases, like rheumatic fever, can cause the shrinking or pulling apart of the valve orifice, while other diseases may result in endocarditis, an inflammation of the endocardium or lining membrane of the atrioventricular orifices and operation of the heart. Defects such as the narrowing of the valve stenosis or the defective closing of the valve result in an accumulation of blood in the heart cavity or regurgitation of blood past the valve. If uncorrected, prolonged valvular stenosis or insufficiency may result in cardiac hypertrophy and associated damage to the heart muscle, which may eventually necessitate valve replacement.

[0348] The term "immune related disease" means a disease in which a component of the immune system of a mammal causes, mediates or otherwise contributes to a morbidity in the mammal. Also included are diseases in which stimulation or intervention of the immune response has an ameliorative effect on progression of the disease. Included within this term are immune-mediated inflammatory diseases, non-immune-mediated inflammatory diseases, infectious diseases, immunodeficiency diseases, neoplasia, etc.

[0349] The term "T cell mediated disease" means a disease in which T cells directly or indirectly mediate or otherwise contribute to a morbidity in a mammal The T cell mediated disease may be associated with cell mediated effects, lymphokine mediated effects, etc., and even effects associated with B cells if the B cells are stimulated, for example, by the lymphokines secreted by T cells.

[0350] "Autoimmune disease" can be an organ-specific disease (i.e., the immune response is specifically directed against an organ system such as the endocrine system, the hematopoietic system, the skin, the cardiopulmonary system, the gastrointestinal and liver systems, the renal system, the thyroid, the ears, the neuromuscular system, the central nervous system, etc.) or a systemic disease which can affect multiple organ systems (for example, systemic lupus erythematosus (SLE), rheumatoid arthritis, polymyositis, etc.). Preferred such diseases include autoimmune rheumatologic disorders (such as, for example, rheumatoid arthritis, Sjogren's syndrome, scleroderma, lupus such as SLE and lupus nephritis, polymyositis/dermatomyositis, cryoglobulinemia, anti-phospholipid antibody syndrome, and psoriatic arthritis), autoimmune gastrointestinal and liver disorders (such as, for example, inflammatory bowel diseases (e.g., ulcerative colitis and Crohn's disease), autoimmune gastritis and pernicious anemia, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, and celiac disease), vasculitis (such as, for example, ANCA-associated vasculitis, including Churg-Strauss vasculitis, Wegener's granulomatosis, and polyarteriitis), autoimmune neurological disorders (such as, for example, multiple sclerosis, opsoclonus myoclonus syndrome, myasthenia gravis, neuromyelitis optica, Parkinson's disease, Alzheimer's disease, and autoimmune polyneuropathies), renal disorders (such as, for example, glomerulonephritis, Goodpasture's syndrome, and Berger's disease), autoimmune dermatologic disorders (such as, for example, psoriasis, urticaria, hives, pemphigus vulgaris, bullous pemphigoid, and cutaneous lupus erythematosus), hematologic disorders (such as, for example, thrombocytopenic purpura, thrombotic thrombocytopenic purpura, post-transfusion purpura, and autoimmune hemolytic anemia), atherosclerosis, uveitis, autoimmune hearing diseases (such as, for example, inner ear disease and hearing loss), Behcet's disease, Raynaud's syndrome, organ transplant, and autoimmune endocrine disorders (such as, for example, diabetic-related autoimmune diseases such as insulin-dependent diabetes mellitus (IDDM), Addison's disease, and autoimmune thyroid disease (e.g., Graves' disease and thyroiditis)). More preferred such diseases include, for example, rheumatoid arthritis, ulcerative colitis, ANCA-associated vasculitis, lupus, multiple sclerosis, Sjogren's syndrome, Graves' disease, IDDM, pernicious anemia, thyroiditis, and glomerulonephritis.

[0351] Specific examples of other autoimmune diseases as defined herein, which in some cases encompass those listed above, include, but are not limited to, arthritis (acute and chronic, rheumatoid arthritis including juvenile-onset rheumatoid arthritis and stages such as rheumatoid synovitis, gout or gouty arthritis, acute immunological arthritis, chronic inflammatory arthritis, degenerative arthritis, type II collagen-induced arthritis, infectious arthritis, Lyme arthritis, proliferative arthritis, psoriatic arthritis, Still's disease, vertebral arthritis, osteoarthritis, arthritis chronica progrediente, arthritis deformans, polyarthritis chronicaprimaria, reactive arthritis, menopausal arthritis, estrogen-depletion arthritis, and ankylosing spondylitis/rheumatoid spondylitis), autoimmune lymphoproliferative disease, inflammatory hyperproliferative skin diseases, psoriasis such as plaque psoriasis, gutatte psoriasis, pustular psoriasis, and psoriasis of the nails, atopy including atopic diseases such as hay fever and Job's syndrome, dermatitis including contact dermatitis, chronic contact dermatitis, exfoliative dermatitis, allergic dermatitis, allergic contact dermatitis, hives, dermatitis herpetiformis, nummular dermatitis, seborrheic dermatitis, non-specific dermatitis, primary irritant contact dermatitis, and atopic dermatitis, x-linked hyper IgM syndrome, allergic intraocular inflammatory diseases, urticaria such as chronic allergic urticaria and chronic idiopathic urticaria, including chronic autoimmune urticaria, myositis, polymyositis/dermatomyositis, juvenile dermatomyositis, toxic epidermal necrolysis, scleroderma (including systemic scleroderma), sclerosis such as systemic sclerosis, multiple sclerosis (MS) such as spino-optical MS, primary progressive MS (PPMS), and relapsing remitting MS (RRMS), progressive systemic sclerosis, atherosclerosis, arteriosclerosis, sclerosis disseminata, ataxic sclerosis, neuromyelitis optica (NMO), inflammatory bowel disease (IBD) (for example, Crohn's disease, autoimmune-mediated gastrointestinal diseases, gastrointestinal inflammation, colitis such as ulcerative colitis, colitis ulcerosa, microscopic colitis, collagenous colitis, colitis polyposa, necrotizing enterocolitis, and transmural colitis, and autoimmune inflammatory bowel disease), bowel inflammation, pyoderma gangrenosum, erythema nodosum, primary sclerosing cholangitis, respiratory distress syndrome, including adult or acute respiratory distress syndrome (ARDS), meningitis, inflammation of all or part of the uvea, iritis, choroiditis, an autoimmune hematological disorder, graft-versus-host disease, angioedema such as hereditary angioedema, cranial nerve damage as in meningitis, herpes gestationis, pemphigoid gestationis, pruritis scroti, autoimmune premature ovarian failure, sudden hearing loss due to an autoimmune condition, IgE-mediated diseases such as anaphylaxis and allergic and atopic rhinitis, encephalitis such as Rasmussen's encephalitis and limbic and/or brainstem encephalitis, uveitis, such as anterior uveitis, acute anterior uveitis, granulomatous uveitis, nongranulomatous uveitis, phacoantigenic uveitis, posterior uveitis, or autoimmune uveitis, glomerulonephritis (GN) with and without nephrotic syndrome such as chronic or acute glomerulonephritis such as primary GN, immune-mediated GN, membranous GN (membranous nephropathy), idiopathic membranous GN or idiopathic membranous nephropathy, membrano- or membranous proliferative GN (MPGN), including Type I and Type II, and rapidly progressive GN (RPGN), proliferative nephritis, autoimmune polyglandular endocrine failure, balanitis including balanitis circumscripta plasmacellularis, balanoposthitis, erythema annulare centrifugum, erythema dyschromicum perstans, eythema multiform, granuloma annulare, lichen nitidus, lichen sclerosus et atrophicus, lichen simplex chronicus, lichen spinulosus, lichen planus, lamellar ichthyosis, epidermolytic hyperkeratosis, premalignant keratosis, pyoderma gangrenosum, allergic conditions and responses, food allergies, drug allergies, insect allergies, rare allergic disorders such as mastocytosis, allergic reaction, eczema including allergic or atopic eczema, asteatotic eczema, dyshidrotic eczema, and vesicular palmoplantar eczema, asthma such as asthma bronchiale, bronchial asthma, and auto-immune asthma, conditions involving infiltration of T cells and chronic inflammatory responses, immune reactions against foreign antigens such as fetal A-B-O blood groups during pregnancy, chronic pulmonary inflammatory disease, autoimmune myocarditis, leukocyte adhesion deficiency, lupus, including lupus nephritis, lupus cerebritis, pediatric lupus, non-renal lupus, extra-renal lupus, discoid lupus and discoid lupus erythematosus, alopecia lupus, SLE, such as cutaneous SLE or subacute cutaneous SLE, neonatal lupus syndrome (NLE), and lupus erythematosus disseminatus, juvenile onset (Type I) diabetes mellitus, including pediatric IDDM, adult onset diabetes mellitus (Type II diabetes), autoimmune diabetes, idiopathic diabetes insipidus, diabetic retinopathy, diabetic nephropathy, diabetic colitis, diabetic large-artery disorder, immune responses associated with acute and delayed hypersensitivity mediated by cytokines and T-lymphocytes, tuberculosis, sarcoidosis, granulomatosis including lymphomatoid granulomatosis, Wegener's granulomatosis, agranulocytosis, vasculitides, including vasculitis, large-vessel vasculitis (including polymyalgia rheumatica and giant-cell (Takayasu's) arteritis), medium-vessel vasculitis (including Kawasaki's disease and polyarteritis nodosa/periarteritis nodosa), microscopic polyarteritis, immunovasculitis, CNS vasculitis, cutaneous vasculitis, hypersensitivity vasculitis, necrotizing vasculitis such as systemic necrotizing vasculitis, and ANCA-associated vasculitis, such as Churg-Strauss vasculitis or syndrome (CSS) and ANCA-associated small-vessel vasculitis, temporal arteritis, aplastic anemia, autoimmune aplastic anemia, Coombs positive anemia, Diamond Blackfan anemia, hemolytic anemia or immune hemolytic anemia including autoimmune hemolytic anemia (AIHA), pernicious anemia (anemia perniciosa), Addison's disease, pure red cell anemia or aplasia (PRCA), Factor VIII deficiency, hemophilia A, autoimmune neutropenia(s), cytopenias such as pancytopenia, leukopenia, diseases involving leukocyte diapedesis, CNS inflammatory disorders, Alzheimer's disease, Parkinson's disease, multiple organ injury syndrome such as those secondary to septicemia, trauma or hemorrhage, antigen-antibody complex-mediated diseases, anti-glomerular basement membrane disease, anti-phospholipid antibody syndrome, motoneuritis, allergic neuritis, Behcet's disease/syndrome, Castleman's syndrome, Goodpasture's syndrome, Reynaud's syndrome, Sjogren's syndrome, Stevens-Johnson syndrome, pemphigoid such as pemphigoid bullous and skin pemphigoid, pemphigus (including pemphigus vulgaris, pemphigus foliaceus, pemphigus mucus-membrane pemphigoid, and pemphigus erythematosus), autoimmune polyendocrinopathies, Reiter's disease or syndrome, thermal injury due to an autoimmune condition, preeclampsia, an immune complex disorder such as immune complex nephritis, antibody-mediated nephritis, neuroinflammatory disorders, polyneuropathies, chronic neuropathy such as IgM polyneuropathies or IgM-mediated neuropathy, thrombocytopenia (as developed by myocardial infarction patients, for example), including thrombotic thrombocytopenic purpura (TTP), post-transfusion purpura (PTP), heparin-induced thrombocytopenia, and autoimmune or immune-mediated thrombocytopenia including, for example, idiopathic thrombocytopenic purpura (ITP) including chronic or acute ITP, scleritis such as idiopathic cerato-scleritis, episcleritis, autoimmune disease of the testis and ovary including autoimmune orchitis and oophoritis, primary hypothyroidism, hypoparathyroidism, autoimmune endocrine diseases including thyroiditis such as autoimmune thyroiditis, Hashimoto's disease, chronic thyroiditis (Hashimoto's thyroiditis), or subacute thyroiditis, autoimmune thyroid disease, idiopathic hypothyroidism, Grave's disease, polyglandular syndromes such as autoimmune polyglandular syndromes, for example, type I (or polyglandular endocrinopathy syndromes), paraneoplastic syndromes, including neurologic paraneoplastic syndromes such as Lambert-Eaton myasthenic syndrome or Eaton-Lambert syndrome, stiff-man or stiff-person syndrome, encephalomyelitis such as allergic encephalomyelitis or encephalomyelitis allergica and experimental allergic encephalomyelitis (EAE), myasthenia gravis such as thymoma-associated myasthenia gravis, cerebellar degeneration, neuromyotonia, opsoclonus or opsoclonus myoclonus syndrome (OMS), and sensory neuropathy, multifocal motor neuropathy, Sheehan's syndrome, autoimmune hepatitis, chronic hepatitis, lupoid hepatitis, giant-cell hepatitis, chronic active hepatitis or autoimmune chronic active hepatitis, pneumonitis such as lymphoid interstitial pneumonitis (LIP), bronchiolitis obliterans (non-transplant) vs NSIP, Guillain-Barre syndrome, Berger's disease (IgA nephropathy), idiopathic IgA nephropathy, linear IgA dermatosis, acute febrile neutrophilic dermatosis, subcorneal pustular dermatosis, transient acantholytic dermatosis, cirrhosis such as primary biliary cirrhosis and pneumonocirrhosis, autoimmune enteropathy syndrome, Celiac or Coeliac disease, celiac sprue (gluten enteropathy), refractory sprue, idiopathic sprue, cryoglobulinemia such as mixed cryoglobulinemia, amylotrophic lateral sclerosis (ALS; Lou Gehrig's disease), coronary artery disease, autoimmune ear disease such as autoimmune inner ear disease (AIED), autoimmune hearing loss, polychondritis such as refractory or relapsed or relapsing polychondritis, pulmonary alveolar proteinosis, Cogan's syndrome/nonsyphilitic interstitial keratitis, Bell's palsy, Sweet's disease/syndrome, rosacea autoimmune, zoster-associated pain, amyloidosis, a non-cancerous lymphocytosis, a primary lymphocytosis, which includes monoclonal B cell lymphocytosis (e.g., benign monoclonal gammopathy and monoclonal gammopathy of undetermined significance, MGUS), peripheral neuropathy, paraneoplastic syndrome, channelopathies such as epilepsy, migraine, arrhythmia, muscular disorders, deafness, blindness, periodic paralysis, and channelopathies of the CNS, autism, inflammatory myopathy, focal or segmental or focal segmental glomerulosclerosis (FSGS), endocrine ophthalmopathy, uveoretinitis, chorioretinitis, autoimmune hepatological disorder, fibromyalgia, multiple endocrine failure, Schmidt's syndrome, adrenalitis, gastric atrophy, presenile dementia, demyelinating diseases such as autoimmune demyelinating diseases and chronic inflammatory demyelinating polyneuropathy, Dressler's syndrome, alopecia greata, alopecia totalis, CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyl), and telangiectasia), male and female autoimmune infertility, e.g., due to anti-spermatozoan antibodies, mixed connective tissue disease, Chagas' disease, rheumatic fever, recurrent abortion, farmer's lung, erythema multiforme, post-cardiotomy syndrome, Cushing's syndrome, bird-fancier's lung, allergic granulomatous angiitis, benign lymphocytic angiitis, Alport's syndrome, alveolitis such as allergic alveolitis and fibrosing alveolitis, interstitial lung disease, transfusion reaction, leprosy, malaria, parasitic diseases such as leishmaniasis, kypanosomiasis, schistosomiasis, ascariasis, aspergillosis, Sampter's syndrome, Caplan's syndrome, dengue, endocarditis, endomyocardial fibrosis, diffuse interstitial pulmonary fibrosis, interstitial lung fibrosis, fibrosing mediastinitis, pulmonary fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis, endophthalmitis, erythema elevatum et diutinum, erythroblastosis fetalis, eosinophilic faciitis, Shulman's syndrome, Felty's syndrome, flariasis, cyclitis such as chronic cyclitis, heterochronic cyclitis, iridocyclitis (acute or chronic), or Fuch's cyclitis, Henoch-Schonlein purpura, human immunodeficiency virus (HIV) infection, SCID, acquired immune deficiency syndrome (AIDS), echovirus infection, sepsis (systemic inflammatory response syndrome (SIRS)), endotoxemia, pancreatitis, thyroxicosis, parvovirus infection, rubella virus infection, post-vaccination syndromes, congenital rubella infection, Epstein-Barr virus infection, mumps, Evan's syndrome, autoimmune gonadal failure, Sydenham's chorea, post-streptococcal nephritis, thromboangitis ubiterans, thyrotoxicosis, tabes dorsalis, chorioiditis, giant-cell polymyalgia, chronic hypersensitivity pneumonitis, conjunctivitis, such as vernal catarrh, keratoconjunctivitis sicca, and epidemic keratoconjunctivitis, idiopathic nephritic syndrome, minimal change nephropathy, benign familial and ischemia-reperfusion injury, transplant organ reperfusion, retinal autoimmunity, joint inflammation, bronchitis, chronic obstructive airway/pulmonary disease, silicosis, aphthae, aphthous stomatitis, arteriosclerotic disorders (cerebral vascular insufficiency) such as arteriosclerotic encephalopathy and arteriosclerotic retinopathy, aspermiogenese, autoimmune hemolysis, Boeck's disease, cryoglobulinemia, Dupuytren's contracture, endophthalmia phacoanaphylactica, enteritis allergica, erythema nodosum leprosum, idiopathic facial paralysis, chronic fatigue syndrome, febris rheumatica, Hamman-Rich's disease, sensoneural hearing loss, haemoglobinuria paroxysmatica, hypogonadism, ileitis regionalis, leucopenia, mononucleosis infectiosa, traverse myelitis, primary idiopathic myxedema, nephrosis, ophthalmia symphatica, orchitis granulomatosa, pancreatitis, polyradiculitis acuta, pyoderma gangrenosum, Quervain's thyreoiditis, acquired spenic atrophy, non-malignant thymoma, lymphofollicular thymitis, vitiligo, toxic-shock syndrome, food poisoning, conditions involving infiltration of T cells, leukocyte-adhesion deficiency, immune responses associated with acute and delayed hypersensitivity mediated by cytokines and T-lymphocytes, diseases involving leukocyte diapedesis, multiple organ injury syndrome, antigen-antibody complex-mediated diseases, antiglomerular basement membrane disease, autoimmune polyendocrinopathies, oophoritis, primary myxedema, autoimmune atrophic gastritis, sympathetic ophthalmia, rheumatic diseases, mixed connective tissue disease, nephrotic syndrome, insulitis, polyendocrine failure, autoimmune polyglandular syndromes, including polyglandular syndrome type I, adult-onset idiopathic hypoparathyroidism (AOIH), cardiomyopathy such as dilated cardiomyopathy, epidermolisis bullosa acquisita (EBA), hemochromatosis, myocarditis, nephrotic syndrome, primary sclerosing cholangitis, purulent or nonpurulent sinusitis, acute or chronic sinusitis, ethmoid, frontal, maxillary, or sphenoid sinusitis, allergic sinusitis, an eosinophil-related disorder such as eosinophilia, pulmonary infiltration eosinophilia, eosinophilia-myalgia syndrome, Loffler's syndrome, chronic eosinophilic pneumonia, tropical pulmonary eosinophilia, bronchopneumonic aspergillosis, aspergilloma, or granulomas containing eosinophils, anaphylaxis, spondyloarthropathies, seronegative spondyloarthritides, polyendocrine autoimmune disease, sclerosing cholangitis, sclera, episclera, chronic mucocutaneous candidiasis, Bruton's syndrome, transient hypogammaglobulinemia of infancy, Wiskott-Aldrich syndrome, ataxia telangiectasia syndrome, angiectasis, autoimmune disorders associated with collagen disease, rheumatism such as chronic arthrorheumatism, lymphadenitis, reduction in blood pressure response, vascular dysfunction, tissue injury, cardiovascular ischemia, hyperalgesia, renal ischemia, cerebral ischemia, and disease accompanying vascularization, allergic hypersensitivity disorders, glomerulonephritides, reperfusion injury, ischemic re-perfusion disorder, reperfusion injury of myocardial or other tissues, lymphomatous tracheobronchitis, inflammatory dermatoses, dermatoses with acute inflammatory components, multiple organ failure, bullous diseases, renal cortical necrosis, acute purulent meningitis or other central nervous system inflammatory disorders, ocular and orbital inflammatory disorders, granulocyte transfusion-associated syndromes, cytokine-induced toxicity, narcolepsy, acute serious inflammation, chronic intractable inflammation, pyelitis, endarterial hyperplasia, peptic ulcer, valvulitis, and endometriosis.

[0352] The phrase "anxiety related disorders" refers to disorders of anxiety, mood, and substance abuse, including but not limited to: depression, generalized anxiety disorders, attention deficit disorder, sleep disorder, hyperactivity disorder, obsessive compulsive disorder, schizophrenia, cognitive disorders, hyperalgesia and sensory disorders. Such disorders include the mild to moderate anxiety, anxiety disorder due to a general medical condition, anxiety disorder not otherwise specified, generalized anxiety disorder, panic attack, panic disorder with agoraphobia, panic disorder without agoraphobia, posttraumatic stress disorder, social phobia, social anxiety, autism, specific phobia, substance-induced anxiety disorder, acute alcohol withdrawal, obsessive compulsive disorder, agoraphobia, monopolar disorders, bipolar disorder I or II, bipolar disorder not otherwise specified, cyclothymic disorder, depressive disorder, major depressive disorder, mood disorder, substance-induced mood disorder, enhancement of cognitive function, loss of cognitive function associated with but not limited to Alzheimer's disease, stroke, or traumatic injury to the brain, seizures resulting from disease or injury including but not limited to epilepsy, learning disorders/disabilities, cerebral palsy. In addition, anxiety disorders may apply to personality disorders including but not limited to the following types: paranoid, antisocial, avoidant behavior, borderline personality disorders, dependent, histronic, narcissistic, obsessive-compulsive, schizoid, and schizotypal.

[0353] The term "lipid metabolic disorder" refers to abnormal clinical chemistry levels of cholesterol and triglycerides, wherein elevated levels of these lipids is an indication for atherosclerosis. Additionally, abnormal serum lipid levels may be an indication of various cardiovascular diseases including hypertension, stroke, coronary artery diseases, diabetes and/or obesity.

[0354] The phrase "eye abnormality" refers to such potential disorders of the eye as they may be related to atherosclerosis or various ophthalmological abnormalities. Such disorders include but are not limited to the following: retinal dysplasia, various retinopathies, restenosis, retinal artery obstruction or occlusion; retinal degeneration causing secondary atrophy of the retinal vasculature, retinitis pigmentosa, macular dystrophies, Stargardt's disease, congenital stationary night blindness, choroideremia, gyrate atrophy, Leber's congenital amaurosis, retinoschisis disorders, Wagner's syndrome, Usher syndromes, Zellweger syndrome, Saldino-Mainzer syndrome, Senior-Loken syndrome, Bardet-Biedl syndrome, Alport's syndrome, Alstrom's syndrome, Cockayne's syndrome, dysplais a spondyloepiphysaria congentia, Flynn-Aird syndrome, Friedreich ataxia, Hallgren syndrome, Marshall syndrome, Albers-Schnoberg disease, Refsum's disease, Kearns-Sayre syndrome, Waardenburg's syndrome, Alagile syndrome, myotonic dystrophy, olivopontocerebellar atrophy, Pierre-Marie dunsdrome, Stickler syndrome, carotinemeia, cystinosis, Wolfram syndrome, Bassen-Kornzweig syndrome, abetalipoproteinemia, incontinentia pigmenti, Batten's disease, mucopolysaccharidoses, homocystinuria, or mannosidosis. Cataracts are also considered an eye abnormality and are associated with such systemic diseases as: Human Down's syndrome, Hallerman-Streiff syndrome, Lowe syndrome, galactosemia, Marfan syndrome, Trismoy 13-15 condition, Alport syndrome, myotonic dystrophy, Fabry disease, hypothroidisms, or Conradi syndrome. Other ocular developmental anomalies include: Aniridia, anterior segment and dysgenesis syndrome. Cataracts may also occur as a result of an intraocular infection or inflammation (uveitis).

[0355] A "growth inhibitory amount" of an anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibody, PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 binding oligopeptide or PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 binding organic molecule is an amount capable of inhibiting the growth of a cell, especially tumor, e.g., cancer cell, either in vitro or in viva A "growth inhibitory amount" of an anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibody, PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 binding oligopeptide or PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 binding organic molecule for purposes of inhibiting neoplastic cell growth may be determined empirically and in a routine manner

[0356] A "cytotoxic amount" of an anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibody, PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 binding oligopeptide or PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 binding organic molecule is an amount capable of causing the destruction of a cell, especially tumor, e.g., cancer cell, either in vitro or in vivo. A "cytotoxic amount" of an anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibody, PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 binding oligopeptide or PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 binding organic molecule for purposes of inhibiting neoplastic cell growth may be determined empirically and in a routine manner.

[0357] The term "antibody" is used in the broadest sense and specifically covers, for example, single anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibody monoclonal antibodies (including agonist, antagonist, and neutralizing antibodies), anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibody compositions with polyepitopic specificity, polyclonal antibodies, single chain anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibodies, and fragments of anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibodies (see below) as long as they exhibit the desired biological or immunological activity. The term "immunoglobulin" (Ig) is used interchangeable with antibody herein.

[0358] An "isolated antibody" is one which has been identified and separated and/or recovered from a component of its natural environment. Contaminant components of its natural environment are materials which would interfere with diagnostic or therapeutic uses for the antibody, and may include enzymes, hormones, and other proteinaceous or nonproteinaceous solutes. The invention provides that the antibody will be purified (1) to greater than 95% by weight of antibody as determined by the Lowry method, and most preferably more than 99% by weight, (2) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use of a spinning cup sequenator, or (3) to homogeneity by SDS-PAGE under reducing or nonreducing conditions using Coomassie blue or, preferably, silver stain. Isolated antibody includes the antibody in situ within recombinant cells since at least one component of the antibody's natural environment will not be present. Ordinarily, however, isolated antibody will be prepared by at least one purification step.

[0359] The basic 4-chain antibody unit is a heterotetrameric glycoprotein composed of two identical light (L) chains and two identical heavy (H) chains (an IgM antibody consists of 5 of the basic heterotetramer unit along with an additional polypeptide called J chain, and therefore contain 10 antigen binding sites, while secreted IgA antibodies can polymerize to form polyvalent assemblages comprising 2-5 of the basic 4-chain units along with J chain). In the case of IgGs, the 4-chain unit is generally about 150,000 daltons. Each L chain is linked to a H chain by one covalent disulfide bond, while the two H chains are linked to each other by one or more disulfide bonds depending on the H chain isotype. Each H and L chain also has regularly spaced intrachain disulfide bridges. Each H chain has at the N-terminus, a variable domain (V.sub.H) followed by three constant domains (C.sub.H) for each of the .alpha. and .gamma. chains and four C.sub.H domains for .mu. and .epsilon. isotypes. Each L chain has at the N-terminus, a variable domain (V.sub.L) followed by a constant domain (C.sub.L) at its other end. The V.sub.L is aligned with the V.sub.H and the C.sub.L is aligned with the first constant domain of the heavy chain (C.sub.H 1). Particular amino acid residues are believed to form an interface between the light chain and heavy chain variable domains. The pairing of a V.sub.H and V.sub.L together forms a single antigen-binding site. For the structure and properties of the different classes of antibodies, see, e.g., Basic and Clinical Immunology, 8th edition, Daniel P. Stites, Abba I. Terr and Tristram G. Parslow (eds.), Appleton & Lange, Norwalk, Conn., 1994, page 71 and Chapter 6.

[0360] The L chain from any vertebrate species can be assigned to one of two clearly distinct types, called kappa and lambda, based on the amino acid sequences of their constant domains. Depending on the amino acid sequence of the constant domain of their heavy chains (C.sub.H), immunoglobulins can be assigned to different classes or isotypes. There are five classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, having heavy chains designated .alpha., .delta., .epsilon., .gamma., and respectively. The .gamma. and .alpha. classes are further divided into subclasses on the basis of relatively minor differences in C.sub.H sequence and function, e.g., humans express the following subclasses: IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2.

[0361] The term "variable" refers to the fact that certain segments of the variable domains differ extensively in sequence among antibodies. The V domain mediates antigen binding and define specificity of a particular antibody for its particular antigen. However, the variability is not evenly distributed across the 110-amino acid span of the variable domains. Instead, the V regions consist of relatively invariant stretches called framework regions (FRs) of 15-30 amino acids separated by shorter regions of extreme variability called "hypervariable regions" that are each 9-12 amino acids long. The variable domains of native heavy and light chains each comprise four FRs, largely adopting a .beta.-sheet configuration, connected by three hypervariable regions, which form loops connecting, and in some cases forming part of, the .beta.-sheet structure. The hypervariable regions in each chain are held together in close proximity by the FRs and, with the hypervariable regions from the other chain, contribute to the formation of the antigen-binding site of antibodies (see Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)). The constant domains are not involved directly in binding an antibody to an antigen, but exhibit various effector functions, such as participation of the antibody in antibody dependent cellular cytotoxicity (ADCC).

[0362] The term "hypervariable region" when used herein refers to the amino acid residues of an antibody which are responsible for antigen-binding. The hypervariable region generally comprises amino acid residues from a "complementarity determining region" or "CDR" (e.g. around about residues 24-34 (L1), 50-56 (L2) and 89-97 (L3) in the V.sub.L, and around about 1-35 (H1), 50-65 (H2) and 95-102 (H3) in the V.sub.H; Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)) and/or those residues from a "hypervariable loop" (e.g. residues 26-32 (L1), 50-52 (L2) and 91-96 (L3) in the V.sub.L, and 26-32 (H1), 53-55 (H2) and 96-101 (H3) in the V.sub.H; Chothia and Lesk J. Mol. Biol. 196:901-917 (1987)).

[0363] The term "monoclonal antibody" as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site. Furthermore, in contrast to polyclonal antibody preparations which include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. In addition to their specificity, the monoclonal antibodies are advantageous in that they may be synthesized uncontaminated by other antibodies. The modifier "monoclonal" is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies useful in the present invention may be prepared by the hybridoma methodology first described by Kohler et al., Nature, 256:495 (1975), or may be made using recombinant DNA methods in bacterial, eukaryotic animal or plant cells (see, e.g., U.S. Pat. No. 4,816,567). The "monoclonal antibodies" may also be isolated from phage antibody libraries using the techniques described in Clackson et al., Nature, 352:624-628 (1991) and Marks et al., J. Mol. Biol., 222:581-597 (1991), for example.

[0364] The monoclonal antibodies herein include "chimeric" antibodies in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (see U.S. Pat. No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984)). Chimeric antibodies of interest herein include "primatized" antibodies comprising variable domain antigen-binding sequences derived from a non-human primate (e.g. Old World Monkey, Ape etc), and human constant region sequences.

[0365] An "intact" antibody is one which comprises an antigen-binding site as well as a C.sub.L and at least heavy chain constant domains, C.sub.H 1, C.sub.H 2 and C.sub.H 3. The constant domains may be native sequence constant domains (e.g. human native sequence constant domains) or amino acid sequence variant thereof. Preferably, the intact antibody has one or more effector functions.

[0366] "Antibody fragments" comprise a portion of an intact antibody, preferably the antigen binding or variable region of the intact antibody. Examples of antibody fragments include Fab, Fab', F(ab').sub.2, and Fv fragments; diabodies; linear antibodies (see U.S. Pat. No. 5,641,870, Example 2; Zapata et al., Protein Eng. 8(10): 1057-1062 [1995]); single-chain antibody molecules; and multispecific antibodies formed from antibody fragments.

[0367] Papain digestion of antibodies produces two identical antigen-binding fragments, called "Fab" fragments, and a residual "Fc" fragment, a designation reflecting the ability to crystallize readily. The Fab fragment consists of an entire L chain along with the variable region domain of the H chain (V.sub.H), and the first constant domain of one heavy chain (C.sub.H 1). Each Fab fragment is monovalent with respect to antigen binding, i.e., it has a single antigen-binding site. Pepsin treatment of an antibody yields a single large F(ab').sub.2 fragment which roughly corresponds to two disulfide linked Fab fragments having divalent antigen-binding activity and is still capable of cross-linking antigen. Fab' fragments differ from Fab fragments by having additional few residues at the carboxy terminus of the C.sub.H 1 domain including one or more cysteines from the antibody hinge region. Fab'-SH is the designation herein for Fab' in which the cysteine residue(s) of the constant domains bear a free thiol group. F(ab').sub.2 antibody fragments originally were produced as pairs of Fab' fragments which have hinge cysteines between them. Other chemical couplings of antibody fragments are also known.

[0368] The Fc fragment comprises the carboxy-terminal portions of both H chains held together by disulfides. The effector functions of antibodies are determined by sequences in the Fc region, which region is also the part recognized by Fc receptors (FcR) found on certain types of cells.

[0369] "Fv" is the minimum antibody fragment which contains a complete antigen-recognition and -binding site. This fragment consists of a dimer of one heavy- and one light-chain variable region domain in tight, non-covalent association. From the folding of these two domains emanate six hypervariable loops (3 loops each from the H and L chain) that contribute the amino acid residues for antigen binding and confer antigen binding specificity to the antibody. However, even a single variable domain (or half of an Fv comprising only three CDRs specific for an antigen) has the ability to recognize and bind antigen, although at a lower affinity than the entire binding site.

[0370] "Single-chain Fv" also abbreviated as "sFv" or "scFv" are antibody fragments that comprise the V.sub.H and V.sub.L antibody domains connected into a single polypeptide chain. Preferably, the sFv polypeptide further comprises a polypeptide linker between the V.sub.H and V.sub.L domains which enables the sFv to form the desired structure for antigen binding. For a review of sFv, see Pluckthun in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315 (1994); Borrebaeck 1995, infra.

[0371] The term "diabodies" refers to small antibody fragments prepared by constructing sFv fragments (see preceding paragraph) with short linkers (about 5-10 residues) between the V.sub.H and V.sub.L domains such that inter-chain but not intra-chain pairing of the V domains is achieved, resulting in a bivalent fragment, i.e., fragment having two antigen-binding sites. Bispecific diabodies are heterodimers of two "crossover" sFv fragments in which the V.sub.H and V.sub.L domains of the two antibodies are present on different polypeptide chains. Diabodies are described more fully in, for example, EP 404,097; WO 93/11161; and Hollinger et al., Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993).

[0372] "Humanized" forms of non-human (e.g., rodent) antibodies are chimeric antibodies that contain minimal sequence derived from the non-human antibody. For the most part, humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a hypervariable region of the recipient are replaced by residues from a hypervariable region of a non-human species (donor antibody) such as mouse, rat, rabbit or non-human primate having the desired antibody specificity, affinity, and capability. In some instances, framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies may comprise residues that are not found in the recipient antibody or in the donor antibody. These modifications are made to further refine antibody performance. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the FRs are those of a human immunoglobulin sequence. The humanized antibody optionally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For further details, see Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol. 2:593-596 (1992).

[0373] A "species-dependent antibody," e.g., a mammalian anti-human IgE antibody, is an antibody which has a stronger binding affinity for an antigen from a first mammalian species than it has for a homologue of that antigen from a second mammalian species. Normally, the species-dependent antibody "bind specifically" to a human antigen (i.e., has a binding affinity (Kd) value of no more than about 1.times.10.sup.-7 M, preferably no more than about 1.times.10.sup.-8 and most preferably no more than about 1.times.M) but has a binding affinity for a homologue of the antigen from a second non-human mammalian species which is at least about 50 fold, or at least about 500 fold, or at least about 1000 fold, weaker than its binding affinity for the human antigen. The species-dependent antibody can be of any of the various types of antibodies as defined above, but preferably is a humanized or human antibody.

[0374] A "PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 binding oligopeptide" is an oligopeptide that binds, preferably specifically, to a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide as described herein. PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 binding oligopeptides may be chemically synthesized using known oligopeptide synthesis methodology or may be prepared and purified using recombinant technology. PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 binding oligopeptides usually are or are at least about 5 amino acids in length, alternatively are or are at least about 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 amino acids in length or more, wherein such oligopeptides that are capable of binding, preferably specifically, to a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide as described herein. PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 binding oligopeptides may be identified without undue experimentation using well known techniques. In this regard, it is noted that techniques for screening oligopeptide libraries for oligopeptides that are capable of specifically binding to a polypeptide target are well known in the art (see, e.g., U.S. Pat. Nos. 5,556,762, 5,750,373, 4,708,871, 4,833,092, 5,223,409, 5,403,484, 5,571,689, 5,663,143; PCT Publication Nos. WO 84/03506 and WO84/03564; Geysen et al., Proc. Natl. Acad. Sci. U.S.A., 81:3998-4002 (1984); Geysen et al., Proc. Natl. Acad. Sci. U.S.A., 82:178-182 (1985); Geysen et al., in Synthetic Peptides as Antigens, 130-149 (1986); Geysen et al., J. Immunol. Meth., 102:259-274 (1987); Schoofs et al., J. Immunol., 140:611-616 (1988), Cwirla, S. E. et al. (1990) Proc. Natl. Acad. Sci. USA, 87:6378; Lowman, H. B. et al. (1991) Biochemistry, 30:10832; Clackson, T. et al. (1991) Nature, 352: 624; Marks, J. D. et al. (1991), J. Mol. Biol., 222:581; Kang, A. S. et at (1991) Proc. Natl. Acad. Sci. USA, 88:8363, and Smith, G. P. (1991) Current Opin. Biotechnol., 2:668).

[0375] A "PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 binding organic molecule" is an organic molecule other than an oligopeptide or antibody as defined herein that binds, preferably specifically, to a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide as described herein. PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 binding organic molecules may be identified and chemically synthesized using known methodology (see, e.g., PCT Publication Nos. WO00/00823 and WO00/39585). PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 binding organic molecules are usually less than about 2000 daltons in size, alternatively less than about 1500, 750, 500, 250 or 200 daltons in size, wherein such organic molecules that are capable of binding, preferably specifically, to a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide as described herein may be identified without undue experimentation using well known techniques. In this regard, it is noted that techniques for screening organic molecule libraries for molecules that are capable of binding to a polypeptide target are well known in the art (see, e.g., PCT Publication Nos. WO00/00823 and WO00/39585).

[0376] An antibody, oligopeptide or other organic molecule "which binds" an antigen of interest, e.g. a tumor-associated polypeptide antigen target, is one that binds the antigen with sufficient affinity such that the antibody, oligopeptide or other organic molecule is preferably useful as a diagnostic and/or therapeutic agent in targeting a cell or tissue expressing the antigen, and does not significantly cross-react with other proteins. The extent of binding of the antibody, oligopeptide or other organic molecule to a "non-target" protein will be less than about 10% of the binding of the antibody, oligopeptide or other organic molecule to its particular target protein as determined by fluorescence activated cell sorting (FACS) analysis or radioimmunoprecipitation (RIA). With regard to the binding of an antibody, oligopeptide or other organic molecule to a target molecule, the term "specific binding" or "specifically binds to" or is "specific for" a particular polypeptide or an epitope on a particular polypeptide target means binding that is measurably different from a non-specific interaction. Specific binding can be measured, for example, by determining binding of a molecule compared to binding of a control molecule, which generally is a molecule of similar structure that does not have binding activity. For example, specific binding can be determined by competition with a control molecule that is similar to the target, for example, an excess of non-labeled target. In this case, specific binding is indicated if the binding of the labeled target to a probe is competitively inhibited by excess unlabeled target. The term "specific binding" or "specifically binds to" or is "specific for" a particular polypeptide or an epitope on a particular polypeptide target as used herein can be exhibited, for example, by a molecule having a Kd for the target of at least about 10.sup.-4 M, alternatively at least about 10.sup.-5M, alternatively at least about 10.sup.-6M, alternatively at least about 10.sup.-7M, alternatively at least about 10.sup.-8M, alternatively at least about 10.sup.-8 M, alternatively at least about 10.sup.-16 M, alternatively at least about 10.sup.-11 M, alternatively at least about 10.sup.-12 M, or greater. The term "specific binding" refers to binding where a molecule binds to a particular polypeptide or epitope on a particular polypeptide without substantially binding to any other polypeptide or polypeptide epitope.

[0377] An antibody, oligopeptide or other organic molecule that "inhibits the growth of tumor cells expressing a "PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250" or a "growth inhibitory" antibody, oligopeptide or other organic molecule is one which results in measurable growth inhibition of cancer cells expressing or overexpressing the appropriate PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide. The PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide may be a transmembrane polypeptide expressed on the surface of a cancer cell or may be a polypeptide that is produced and secreted by a cancer cell. Preferred growth inhibitory anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibodies, oligopeptides or organic molecules inhibit growth of PRO69122-, PRO204-, PRO214-, PRO222-, PRO234-, PRO265-, PRO309-, PRO332-, PRO342-, PRO356-, PRO540-, PRO618-, PRO944-, PRO994-, PRO1079-, PRO1110-, PRO1122-, PRO1138-, PRO1190-, PRO1272-, PRO1286-, PRO1295-, PRO1309-, PRO1316-, PRO1383-, PRO1384-, PRO1431-, PRO1434-, PRO1475-, PRO1481-, PRO1568-, PRO1573-, PRO1599-, PRO1604-, PRO1605-, PRO1693-, PRO1753-, PRO1755-, PRO1777-, PRO1788-, PRO1864-, PRO1925-, PRO1926-, PRO3566-, PRO4330-, PRO4423-, PRO36935-, PRO4977-, PRO4979-, PRO4980-, PRO4981-, PRO5801-, PRO5995-, PRO6001-, PRO6095-, PRO6182-, PRO7170-, PRO7171-, PRO7436-, PRO9912-, PRO9917-, PRO37337-, PRO37496-, PRO19646-, PRO21718-, PRO19820-, PRO21201-, PRO20026-, PRO20110-, PRO23203- or PRO35250-expressing tumor cells by or by greater than 20%, preferably from about 20% to about 50%, and even more preferably, by or by greater than 50% (e.g., from about 50% to about 100%) as compared to the appropriate control, the control typically being tumor cells not treated with the antibody, oligopeptide or other organic molecule being tested. Growth inhibition can be measured at an antibody concentration of about 0.1 to 30 .mu.g/ml or about 0.5 nM to 200 nM in cell culture, where the growth inhibition is determined 1-10 days after exposure of the tumor cells to the antibody. Growth inhibition of tumor cells in vivo can be determined in various ways. The antibody is growth inhibitory in vivo if administration of the anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibody at about 1 .mu.g/kg to about 100 mg/kg body weight results in reduction in tumor size or tumor cell proliferation within about 5 days to 3 months from the first administration of the antibody, preferably within about 5 to 30 days.

[0378] An antibody, oligopeptide or other organic molecule which "induces apoptosis" is one which induces programmed cell death as determined by binding of annexin V, fragmentation of DNA, cell shrinkage, dilation of endoplasmic reticulum, cell fragmentation, and/or formation of membrane vesicles (called apoptotic bodies). The cell is usually one which overexpresses a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide. Preferably the cell is a tumor cell, e.g., a prostate, breast, ovarian, stomach, endometrial, lung, kidney, colon, bladder cell. Various methods are available for evaluating the cellular events associated with apoptosis. For example, phosphatidyl serine (PS) translocation can be measured by annexin binding; DNA fragmentation can be evaluated through DNA laddering; and nuclear/chromatin condensation along with DNA fragmentation can be evaluated by any increase in hypodiploid cells. Preferably, the antibody, oligopeptide or other organic molecule which induces apoptosis is one which results in or in about 2 to 50 fold, preferably in or in about 5 to 50 fold, and most preferably in or in about 10 to 50 fold, induction of annexin binding relative to untreated cell in an annexin binding assay.

[0379] Antibody "effector functions" refer to those biological activities attributable to the Fc region (a native sequence Fc region or amino acid sequence variant Fc region) of an antibody, and vary with the antibody isotype. Examples of antibody effector functions include: C1q binding and complement dependent cytotoxicity; Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; down regulation of cell surface receptors (e.g., B cell receptor); and B cell activation.

[0380] "Antibody-dependent cell-mediated cytotoxicity" or "ADCC" refers to a form of cytotoxicity in which secreted Ig bound onto Fc receptors (FcRs) present on certain cytotoxic cells (e.g., Natural Killer (NK) cells, neutrophils, and macrophages) enable these cytotoxic effector cells to bind specifically to an antigen-bearing target cell and subsequently kill the target cell with cytotoxins. The antibodies "arm" the cytotoxic cells and are absolutely required for such killing. The primary cells for mediating ADCC, NK cells, express Fc.gamma.RIII only, whereas monocytes express Fc.gamma.RI, Fc.gamma.RII and Fc.gamma.RIII. FcR expression on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol. 9:457-92 (1991). To assess ADCC activity of a molecule of interest, an in vitro ADCC assay, such as that described in U.S. Pat. No. 5,500,362 or 5,821,337 may be performed. Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and Natural Killer (NK) cells. Alternatively, or additionally, ADCC activity of the molecule of interest may be assessed in vivo, e.g., in a animal model such as that disclosed in Clynes et al. Proc. Natl. Acad. Sci. U.S.A. 95:652-656 (1998).

[0381] "Fc receptor" or "FcR" describes a receptor that binds to the Fc region of an antibody. The preferred FcR is a native sequence human FcR. Moreover, a preferred FcR is one which binds an IgG antibody (a gamma receptor) and includes receptors of the Fc.gamma.RI, Fc.gamma.RII and Fc.gamma.RIII subclasses, including allelic variants and alternatively spliced forms of these receptors. Fc.gamma.RII receptors include Fc.gamma.RIIA (an "activating receptor") and Fc.gamma.RIIB (an "inhibiting receptor"), which have similar amino acid sequences that differ primarily in the cytoplasmic domains thereof. Activating receptor Fc.gamma.RIIA contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain. Inhibiting receptor Fc.gamma.RIIB contains an immunoreceptor tyrosine-based inhibition motif (ITIM) in its cytoplasmic domain. (see review M. in Daeron, Annu. Rev. Immunol. 15:203-234 (1997)). FcRs are reviewed in Ravetch and Kinet, Annu. Rev. Immunol. 9:457-492 (1991); Capel et al., Immunomethods 4:25-34 (1994); and de Haas et al., J. Lab. Clin. Med. 126:330-41 (1995). Other FcRs, including those to be identified in the future, are encompassed by the term "FcR" herein. The term also includes the neonatal receptor, FcRn, which is responsible for the transfer of maternal IgGs to the fetus (Guyer et al., J. Immunol. 117:587 (1976) and Kim et al., J. Immunol. 24:249 (1994)).

[0382] "Human effector cells" are leukocytes which express one or more FcRs and perform effector functions. Preferably, the cells express at least Fc.gamma.RIII and perform ADCC effector function. Examples of human leukocytes which mediate ADCC include peripheral blood mononuclear cells (PBMC), natural killer (NK) cells, monocytes, cytotoxic T cells and neutrophils; with PBMCs and NK cells being preferred. The effector cells may be isolated from a native source, e.g., from blood.

[0383] "Complement dependent cytotoxicity" or "CDC" refers to the lysis of a target cell in the presence of complement. Activation of the classical complement pathway is initiated by the binding of the first component of the complement system (C1q) to antibodies (of the appropriate subclass) which are bound to their cognate antigen. To assess complement activation, a CDC assay, e.g., as described in Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996), may be performed.

[0384] The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. Examples of cancer include but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia. More particular examples of such cancers include squamous cell cancer, lung cancer (including small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, and squamous carcinoma of the lung), cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer (including gastrointestinal cancer), pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, liver cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma and various types of head and neck cancer, as well as B-cell lymphoma (including low grade/follicular non-Hodgkin's lymphoma (NHL); small lymphocytic (SL) NHL; intermediate grade/follicular NHL; intermediate grade diffuse NHL; high grade immunoblastic NHL; high grade lymphoblastic NHL; high grade small non-cleaved cell NHL; bulky disease NHL; mantle cell lymphoma; AIDS-related lymphoma; and Waldenstrom's Macroglobulinemia); chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL); Hairy cell leukemia; chronic myeloblastic leukemia; and post-transplant lymphoproliferative disorder (PTLD). Preferably, the cancer comprises a tumor that expresses an IGF receptor, more preferably breast cancer, lung cancer, colorectal cancer, or prostate cancer, and most preferably breast or prostate cancer.

[0385] A "chemotherapeutic agent" is a chemical compound useful in the treatment of cancer. Examples of chemotherapeutic agents include alkylating agents such as thiotepa and CYTOXAN.RTM. cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gamma1I and calicheamicin omegaI1 (see, e.g., Agnew, Chem. Intl. Ed. Engl., 33: 183-186 (1994)); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN.RTM. doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK.RTM. polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; diaziquone; 2,2',2''-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL.RTM. paclitaxel (Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE.TM. Cremophor-free, albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), and TAXOTERE.RTM. doxetaxel (Rhone-Poulenc Rorer, Antony, France); chloranbucil; GEMZAR.RTM. gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE.RTM. vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above.

[0386] Also included in this definition are anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX.RTM. tamoxifen), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and FARESTON toremifene; aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASE.RTM. megestrol acetate, AROMASIN.RTM. exemestane, formestanie, fadrozole, RIVIS OR.RTM. vorozole, FEMARA.RTM. letrozole, and ARIMIDEX.RTM. anastrozole; and anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; as well as troxacitabine (a 1,3-dioxolane nucleoside cytosine analog); antisense oligonucleotides, particularly those which inhibit expression of genes in signaling pathways implicated in abherant cell proliferation, such as, for example, PKC-alpha, Ralf and H-Ras; ribozymes such as a VEGF expression inhibitor (e.g., ANGIOZYME.RTM. ribozyme) and a HER2 expression inhibitor; vaccines such as gene therapy vaccines, for example, ALLOVECTIN.RTM. vaccine, LEUVECTIN.RTM. vaccine, and VAXID.RTM. vaccine; PROLEUKIN.RTM. rIL-2; LURTOTECAN.RTM. topoisomerase 1 inhibitor; ABARELIX.RTM. rmRH; and pharmaceutically acceptable salts, acids or derivatives of any of the above.

[0387] The terms "cell proliferative disorder" and "proliferative disorder" refer to disorders that are associated with some degree of abnormal cell proliferation. In one aspect of the invention, the cell proliferative disorder is cancer.

[0388] "Tumor", as used herein, refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues.

[0389] An antibody, oligopeptide or other organic molecule which "induces cell death" is one which causes a viable cell to become nonviable. The cell is one which expresses a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, preferably a cell that overexpresses a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide as compared to a normal cell of the same tissue type. The PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide may be a transmembrane polypeptide expressed on the surface of a cancer cell or may be a polypeptide that is produced and secreted by a cancer cell. Preferably, the cell is a cancer cell, e.g., a breast, ovarian, stomach, endometrial, salivary gland, lung, kidney, colon, thyroid, pancreatic or bladder cell. Cell death in vitro may be determined in the absence of complement and immune effector cells to distinguish cell death induced by antibody-dependent cell-mediated cytotoxicity (ADCC) or complement dependent cytotoxicity (CDC). Thus, the assay for cell death may be performed using heat inactivated serum (i.e., in the absence of complement) and in the absence of immune effector cells. To determine whether the antibody, oligopeptide or other organic molecule is able to induce cell death, loss of membrane integrity as evaluated by uptake of propidium iodide (PI), trypan blue (see Moore et al. Cytotechnology 17:1-11 (1995)) or 7AAD can be assessed relative to untreated cells. Preferred cell death-inducing antibodies, oligopeptides or other organic molecules are those which induce PI uptake in the PI uptake assay in BT474 cells.

[0390] As used herein, the term "immunoadhesion" designates antibody-like molecules which combine the binding specificity of a heterologous protein (an "adhesion") with the effector functions of immunoglobulin constant domains. Structurally, the immunoadhesions comprise a fusion of an amino acid sequence with the desired binding specificity which is other than the antigen recognition and binding site of an antibody (i.e., is "heterologous"), and an immunoglobulin constant domain sequence. The adhesion part of an immunoadhesion molecule typically is a contiguous amino acid sequence comprising at least the binding site of a receptor or a ligand. The immunoglobulin constant domain sequence in the immunoadhesion may be obtained from any immunoglobulin, such as IgG-1, IgG-2, IgG-3, or IgG-4 subtypes, IgA (including IgA-1 and IgA-2), IgE, IgD or IgM.

[0391] The word "label" when used herein refers to a detectable compound or composition which is conjugated directly or indirectly to the antibody so as to generate a "labeled" antibody. The label may be detectable by itself (e.g. radioisotope labels or fluorescent labels) or, in the case of an enzymatic label, may catalyze chemical alteration of a substrate compound or composition which is detectable.

[0392] "Replication-preventing agent" is an agent wherein replication, function, and/or growth of the cells is inhibited or prevented, or cells are destroyed, no matter what the mechanism, such as by apoptosis, angiostaxis, cytosis, tumoricide, mytosis inhibition, blocking cell cycle progression, arresting cell growth, binding to tumors, acting as cellular mediators, etc. Such agents include a chemotherapeutic agent, cytotoxic agent, cytokine, growth-inhibitory agent, or anti-hormonal agent, e.g., an anti-estrogen compound such as tamoxifen, an anti-progesterone such as onapristone (see, EP 616 812); or an anti-androgen such as flutamide, as well as aromidase inhibitors, or a hormonal agent such as an androgen.

[0393] The term "cytotoxic agent" as used herein refers to a substance that inhibits or prevents the function of cells and/or causes destruction of cells. The term is intended to include radioactive isotopes (e.g., At.sup.211, I.sup.131, I.sup.125, Y.sup.90, Re.sup.186, Re.sup.188, Sm.sup.153, Bi.sup.212, P.sup.32 and radioactive isotopes of Lu), chemotherapeutic agents e.g. methotrexate, adriamicin, vinca alkaloids (vincristine, vinblastine, etoposide), doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin or other intercalating agents, enzymes and fragments thereof such as nucleolytic enzymes, antibiotics, and toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and/or variants thereof, and the various antitumor or anticancer agents disclosed below. Other cytotoxic agents are described below. A tumoricidal agent causes destruction of tumor cells.

[0394] Preferred cytotoxic agents herein for the specific tumor types to use in combination with the antagonists herein are as follows:

1. Prostate cancer: androgens, docetaxel, paclitaxel, estramustine, doxorubicin, mitoxantrone, antibodies to ErbB2 domain(s) such as 2C4 (WO 01/00245; hybridoma ATCC HB-12697), which binds to a region in the extracellular domain of ErbB2 (e.g., any one or more residues in the region from about residue 22 to about residue 584 of ErbB2, inclusive), AVASTIN'' anti-vascular endothelial growth factor (VEGF), TARCEVA.TM. OSI-774 (erlotinib) (Genenetech and OSI Pharmaceuticals), or other epidermal growth factor, receptor tyrosine kinase inhibitors (EGFR TKI's). 2. Stomach cancer: 5-fluorouracil (5FU), XELODA.TM. capecitabine, methotrexate, etoposide, cisplatin/carboplatin, pacliitaxel, docetaxel, gemcitabine, doxorubicin, and CPT-11 (camptothcin-11; irinotecan, USA Brand Name: CAMPTOSAR.RTM.). 3. Pancreatic cancer: gemcitabine, 5FU, XELODA.TM. capecitabine, CPT-11, docetaxel, paclitaxel, cisplatin, carboplatin, TARCEVA.TM. erlotinib, and other EGFR TKI's. 4. Colorectal cancer: 5FU, XELODA.TM. capecitabine, CPT-11, oxaliplatin, AVASTIN.TM. anti-VEGF, TARCEVA.TM. erlotinib and other EGFR TKI's, and ERBITUX.TM. (formerly known as IMC-C225) human:murine-chimerized monoclonal antibody that binds to EGFR and blocks the ability of EGF to initiate receptor activation and signaling to the tumor. 5. Renal cancer: IL-2, interferon alpha, AVASTIN.TM. anti-VEGF, MEGACE.TM. (Megestrol acetate) progestin, vinblastine, TARCEVA.TM. erlotinib, and other EGFR TKI's.

[0395] A "growth inhibitory agent" when used herein refers to a compound or composition which inhibits growth of a cell, especially a PRO69122-, PRO204-, PRO214-, PRO222-, PRO234-, PRO265-, PRO309-, PRO332-, PRO342-, PRO356-, PRO540-, PRO618-, PRO944-, PRO994-, PRO1079-, PRO1110-, PRO1122-, PRO1138-, PRO1190-, PRO1272-, PRO1286-, PRO1295-, PRO1309-, PRO1316-, PRO1383-, PRO1384-, PRO1431-, PRO1434-, PRO1475-, PRO1481-, PRO1568-, PRO1573-, PRO1599-, PRO1604-, PRO1605-, PRO1693-, PRO1753-, PRO1755-, PRO1777-, PRO1788-, PRO1864-, PRO1925-, PRO1926-, PRO3566-, PRO4330-, PRO4423-, PRO36935-, PRO4977-, PRO4979-, PRO4980-, PRO4981-, PRO5801-, PRO5995-, PRO6001-, PRO6095-, PRO6182-, PRO7170-, PRO7171-, PRO7436-, PRO9912-, PRO9917-, PRO37337-, PRO37496-, PRO19646-, PRO21718-, PRO19820-, PRO21201-, PRO20026-, PRO20110-, PRO23203- or PRO35250-expressing cancer cell, either in vitro or in vivo. Thus, the growth inhibitory agent may be one which significantly reduces the percentage of PRO69122-, PRO204-, PRO214-, PRO222-, PRO234-, PRO265-, PRO309-, PRO332-, PRO342-, PRO356-, PRO540-, PRO618-, PRO944-, PRO994-, PRO1079-, PRO1110-, PRO1122-, PRO1138-, PRO1190-, PRO1272-, PRO1286-, PRO1295-, PRO1309-, PRO1316-, PRO1383-, PRO1384-, PRO1431-, PRO1434-, PRO1475-, PRO1481-, PRO1568-, PRO1573-, PRO1599-, PRO1604-, PRO1605-, PRO1693-, PRO1753-, PRO1755-, PRO1777-, PRO1788-, PRO1864-, PRO1925-, PRO1926-, PRO3566-, PRO4330-, PRO4423-, PRO36935-, PRO4977-, PRO4979-, PRO4980-, PRO4981-, PRO5801-, PRO5995-, PRO6001-, PRO6095-, PRO6182-, PRO7170-, PRO7171-, PRO7436-, PRO9912-, PRO9917-, PRO37337-, PRO37496-, PRO19646-, PRO21718-, PRO19820-, PRO21201-, PRO20026-, PRO20110-, PRO23203- or PRO35250-expressing cells in S phase. Examples of growth inhibitory agents include agents that block cell cycle progression (at a place other than S phase), such as agents that induce G1 arrest and M-phase arrest. Classical M-phase blockers include the vincas (vincristine and vinblastine), taxanes, and topoisomerase II inhibitors such as doxorubicin, epirubicin, daunorubicin, etoposide, and bleomycin. Those agents that arrest G1 also spill over into S-phase arrest, for example, DNA alkylating agents such as tamoxifen, prednisone, dacarbazine, mechlorethamine, cisplatin, methotrexate, 5-fluorouracil, and ara-C. Further information can be found in The Molecular Basis of Cancer, Mendelsohn and Israel, eds., Chapter 1, entitled "Cell cycle regulation, oncogenes, and antineoplastic drugs" by Murakami at al. (WB Saunders: Philadelphia, 1995), especially p. 13. The taxanes (paclitaxel and docetaxel) are anticancer drugs both derived from the yew tree. Docetaxel (TAXOTERE.RTM., Rhone-Poulenc Rorer), derived from the European yew, is a semisynthetic analogue of paclitaxel (TAXOL.RTM., Bristol-Myers Squibb). Paclitaxel and docetaxel promote the assembly of microtubules from tubulin dimers and stabilize microtubules by preventing depolymerization, which results in the inhibition of mitosis in cells.

[0396] "Doxorubicin" is an anthracycline antibiotic. The full chemical name of doxorubicin is (8S-cis)-10-[(3-amino-2,3,6-trideoxy-.alpha.-L-lyxo-hexapyranosyl)oxy]-7,- 8,9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-5,12-napht- hacenedione.

[0397] The term "cytokine" is a generic term for proteins released by one cell population which act on another cell as intercellular mediators. Examples of such cytokines are lymphokines, monokines, and traditional polypeptide hormones. Included among the cytokines are growth hormone such as human growth hormone, N-methionyl human growth hormone, and bovine growth hormone; parathyroid hormone; thyroxine; insulin; proinsulin; relaxin; prorelaxin; glycoprotein hormones such as follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), and luteinizing hormone (LH); hepatic growth factor; fibroblast growth factor; prolactin; placental lactogen; tumor necrosis factor-.alpha. and -.beta.; mullerian-inhibiting substance; mouse gonadotropin-associated peptide; inhibin; activin; vascular endothelial growth factor; integrin; thrombopoietin (TPO); nerve growth factors such as NGF-.beta.; platelet-growth factor; transforming growth factors (TGFs) such as TGF-.alpha. and TGF-.beta.; insulin-like growth factor-I and -II; erythropoietin (EPO); osteoinductive factors; interferons such as interferon-.alpha., -.beta., and -.gamma.; colony stimulating factors (CSFs) such as macrophage-CSF (M-CSF); granulocyte-macrophage-CSF (GM-CSF); and granulocyte-CSF (G-CSF); interleukins (ILs) such as IL-1, IL-1a, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-11, IL-12; a tumor necrosis factor such as TNF-.alpha. or TNF-.beta.; and other polypeptide factors including LIP and kit ligand (KL). As used herein, the term cytokine includes proteins from natural sources or from recombinant cell culture and biologically active equivalents of the native sequence cytokines.

[0398] The term "package insert" is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, contraindications and/or warnings concerning the use of such therapeutic products.

[0399] The term "gene" refers to (a) a gene containing at least one of the DNA sequences disclosed herein; (b) any DNA sequence that encodes the amino acid sequence encoded by the DNA sequences disclosed herein and/or; (c) any DNA sequence that hybridizes to the complement of the coding sequences disclosed herein. Preferably, the term includes coding as well as noncoding regions, and preferably includes all sequences necessary for normal gene expression.

[0400] The term "gene targeting" refers to a type of homologous recombination that occurs when a fragment of genomic DNA is introduced into a mammalian cell and that fragment locates and recombines with endogenous homologous sequences. Gene targeting by homologous recombination employs recombinant DNA technologies to replace specific genomic sequences with exogenous DNA of particular design.

[0401] The term "homologous recombination" refers to the exchange of DNA fragments between two DNA molecules or chromatids at the site of homologous nucleotide sequences.

[0402] The term "target gene" (alternatively referred to as "target gene sequence" or "target DNA sequence") refers to any nucleic acid molecule, polynucleotide, or gene to be modified by homologous recombination. The target sequence includes an intact gene, an exon or intron, a regulatory sequence or any region between genes. The target gene my comprise a portion of a particular gene or genetic locus in the individual's genomic DNA.

[0403] "Disruption" of a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 gene occurs when a fragment of genomic DNA locates and recombines with an endogenous homologous sequence wherein the disruption is a deletion of the native gene or a portion thereof, or a mutation in the native gene or wherein the disruption is the functional inactivation of the native gene. Alternatively, sequence disruptions may be generated by nonspecific insertional inactivation using a gene trap vector (i.e. non-human transgenic animals containing and expressing a randomly inserted transgene; see for example U.S. Pat. No. 6,436,707 issued Aug. 20, 2002). These sequence disruptions or modifications may include insertions, missense, frameshift, deletion, or substitutions, or replacements of DNA sequence, or any combination thereof. Insertions include the insertion of entire genes, which may be of animal, plant, fungal, insect, prokaryotic, or viral origin. Disruption, for example, can alter the normal gene product by inhibiting its production partially or completely or by enhancing the normal gene product's activity. Preferably, the disruption is a null disruption, wherein there is no significant expression of the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 gene.

[0404] The term "native expression" refers to the expression of the full-length polypeptide encoded by the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 gene, at expression levels present in the wild-type mouse. Thus, a disruption in which there is "no native expression" of the endogenous PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 gene refers to a partial or complete reduction of the expression of at least a portion of a polypeptide encoded by an endogenous PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 gene of a single cell, selected cells, or all of the cells of a mammal.

[0405] The term "knockout" refers to the disruption of a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 gene wherein the disruption results in: the functional inactivation of the native gene; the deletion of the native gene or a portion thereof; or a mutation in the native gene.

[0406] The term "knock-in" refers to the replacement of the mouse ortholog (or other mouse gene) with a human cDNA encoding any of the specific human PRO69122-, PRO204-, PRO214-, PRO222-, PRO234-, PRO265-, PRO309-, PRO332-, PRO342-, PRO356-, PRO540-, PRO618-, PRO944-, PRO994-, PRO1079-, PRO1110-, PRO1122-, PRO1138-, PRO1190-, PRO1272-, PRO1286-, PRO1295-, PRO1309-, PRO1316-, PRO1383-, PRO1384-, PRO1431-, PRO1434-, PRO1475-, PRO1481-, PRO1568-, PRO1573-, PRO1599-, PRO1604-, PRO1605-, PRO1693-, PRO1753-, PRO1755-, PRO1777-, PRO1788-, PRO1864-, PRO1925-, PRO1926-, PRO3566-, PRO4330-, PRO4423-, PRO36935-, PRO4977-, PRO4979-, PRO4980-, PRO4981-, PRO5801-, PRO5995-, PRO6001-, PRO6095-, PRO6182-, PRO7170-, PRO7171-, PRO7436-, PRO9912-, PRO9917-, PRO37337-, PRO37496-, PRO19646-, PRO21718-, PRO19820-, PRO21201-, PRO20026-, PRO20110-, PRO23203- or PRO35250-encoding genes or variants thereof (ie. the disruption results in a replacement of a native mouse gene with a native human gene).

[0407] The term "construct" or "targeting construct" refers to an artificially assembled DNA segment to be transferred into a target tissue, cell line or animal. Typically, the targeting construct will include a gene or a nucleic acid sequence of particular interest, a marker gene and appropriate control sequences. As provided herein, the targeting construct comprises a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 targeting construct. A "PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 targeting construct" includes a DNA sequence homologous to at least one portion of a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 gene and is capable of producing a disruption in a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 gene in a host cell.

[0408] The term "transgenic cell" refers to a cell containing within its genome a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 gene that has been disrupted, modified, altered, or replaced completely or partially by the method of gene targeting.

[0409] The term "transgenic animal" refers to an animal that contains within its genome a specific gene that has been disrupted or otherwise modified or mutated by the methods described herein or methods otherwise well known in the art. Preferably the non-human transgenic animal is a mammal. More preferably, the mammal is a rodent such as a rat or mouse. In addition, a "transgenic animal" may be a heterozygous animal (i.e., one defective allele and one wild-type allele) or a homozygous animal (i.e., two defective alleles). An embryo is considered to fall within the definition of an animal. The provision of an animal includes the provision of an embryo or foetus in utero, whether by mating or otherwise, and whether or not the embryo goes to term.

[0410] As used herein, the terms "selective marker" and position selection marker" refer to a gene encoding a product that enables only the cells that carry the gene to survive and/or grow under certain conditions. For example, plant and animal cells that express the introduced neomycin resistance (Neo') gene are resistant to the compound G418. Cells that do not carry the Neo.sup.r gene marker are killed by G418. Other positive selection markers are known to, or are within the purview of, those of ordinary skill in the art.

[0411] The term "modulates" or "modulation" as used herein refers to the decrease, inhibition, reduction, amelioration, increase or enhancement of a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 gene function, expression, activity, or alternatively a phenotype associated with PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 gene.

[0412] The term "ameliorates" or "amelioration" as used herein refers to a decrease, reduction or elimination of a condition, disease, disorder, or phenotype, including an abnormality or symptom.

[0413] The term "abnormality" refers to any disease, disorder, condition, or phenotype in which PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 is implicated, including pathological conditions and behavioral observations.

TABLE-US-00001 TABLE 1 /* * * C-C increased from 12 to 15 * Z is average of EQ * B is average of ND * match with stop is _M; stop-stop = 0; J (joker) match = 0 */ #define _M -8 /* value of a match with a stop */ int _day[26][26] = { /* A B C D E F G H I J K L M N O P Q R S T U V W X Y Z */ /* A */ { 2, 0,-2, 0, 0,-4, 1,-1,-1, 0,-1,-2,-1, 0,_M, 1, 0,-2, 1, 1, 0, 0,-6, 0,-3, 0}, /* B */ { 0, 3,-4, 3, 2,-5, 0, 1,-2, 0, 0,-3,-2, 2,_M,-1, 1, 0, 0, 0, 0,-2,-5, 0,-3, 1}, /* C */ {-2,-4,15,-5,-5,-4,-3,-3,-2, 0,-5,-6,-5,-4,_M,-3,-5,-4, 0,-2, 0,-2,-8, 0, 0,-5}, /* D */ { 0, 3,-5, 4, 3,-6, 1, 1,-2, 0, 0,-4,-3, 2,_M,-1, 2,-1, 0, 0, 0,-2,-7, 0,-4, 2}, /* E */ { 0, 2,-5, 3, 4,-5, 0, 1,-2, 0, 0,-3,-2, 1,_M,-1, 2,-1, 0, 0, 0,-2,-7, 0,-4, 3}, /* F */ {-4,-5,-4,-6,-5, 9,-5,-2, 1, 0,-5, 2, 0,-4,_M,-5,-5,-4,-3,-3, 0,-1, 0, 0, 7,-5}, /* G */ { 1, 0,-3, 1, 0,-5, 5,-2,-3, 0,-2,-4,-3, 0,_M,-1,-1,-3, 1, 0, 0,-1,-7, 0,-5, 0}, /* H */ {-1, 1,-3, 1, 1,-2,-2, 6,-2, 0, 0,-2,-2, 2,_M, 0, 3, 2,-1,-1, 0,-2,-3, 0, 0, 2}, /* I */ {-1,-2,-2,-2,-2, 1,-3,-2, 5, 0,-2, 2, 2,-2,_M,-2,-2,-2,-1, 0, 0, 4,-5, 0,-1,-2}, /* J */ { 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0,_M, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0}, /* K */ {-1, 0,-5, 0, 0,-5,-2, 0,-2, 0, 5,-3, 0, 1,_M,-1, 1, 3, 0, 0, 0,-2,-3, 0,-4, 0}, /* L */ {-2,-3,-6,-4,-3, 2,-4,-2, 2, 0,-3, 6, 4,-3,_M,-3,-2,-3,-3,-1, 0, 2,-2, 0,-1,-2}, /* M */ {-1,-2,-5,-3,-2, 0,-3,-2, 2, 0, 0, 4, 6,-2,_M,-2,-1, 0,-2,-1, 0, 2,-4, 0,-2,-1}, /* N */ { 0, 2,-4, 2, 1,-4, 0, 2,-2, 0, 1,-3,-2, 2,_M,-1, 1, 0, 1, 0, 0,-2,-4, 0,-2, 1}, /* O */ {_M,_M,_M,_M,_M,_M,_M,_M,_M,_M,_M,_M,_M,_M, 0,_M,_M,_M,_M,_M,_M,_M,_M,_M,_M,_M}, /* P */ { 1,-1,-3,-1,-1,-5,-1, 0,-2, 0,-1,-3,-2,-1,_M, 6, 0, 0, 1, 0, 0,-1,-6, 0,-5, 0}, /* Q */ { 0, 1,-5, 2, 2,-5,-1, 3,-2, 0, 1,-2,-1, 1,_M, 0, 4, 1,-1,-1, 0,-2,-5, 0,-4, 3}, /* R */ {-2, 0,-4,-1,-1,-4,-3, 2,-2, 0, 3,-3, 0, 0,_M, 0, 1, 6, 0,-1, 0,-2, 2, 0,-4, 0}, /* S */ { 1, 0, 0, 0, 0,-3, 1,-1,-1, 0, 0,-3,-2, 1,_M, 1,-1, 0, 2, 1, 0,-1,-2, 0,-3, 0}, /* T */ { 1, 0,-2, 0, 0,-3, 0,-1, 0, 0, 0,-1,-1, 0,_M, 0,-1,-1, 1, 3, 0, 0,-5, 0,-3, 0}, /* U */ { 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0,_M, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0}, /* V */ { 0,-2,-2,-2,-2,-1,-1,-2, 4, 0,-2, 2, 2,-2,_M,-1,-2,-2,-1, 0, 0, 4,-6, 0,-2,-2}, /* W */ {-6,-5,-8,-7,-7, 0,-7,-3,-5, 0,-3,-2,-4,-4,_M,-6,-5, 2,-2,-5, 0,-6,17, 0, 0,-6}, /* X */ { 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0,_M, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0}, /* Y */ {-3,-3, 0,-4,-4, 7,-5, 0,-1, 0,-4,-1,-2,-2,_M,-5,-4,-4,-3,-3, 0,-2, 0, 0,10,-4}, /* Z */ { 0, 1,-5, 2, 3,-5, 0, 2,-2, 0, 0,-2,-1, 1,_M, 0, 3, 0, 0, 0, 0,-2,-6, 0,-4, 4} }; /* */ #include <stdio.h> #include <ctype.h> #define MAXJMP 16 /* max jumps in a diag */ #define MAXGAP 24 /* don't continue to penalize gaps larger than this */ #define JMPS 1024 /* max jmps in an path */ #define MX 4 /* save if there's at least MX-1 bases since last jmp */ #define DMAT 3 /* value of matching bases */ #define DMIS 0 /* penalty for mismatched bases */ #define DINS0 8 /* penalty for a gap */ #define DINS1 1 /* penalty per base */ #define PINS0 8 /* penalty for a gap */ #define PINS1 4 /* penalty per residue */ struct jmp { short n[MAXJMP]; /* size of jmp (neg for dely) */ unsigned short x[MAXJMP]; /* base no. of jmp in seq x */ }; /* limits seq to 2{circumflex over ( )}16 -1 */ struct diag { int score; /* score at last jmp */ long offset; /* offset of prev block */ short ijmp; /* current jmp index */ struct jmp jp; /* list of jmps */ }; struct path { int spc; /* number of leading spaces */ short n[JMPS];/* size of jmp (gap) */ int x[JMPS];/* loc of jmp (last elem before gap) */ }; char *ofile; /* output file name */ char *namex[2]; /* seq names: getseqs( ) */ char *prog; /* prog name for err msgs */ char *seqx[2]; /* seqs: getseqs( ) */ int dmax; /* best diag: nw( ) */ int dmax( ); /* final diag */ int dna; /* set if dna: main( ) */ int endgaps; /* set if penalizing end gaps */ int gapx, gapy; /* total gaps in seqs */ int len0, len1; /* seq lens */ int ngapx, ngapy; /* total size of gaps */ int smax; /* max score: nw( ) */ int *xbm; /* bitmap for matching */ long offset; /* current offset in jmp file */ struct diag *dx; /* holds diagonals */ struct path pp[2]; /* holds path for seqs */ char *calloc( ), *malloc( ), *index( ), *strcpy( ); char *getseq( ), *g_calloc( ); /* Needleman-Wunsch alignment program * * usage: progs file1 file2 * where file1 and file2 are two dna or two protein sequences. * The sequences can be in upper- or lower-case an may contain ambiguity * Any lines beginning with `;`, `>` or `<` are ignored * Max file length is 65535 (limited by unsigned short x in the jmp struct) * A sequence with 1/3or more of its elements ACGTU is assumed to be DNA * Output is in the file "align.out" * * The program may create a tmp file in /tmp to hold info about traceback. * Original version developed under BSD 4.3 on a vax 8650 */ #include "nw.h" #include "day.h" static _dbval[26] = { 1,14,2,13,0,0,4,11,0,0,12,0,3,15,0,0,0,5,6,8,8,7,9,0,10,0 }; static _pbval[26] = { 1, 2|(1<<(`D`-`A`))|(1<<(`N`-`A`)), 4, 8, 16, 32, 64, 128, 256, 0xFFFFFFF, 1<<10, 1<<11, 1<<12, 1<<13, 1<<14, 1<<15, 1<<16, 1<<17, 1<<18, 1<<19, 1<<20, 1<<21, 1<<22, 1<<23, 1<<24, 1<<25|(1<<(`E`-`A`))|(1<<(`Q`-`A`)) }; main(ac, av) main int ac; char *av[ ]; { prog = av[0]; if (ac != 3) { fprintf(stderr,"usage: %s file1 file2\n", prog); fprintf(stderr,"where file1 and file2 are two dna or two protein sequences.\n"); fprintf(stderr,"The sequences can be in upper- or lower-case\n"); fprintf(stderr,"Any lines beginning with `;` or `<` are ignored\n"); fprintf(stderr,"Output is in the file \"align.out\"\n"); exit(1); } namex[0] = av[1]; namex[1] = av[2]; seqx[0] = getseq(namex[0], &len0); seqx[1] = getseq(namex[1], &len1); xbm = (dna)? _dbval : _pbval; endgaps = 0; /* 1 to penalize endgaps */ ofile = "align.out"; /* output file */ nw( ); /* fill in the matrix, get the possible jmps */ readjmps( ); /* get the actual jmps */ print( ); /* print stats, alignment */ cleanup(0); /* unlink any tmp files */} /* do the alignment, return best score: main( ) * dna: values in Fitch and Smith, PNAS, 80, 1382-1386, 1983 * pro: PAM 250 values * When scores are equal, we prefer mismatches to any gap, prefer * a new gap to extending an ongoing gap, and prefer a gap in seqx * to a gap in seq y. */ nw( ) nw { char *px, *py; /* seqs and ptrs */ int *ndely, *dely; /* keep track of dely */ int ndelx, delx; /* keep track of delx */ int *tmp; /* for swapping row( ), row1 */ int mis; /* score for each type */ int ins0, ins1; /* insertion penalties */ register id; /* diagonal index */ register ij; /* jmp index */ register *col0, *col1; /* score for curr, last row */ register xx, yy; /* index into seqs */ dx = (struct diag *)g_calloc("to get diags", len0+len1+1, sizeof(struct diag)); ndely = (int *)g_calloc("to get ndely", len1+1, sizeof(int)); dely = (int *)g_calloc("to get dely", len1+1, sizeof(int)); col0 = (int *)g_calloc("to get col0", len1+1, sizeof(int)); col1 = (int *)g_calloc("to get col1", len1+1, sizeof(int)); ins0 = (dna)? DINS0 : PINS0; ins1 = (dna)? DINS1 : PINS1; smax = -10000; if (endgaps) { for (col0[0] = dely[0] = -ins0, yy = 1; yy <= len1; yy++) { col0[yy] = dely[yy] = col0[yy-1] - ins1; ndely[yy] = yy; } col0[0] = 0; /* Waterman Bull Math Biol 84 */ } else for (yy = 1; yy <= len1; yy++) dely[yy] = -ins0; /* fill in match matrix */ for (px = seqx[0], xx = 1; xx <= len0; px++, xx++) { /* initialize first entry in col */ if (endgaps) { if (xx == 1) col1[0] = delx = -(ins0+ins1); else col1[0] = delx = col0[0] - ins1; ndelx = xx; } else { col1[0] = 0; delx = -ins0; ndelx = 0; } ...nw for (py = seqx[1], yy = 1; yy <= len1; py++, yy++) { mis = col0[yy-1]; if (dna) mis += (xbm[*px-`A`]&xbm[*py-`A`])? DMAT : DMIS; else mis += _day[*px-`A`][*py-`A`]; /* update penalty for del in x seq; * favor new del over ongong del * ignore MAXGAP if weighting endgaps */ if (endgaps || ndely[yy] < MAXGAP) { if (col0[yy] - ins0 >= dely[yy]) { dely[yy] = col0[yy] - (ins0+ins1); ndely[yy] = 1; } else { dely[yy] -= ins1; ndely[yy]++; } } else { if (col0[yy] - (ins0+ins1) >= dely[yy]) { dely[yy] = col0[yy] - (ins0+ins1); ndely[yy] = 1; } else ndely[yy]++; } /* update penalty for del in y seq; * favor new del over ongong del */

if (endgaps || ndelx < MAXGAP) { if (col1[yy-1] - ins0 >= delx) { delx = col1[yy-1] - (ins0+ins1); ndelx = 1; } else { delx -= ins1; ndelx++; } } else { if (col1[yy-1] - (ins0+ins1) >= delx) { delx = col1[yy-1] - (ins0+ins1); ndelx = 1; } else ndelx++; } /* pick the maximum score; we're favoring * mis over any del and delx over dely */ ...nw id = xx - yy + len1 - 1; if (mis >= delx && mis >= dely[yy]) col1[yy] = mis; else if (delx >= dely[yy]) { col1[yy] = delx; ij = dx[id].ijmp; if (dx[id].jp.n[0] && (!dna || (ndelx >= MAXJMP && xx > dx[id].jp.x[ij]+MX) || mis > dx[id].score+DINS0)) { dx[id].ijmp++; if (++ij >= MAXJMP) { writejmps(id); ij = dx[id].ijmp = 0; dx[id].offset = offset; offset += sizeof(struct jmp) + sizeof(offset); } } dx[id].jp.n[ij] = ndelx; dx[id].jp.x[ij] = xx; dx[id].score = delx; } else { col1[yy] = dely[yy]; ij = dx[id].ijmp; if (dx[id].jp.n[0] && (!dna || (ndely[yy] >= MAXJMP && xx > dx[id].jp.x[ij]+MX) || mis > dx[id].score+DINS0)) { dx[id].ijmp++; if (++ij >= MAXJMP) { writejmps(id); ij = dx[id].ijmp = 0; dx[id].offset = offset; offset += sizeof(struct jmp) + sizeof(offset); } } dx[id].jp.n[ij] = -ndely[yy]; dx[id].jp.x[ij] = xx; dx[id].score = dely[yy]; } if (xx == len0 && yy < len1) { /* last col */ if (endgaps) col1[yy] -= ins0+ins1*(len1-yy); if (col1[yy] > smax) { smax = col1[yy]; dmax = id; } } } if (endgaps && xx < len0) col1[yy-1] -= ins0+ins1*(len0-xx); if (col1[yy-1] > smax) { smax = col1[yy-1]; dmax = id; } tmp = col0; col0 = col1; col1 = tmp; } (void) free((char *)ndely); (void) free((char *)dely); (void) free((char *)col0); (void) free((char *)col1); } /* * * print( ) -- only routine visible outside this module * * static: * getmat( ) -- trace back best path, count matches: print( ) * pr_align( ) -- print alignment of described in array p[ ]: print( ) * dumpblock( ) -- dump a block of lines with numbers, stars: pr_align( ) * nums( ) -- put out a number line: dumpblock( ) * putline( ) -- put out a line (name, [num], seq, [num]): dumpblock( ) * stars( ) - -put a line of stars: dumpblock( ) * stripname( ) -- strip any path and prefix from a seqname */ #include "nw.h" #define SPC 3 #define P_LINE 256 /* maximum output line */ #define P_SPC 3 /* space between name or num and seq */ extern _day[26][26]; int olen; /* set output line length */ FILE *fx; /* output file */ print( ) print { int lx, ly, firstgap, lastgap; /* overlap */ if ((fx = fopen(ofile, "w")) == 0) { fprintf(stderr,"%s: can't write %s\n", prog, ofile); cleanup(1); } fprintf(fx, "<first sequence: %s (length = %d)\n", namex[0], len0); fprintf(fx, "<second sequence: %s (length = %d)\n", namex[1], len1); olen = 60; lx = len0; ly = len1; firstgap = lastgap = 0; if (dmax < len1 - 1) { /* leading gap in x */ pp[0].spc = firstgap = len1 - dmax - 1; ly -= pp[0].spc; } else if (dmax > len1 - 1) { /* leading gap in y */ pp[1].spc = firstgap = dmax - (len1 - 1); lx -= pp[1].spc; } if (dmax0 < len0 - 1) { /* trailing gap in x */ lastgap = len0 - dmax0 -1; lx -= lastgap; } else if (dmax0 > len0 - 1) { /* trailing gap in y */ lastgap = dmax0 - (len0 - 1); ly -= lastgap; } getmat(lx, ly, firstgap, lastgap); pr_align( ); } /* * trace back the best path, count matches */ static getmat(lx, ly, firstgap, lastgap) getmat int lx, ly; /* "core" (minus endgaps) */ int firstgap, lastgap; /* leading trailing overlap */ { int nm, i0, i1, siz0, siz1; char outx[32]; double pct; register n0, n1; register char *p0, *p1; /* get total matches, score */ i0 = i1 = siz0 = siz1 = 0; p0 = seqx[0] + pp[1].spc; p1 = seqx[1] + pp[0].spc; n0 = pp[1].spc + 1; n1 = pp[0].spc + 1; nm = 0; while ( *p0 && *p1 ) { if (siz0) { p1++; n1++; siz0--; } else if (siz1) { p0++; n0++; siz1--; } else { if (xbm[*p0-`A`]&xbm[*p1-`A`]) nm++; if (n0++ == pp[0].x[i0]) siz0 = pp[0].n[i0++]; if (n1++ == pp[1].x[i1]) siz1 = pp[1].n[i1++]; p0++; p1++; } } /* pct homology: * if penalizing endgaps, base is the shorter seq * else, knock off overhangs and take shorter core */ if (endgaps) lx = (len0 < len1)? len0 : len1; else lx = (lx < ly)? lx : ly; pct = 100.*(double)nm/(double)lx; fprintf(fx, "\n"); fprintf(fx, "<%d match%s in an overlap of %d: %.2f percent similarity\n", nm, (nm == 1)? "" : "es", lx, pct); fprintf(fx, "<gaps in first sequence: %d", gapx); ...getmat if (gapx) { (void) sprintf(outx, " (%d %s%s)", ngapx, (dna)? "base":"residue", (ngapx == 1)? "":"s"); fprintf(fx,"%s", outx); fprintf(fx, ", gaps in second sequence: %d", gapy); if (gapy) { (void) sprintf(outx, " (%d %s%s)", ngapy, (dna)? "base":"residue", (ngapy == 1)? "":"s"); fprintf(fx,"%s", outx); } if (dna) fprintf(fx, "\n<score: %d (match = %d, mismatch = %d, gap penalty = %d + %d per base)\n", smax, DMAT, DMIS, DINS0, DINS1); else fprintf(fx, "\n<score: %d (Dayhoff PAM 250 matrix, gap penalty = %d + %d per residue)\n", smax, PINS0, PINS1); if (endgaps) fprintf(fx, "<endgaps penalized. left endgap: %d %s%s, right endgap: %d %s%s\n", firstgap, (dna)? "base" : "residue", (firstgap == 1)? "" : "s", lastgap, (dna)? "base" : "residue", (lastgap == 1)? "" : "s"); else fprintf(fx, "<endgaps not penalized\n"); } static nm; /* matches in core -- for checking */ static lmax; /* lengths of stripped file names */ static ij[2]; /* jmp index for a path */ static nc[2]; /* number at start of current line */ static ni[2]; /* current elem number -- for gapping */ static siz[2]; static char *ps[2]; /* ptr to current element */ static char *po[2]; /* ptr to next output char slot */ static char out[2][P_LINE]; /* output line */ static char star[P_LINE]; /* set by stars( ) */ /* * print alignment of described in struct path pp[ ] */ static pr_align( ) pr_align { int nn; /* char count */ int more; register I; for (I = 0, lmax = 0; I < 2; I++) { nn = stripname(namex[i]); if (nn > lmax) lmax = nn; nc[i] = 1; ni[i] = 1; siz[i] = ij[i] = 0; ps[i] = seqx[i]; po[i] = out[i]; } for (nn = nm = 0, more = 1; more; ) { ...pr_align for (I = more = 0; I < 2; I++) { /* * do we have more of this sequence? */ if (!*ps[i]) continue; more++; if (pp[i].spc) { /* leading space */

*po[i]++ = ` `; pp[i].spc--; } else if (siz[i]) { /* in a gap */ *po[i]++ = `-`; siz[i]--; } else { /* we're putting a seq element */ *po[i] = *ps[i]; if (islower(*ps[i])) *ps[i] = toupper(*ps[i]); po[i]++; ps[i]++; /* * are we at next gap for this seq? */ if (ni[i] == pp[i].x[ij[i]]) { /* * we need to merge all gaps * at this location */ siz[i] = pp[i].n[ij[i]++]; while (ni[i] == pp[i].x[ij[i]]) siz[i] += pp[i].n[ij[i]++]; } ni[i]++; } } if (++nn == olen || !more && nn) { dumpblock( ); for (I = 0; I < 2; I++) po[i] = out[i]; nn = 0; } } } /* * dump a block of lines, including numbers, stars: pr_align( ) */ static dumpblock( ) dumpblock { register I; for (I = 0; I < 2; I++) *po[i]-- = `\0`; ...dumpblock (void) putc(`\n`, fx); for (I = 0; I < 2; I++) { if (*out[i] && (*out[i] != ` ` || *(po[i]) != ` `)) { if (I == 0) nums(I); if (I == 0 && *out[1]) stars( ); putline(I); if (I == 0 && *out[1]) fprintf(fx, star); if (I == 1) nums(I); } } } /* * put out a number line: dumpblock( ) */ static nums(ix) nums int ix; /* index in out[ ] holding seq line */ { char nline[P_LINE]; register I, j; register char *pn, *px, *py; for (pn = nline, I = 0; I < lmax+P_SPC; I++, pn++) *pn = ` `; for (I = nc[ix], py = out[ix]; *py; py++, pn++) { if (*py == ` ` || *py == `-`) *pn = ` `; else { if (I%10 == 0 || (I == 1 && nc[ix] != 1)) { j = (I < 0)? -I : I; for (px = pn; j; j /= 10, px--) *px = j%10 + `0`; if (I < 0) *px = `-`; } else *pn = ` `; I++; } } *pn = `\0`; nc[ix] = I; for (pn = nline; *pn; pn++) (void) putc(*pn, fx); (void) putc(`\n`, fx); } /* * put out a line (name, [num], seq, [num]): dumpblock( ) */ static putline(ix) putline int ix; { ...putline int I; register char *px; for (px = namex[ix], I = 0; *px && *px != `:`; px++, I++) (void) putc(*px, fx); for (; I < lmax+P_SPC; I++) (void) putc(` `, fx); /* these count from 1: * ni[ ] is current element (from 1) * nc[ ] is number at start of current line */ for (px = out[ix]; *px; px++) (void) putc(*px&0x7F, fx); (void) putc(`\n`, fx); } /* * put a line of stars (seqs always in out[0], out[1]): dumpblock( ) */ static stars( ) stars { int I; register char *p0, *p1, cx, *px; if (!*out[0] || (*out[0] == ` ` && *(po[0]) == ` `) || !*out[1] || (*out[1] == ` ` && *(po[1]) == ` `)) return; px = star; for (I = lmax+P_SPC; I; I--) *px++ = ` `; for (p0 = out[0], p1 = out[1]; *p0 && *p1; p0++, p1++) { if (isalpha(*p0) && isalpha(*p1)) { if (xbm[*p0-`A`]&xbm[*p1-`A`]) { cx = `*`; nm++; } else if (!dna && _day[*p0-`A`][*p1-`A`] > 0) cx = `.`; else cx = ` `; } else cx = ` `; *px++ = cx; } *px++ = `\n`; *px = `\0`; } /* * strip path or prefix from pn, return len: pr_align( ) */ static stripname(pn) stripname char *pn; /* file name (may be path) */ { register char *px, *py; py = 0; for (px = pn; *px; px++) if (*px == `/`) py = px + 1; if (py) (void) strcpy(pn, py); return(strlen(pn)); } /* * cleanup( ) -- cleanup any tmp file * getseq( ) -- read in seq, set dna, len, maxlen * g_calloc( ) -- calloc( ) with error checkin * readjmps( ) -- get the good jmps, from tmp file if necessary * writejmps( ) -- write a filled array of jmps to a tmp file: nw( ) */ #include "nw.h" #include <sys/file.h> char *jname = "/tmp/homgXXXXXX"; /* tmp file for jmps */ FILE *fj; int cleanup( ); /* cleanup tmp file */ long lseek( ); /* * remove any tmp file if we blow */ cleanup(I) cleanup int I; { if (fj) (void) unlink(jname); exit(I); } /* * read, return ptr to seq, set dna, len, maxlen * skip lines starting with `;`, `<`, or `>` * seq in upper or lower case */ char * getseq(file, len) getseq char *file; /* file name */ int *len; /* seq len */ { char line[1024], *pseq; register char *px, *py; int natgc, tlen; FILE *fp; if ((fp = fopen(file,"r")) == 0) { fprintf(stderr,"%s: can't read %s\n", prog, file); exit(1); } tlen = natgc = 0; while (fgets(line, 1024, fp)) { if (*line == `;` || *line == `<` || *line == `>`) continue; for (px = line; *px != `\n`; px++) if (isupper(*px) || islower(*px)) tlen++; } if ((pseq = malloc((unsigned)(tlen+6))) == 0) { fprintf(stderr,"%s: malloc( ) failed to get %d bytes for %s\n", prog, tlen+6, file); exit(1); } pseq[0] = pseq[1] = pseq[2] = pseq[3] = `\0`; ...getseq py = pseq + 4; *len = tlen; rewind(fp); while (fgets(line, 1024, fp)) { if (*line == `;` || *line == `<` || *line == `>`) continue; for (px = line; *px != `\n`; px++) { if (isupper(*px)) *py++ = *px; else if (islower(*px)) *py++ = toupper(*px); if (index("ATGCU",*(py-1))) natgc++; } } *py++ = `\0`; *py = `\0`; (void) fclose(fp); dna = natgc > (tlen/3); return(pseq+4); } char * g_calloc(msg, nx, sz) g_calloc char *msg; /* program, calling routine */ int nx, sz; /* number and size of elements */ { char *px, *calloc( ); if ((px = calloc((unsigned)nx, (unsigned)sz)) == 0) { if (*msg) { fprintf(stderr, "%s: g_calloc( ) failed %s (n=%d, sz=%d)\n", prog, msg,

nx, sz); exit(1); } } return(px); } /* * get final jmps from dx[ ] or tmp file, set pp[ ], reset dmax: main( ) */ readjmps( ) readjmps { int fd = -1; int siz, i0, i1; register I, j, xx; if (fj) { (void) fclose(fj); if ((fd = open(jname, O_RDONLY, 0)) < 0) { fprintf(stderr, "%s: can't open( ) %s\n", prog, jname); cleanup(1); } } for (I = i0 = i1 = 0, dmax0 = dmax, xx = len0; ; I++) { while (1) { for (j = dx[dmax].ijmp; j >= 0 && dx[dmax].jp.x[j] >= xx; j--) ; ...readjmps if (j < 0 && dx[dmax].offset && fj) { (void) lseek(fd, dx[dmax].offset, 0); (void) read(fd, (char *)&dx[dmax].jp, sizeof(struct jmp)); (void) read(fd, (char *)&dx[dmax].offset, sizeof(dx[dmax].offset)); dx[dmax].ijmp = MAXJMP-1; } else break; } if (I >= JMPS) { fprintf(stderr, "%s: too many gaps in alignment\n", prog); cleanup(1); } if (j >= 0) { siz = dx[dmax].jp.n[j]; xx = dx[dmax].jp.x[j]; dmax += siz; if (siz < 0) { /* gap in second seq */ pp[1].n[i1] = -siz; xx += siz; /* id = xx - yy + len1 - 1 */ pp[1].x[i1] = xx - dmax + len1 - 1; gapy++; ngapy -= siz; /* ignore MAXGAP when doing endgaps */ siz = (-siz < MAXGAP || endgaps)? -siz : MAXGAP; i1++; } else if (siz > 0) { /* gap in first seq */ pp[0].n[i0] = siz; pp[0].x[i0] = xx; gapx++; ngapx += siz; /* ignore MAXGAP when doing endgaps */ siz = (siz < MAXGAP || endgaps)? siz : MAXGAP; i0++; } } else break; } /* reverse the order of jmps */ for (j = 0, i0--; j < i0; j++, i0--) { I = pp[0].n[j]; pp[0].n[j] = pp[0].n[i0]; pp[0].n[i0] = I; I = pp[0].x[j]; pp[0].x[j] = pp[0].x[i0]; pp[0].x[i0] = I; } for (j = 0, i1--; j < i1; j++, i1--) { I = pp[1].n[j]; pp[1].n[j] = pp[1].n[i1]; pp[1].n[i1] = I; I = pp[1].x[j]; pp[1].x[j] = pp[1].x[i1]; pp[1].x[i1] = I; } if (fd >= 0) (void) close(fd); if (fj) { (void) unlink(jname); fj = 0; offset = 0; } } /* * write a filled jmp struct offset of the prev one (if any): nw( ) */ writejmps(ix) writejmps int ix; { char *mktemp( ); if (!fj) { if (mktemp(jname) < 0) { fprintf(stderr, "%s: can't mktemp( ) %s\n", prog, jname); cleanup(1); } if ((fj = fopen(jname, "w")) == 0) { fprintf(stderr, "%s: can't write %s\n", prog, jname); exit(1); } } (void) fwrite((char *)&dx[ix].jp, sizeof(struct jmp), 1, fj); (void) fwrite((char *)&dx[ix].offset, sizeof(dx[ix].offset), 1, fj); }

TABLE-US-00002 TABLE 2 PRO XXXXXXXXXXXXXXX (Length = 15 amino acids) Comparison XXXXXYYYYYYY (Length = 12 amino acids) Protein % amino acid sequence identity = (the number of identically matching amino acid residues between the two polypeptide sequences as determined by ALIGN-2) divided by (the total number of amino acid residues of the PRO polypeptide) = 5 divided by 15 = 33.3%

TABLE-US-00003 TABLE 3 PRO XXXXXXXXXX (Length = 10 amino acids) Comparison XXXXXYYYYYYZZYZ (Length = 15 amino acids) Protein % amino acid sequence identity = (the number of identically matching amino acid residues between the two polypeptide sequences as determined by ALIGN-2) divided by (the total number of amino acid residues of the PRO polypeptide) = 5 divided by 10 = 50%

TABLE-US-00004 TABLE 4 PRO-DNA NNNNNNNNNNNNNN (Length = 14 nucleotides) Comparison NNNNNNLLLLLLLLLL (Length = 16 nucleotides) DNA % nucleic acid sequence identity = (the number of identically matching nucleotides between the two nucleic acid sequences as determined by ALIGN-2) divided by (the total number of nucleotides of the PRO-DNA nucleic acid sequence) = 6 divided by 14 = 42.9%

TABLE-US-00005 TABLE 5 PRO-DNA NNNNNNNNNNNN (Length = 12 nucleotides) Comparison NNNNLLLVV (Length = 9 nucleotides) DNA % nucleic acid sequence identity = (the number of identically matching nucleotides between the two nucleic acid sequences as determined by ALIGN-2) divided by (the total number of nucleotides of the PRO-DNA nucleic acid sequence) = 4 divided by 12 = 33.3%

II. Compositions and Methods of the Invention

[0414] A. Full-Length PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 Polypeptides

[0415] The present invention provides newly identified and isolated nucleotide sequences encoding polypeptides referred to in the present application as PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides. In particular, cDNAs encoding various PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides have been identified and isolated, as disclosed in further detail in the Examples below. It is noted that proteins produced in separate expression rounds may be given different PRO numbers but the UNQ number is unique for any given DNA and the encoded protein, and will not be changed. However, for sake of simplicity, in the present specification the protein encoded by the full length native nucleic acid molecules disclosed herein as well as all further native homologues and variants included in the foregoing definition of PRO, will be referred to as "PRO/number", regardless of their origin or mode of preparation.

[0416] As disclosed in the Examples below, various cDNA clones have been deposited with the ATCC. The actual nucleotide sequences of those clones can readily be determined by the skilled artisan by sequencing of the deposited clone using routine methods in the art. The predicted amino acid sequence can be determined from the nucleotide sequence using routine skill. For the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides and encoding nucleic acids described herein, Applicants have identified what is believed to be the reading frame best identifiable with the sequence information available at the time.

[0417] B. PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 Polypeptide Variants

[0418] In addition to the full-length native sequence PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides described herein, it is contemplated that PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 variants can be prepared. PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 variants can be prepared by introducing appropriate nucleotide changes into the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 DNA, and/or by synthesis of the desired PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide. Those skilled in the art will appreciate that amino acid changes may alter post-translational processes of the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, such as changing the number or position of glycosylation sites or altering the membrane anchoring characteristics.

[0419] Variations in the native full-length sequence PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide or in various domains of the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide described herein, can be made, for example, using any of the techniques and guidelines for conservative and non-conservative mutations set forth, for instance, in U.S. Pat. No. 5,364,934. Variations may be a substitution, deletion or insertion of one or more codons encoding the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide that results in a change in the amino acid sequence of the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide as compared with the native sequence PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide. Optionally the variation is by substitution of at least one amino acid with any other amino acid in one or more of the domains of the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide. Guidance in determining which amino acid residue may be inserted, substituted or deleted without adversely affecting the desired activity may be found by comparing the sequence of the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide with that of homologous known protein molecules and minimizing the number of amino acid sequence changes made in regions of high homology. Amino acid substitutions can be the result of replacing one amino acid with another amino acid having similar structural and/or chemical properties, such as the replacement of a leucine with a serine, i.e., conservative amino acid replacements. Insertions or deletions may optionally be in the range of about 1 to 5 amino acids. The variation allowed may be determined by systematically making insertions, deletions or substitutions of amino acids in the sequence and testing the resulting variants for activity exhibited by the full-length or mature native sequence.

[0420] PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide fragments are provided herein. Such fragments may be truncated at the N-terminus or C-terminus, or may lack internal residues, for example, when compared with a full length native protein. Certain fragments lack amino acid residues that are not essential for a desired biological activity of the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide.

[0421] PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 fragments may be prepared by any of a number of conventional techniques. Desired peptide fragments may be chemically synthesized. An alternative approach involves generating PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 fragments by enzymatic digestion, e.g., by treating the protein with an enzyme known to cleave proteins at sites defined by particular amino acid residues, or by digesting the DNA with suitable restriction enzymes and isolating the desired fragment. Yet another suitable technique involves isolating and amplifying a DNA fragment encoding a desired polypeptide fragment, by polymerase chain reaction (PCR). Oligonucleotides that define the desired termini of the DNA fragment are employed at the 5' and 3' primers in the PCR. Preferably, PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide fragments share at least one biological and/or immunological activity with the native PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide disclosed herein.

[0422] Conservative substitutions of interest are shown in Table 6 under the heading of preferred substitutions. If such substitutions result in a change in biological activity, then more substantial changes, denominated exemplary substitutions in Table 6, or as further described below in reference to amino acid classes, are preferably introduced and the products screened.

TABLE-US-00006 TABLE 6 Original Exemplary Preferred Residue Substitutions Substitutions Ala (A) Val; Leu; Ile Val Arg .RTM.) Lys; Gln; Asn Lys Asn (N) Gln; His; Asp; Lys; Arg Gln Asp (D) Glu; Asn Glu Cys .COPYRGT.) Ser; Ala Ser Gln (Q) Asn; Glu Asn Glu (E) Asp; Gln Asp Gly (G) Ala Ala His (H) Asn; Gln; Lys; Arg Arg Ile (I) Leu; Val; Met; Ala; Leu Phe; Norleucine Leu (L) Norleucine; Ile; Val; Ile Met; Ala; Phe Lys (K) Arg; Gln; Asn Arg Met (M) Leu; Phe; Ile Leu Phe (F) Trp; Leu; Val; Ile; Ala; Tyr Tyr Pro (P) Ala Ala Ser (S) Thr Thr Thr (T) Val; Ser Ser Trp (W) Tyr; Phe Tyr Tyr (Y) Trp; Phe; Thr; Ser Phe Val (V) Ile; Leu; Met; Phe; Leu Ala; Norleucine

[0423] Substantial modifications in function or immunological identity of the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO1110, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide are accomplished by selecting substitutions that differ significantly in their effect on maintaining (a) the structure of the polypeptide backbone in the area of the substitution, for example, as a sheet or helical conformation, (b) the charge or hydrophobicity of the molecule at the target site, or (c) the bulk of the side chain. Naturally occurring residues are divided into groups based on common side-chain properties:

[0424] Amino acids may be grouped according to similarities in the properties of their side chains (in A. L. Lehninger, in Biochemistry, second ed., pp. 73-75, Worth Publishers, New York (1975)):

(1) non-polar: Ala (A), Val (V), Leu (L), Ile (I), Pro (P), Phe (F), Trp (W), Met (M) (2) uncharged polar: Gly (G), Ser (S), Thr (T), Cys (C), Tyr (Y), Asn (N), Gln (Q) (3) acidic: Asp (D), Glu (E) (4) basic: Lys (K), Arg (R), H is (H) Alternatively, naturally occurring residues may be divided into groups based on common side-chain properties: (1) hydrophobic: Norleucine, Met, Ala, Val, Leu, Ile; (2) neutral hydrophilic: Cys, Ser, Thr, Asn, Gln; (3) acidic: Asp, Glu; (4) basic: H is, Lys, Arg; (5) residues that influence chain orientation: Gly, Pro; (6) aromatic: Trp, Tyr, Phe.

[0425] Non-conservative substitutions will entail exchanging a member of one of these classes for another class. Such substituted residues also may be introduced into the conservative substitution sites or, more preferably, into the remaining (non-conserved) sites.

[0426] The variations can be made using methods known in the art such as oligonucleotide-mediated (site-directed) mutagenesis, alanine scanning, and PCR mutagenesis. Site-directed mutagenesis [Carter et al., Nucl. Acids Res., 13:4331 (1986); Zoller et al., Nucl. Acids Res., 10:6487 (1987)], cassette mutagenesis [Wells et al., Gene, 34:315 (1985)], restriction selection mutagenesis [Wells et al., Philos. Trans. R. Soc. London SerA, 317:415 (1986)] or other known techniques can be performed on the cloned DNA to produce the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 variant DNA.

[0427] Scanning amino acid analysis can also be employed to identify one or more amino acids along a contiguous sequence. Among the preferred scanning amino acids are relatively small, neutral amino acids. Such amino acids include alanine, glycine, serine, and cysteine. Alanine is typically a preferred scanning amino acid among this group because it eliminates the side-chain beyond the beta-carbon and is less likely to alter the main-chain conformation of the variant [Cunningham and Wells, Science, 244: 1081-1085 (1989)]. Alanine is also typically preferred because it is the most common amino acid. Further, it is frequently found in both buried and exposed positions [Creighton, The Proteins, (W.H. Freeman & Co., N.Y.); Chothia, J. Mol. Biol., 150:1 (1976)]. If alanine substitution does not yield adequate amounts of variant, an isoteric amino acid can be used.

[0428] C. Modifications of PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122. PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 Polypeptides

[0429] Covalent modifications of PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides are included within the scope of this invention.

[0430] One type of covalent modification includes reacting targeted amino acid residues of a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide with an organic derivatizing agent that is capable of reacting with selected side chains or the N- or C-terminal residues of the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide. Derivatization with bifunctional agents is useful, for instance, for crosslinking PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides to a water-insoluble support matrix or surface for use in the method for purifying anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibodies, and vice-versa. Commonly used crosslinking agents include, e.g., 1,1-bis(diazoacetyl)-2-phenylethane, glutaraldehyde, N-hydroxysuccinimide esters, for example, esters with 4-azidosalicylic acid, homobifunctional imidoesters, including disuccinimidyl esters such as 3,3'-dithiobis(succinimidylpropionate), bifunctional maleimides such as bis-N-maleimido-1,8-octane and agents such as methyl-3-[(p-azidophenyl)dithio]propioimidate.

[0431] Other modifications include deamidation of glutaminyl and asparaginyl residues to the corresponding glutamyl and aspartyl residues, respectively, hydroxylation of proline and lysine, phosphorylation of hydroxyl groups of seryl or threonyl residues, methylation of the .alpha.-amino groups of lysine, arginine, and histidine side chains [T. E. Creighton, Proteins: Structure and Molecular Properties, W.H. Freeman & Co., San Francisco, pp. 79-86 (1983)], acetylation of the N-terminal amine, and amidation of any C-terminal carboxyl group.

[0432] Another type of covalent modification of the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide included within the scope of this invention comprises altering the native glycosylation pattern of the polypeptide: "Altering the native glycosylation pattern" is intended for purposes herein to mean deleting one or more carbohydrate moieties found in native sequence PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides (either by removing the underlying glycosylation site or by deleting the glycosylation by chemical and/or enzymatic means), and/or adding one or more glycosylation sites that are not present in the native sequence PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide. In addition, the phrase includes qualitative changes in the glycosylation of the native proteins, involving a change in the nature and proportions of the various carbohydrate moieties present.

[0433] Addition of glycosylation sites to the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide may be accomplished by altering the amino acid sequence. The alteration may be made, for example, by the addition of, or substitution by, one or more serine or threonine residues to the native sequence PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 (for O-linked glycosylation sites). The PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 amino acid sequence may optionally be altered through changes at the DNA level, particularly by mutating the DNA encoding the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide at preselected bases such that codons are generated that will translate into the desired amino acids.

[0434] Another means of increasing the number of carbohydrate moieties on the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide is by chemical or enzymatic coupling of glycosides to the polypeptide. Such methods are described in the art, e.g., in WO 87/05330 published 11 Sep. 1987, and in Aplin and Wriston, CRC Crit. Rev. Biochem., pp. 259-306 (1981).

[0435] Removal of carbohydrate moieties present on the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide may be accomplished chemically or enzymatically or by mutational substitution of codons encoding for amino acid residues that serve as targets for glycosylation. Chemical deglycosylation techniques are known in the art and described, for instance, by Hakimuddin, et al., Arch. Biochem. Biophys., 259:52 (1987) and by Edge et al., Anal. Biochem., 118:131 (1981). Enzymatic cleavage of carbohydrate moieties on polypeptides can be achieved by the use of a variety of endo- and exo-glycosidases as described by Thotakura et al., Meth. Enzymol., 138:350 (1987).

[0436] Another type of covalent modification of PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides comprises linking the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide to one of a variety of nonproteinaceous polymers, e.g., polyethylene glycol (PEG), polypropylene glycol, or polyoxyalkylenes, in the manner set forth in U.S. Pat. No. 4,640,835; 4,496,689; 4,301,144; 4,670,417; 4,791,192 or 4,179,337.

[0437] The PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides of the present invention may also be modified in a way to form a chimeric molecule comprising the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide fused to another, heterologous polypeptide or amino acid sequence.

[0438] Such a chimeric molecule comprises a fusion of the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide with a tag polypeptide which provides an epitope to which an anti-tag antibody can selectively bind. The epitope tag is generally placed at the amino- or carboxyl-terminus of the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide. The presence of such epitope-tagged forms of the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755; PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide can be detected using an antibody against the tag polypeptide. Also, provision of the epitope tag enables the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide to be readily purified by affinity purification using an anti-tag antibody or another type of affinity matrix that binds to the epitope tag. Various tag polypeptides and their respective antibodies are well known in the art. Examples include poly-histidine (poly-his) or poly-histidine-glycine (poly-his-gly) tags; the flu HA tag polypeptide and its antibody 12CA5 [Field et al., Mol. Cell. Biol., 8:2159-2165 (1988)]; the c-myc tag and the 8F9, 3C7, 6E10, 04, B7 and 9E10 antibodies thereto [Evan et al., Molecular and Cellular Biology, 5:3610-3616 (1985)]; and the Herpes Simplex virus glycoprotein D (gD) tag and its antibody [Paborsky et al., Protein Engineering, 3(6):547-553 (1990)]. Other tag polypeptides include the Flag-peptide [Hopp et al., BioTechnology, 6:1204-1210 (1988)]; the KT3 epitope peptide [Martin et al., Science, 255:192-194 (1992)]; an .alpha.-tubulin epitope peptide [Skinner et al., J. Biol. Chem., 266:15163-15166 (1991)]; and the T7 gene 10 protein peptide tag [Lutz-Freyermuth et al., Proc. Natl. Acad. Sci. USA, 87:6393-6397 (1990)].

[0439] The chimeric molecule may comprise a fusion of the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide with an immunoglobulin or a particular region of an immunoglobulin. For a bivalent form of the chimeric molecule (also referred to as an "immunoadhesin"), such a fusion could be to the Fc region of an IgG molecule. The Ig fusions preferably include the substitution of a soluble (transmembrane domain deleted or inactivated) form of a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide in place of at least one variable region within an Ig molecule. In a particularly preferred aspect of the invention, the immunoglobulin fusion includes the hinge, CH2 and CH3, or the hinge, CH1, CH2 and CH3 regions of an IgG1 molecule. For the production of immunoglobulin fusions see also U.S. Pat. No. 5,428,130 issued Jun. 27, 1995.

[0440] D. Preparation of PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO1110, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 Polypeptides

[0441] The description below relates primarily to production of PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides by culturing cells transformed or transfected with a vector containing PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 nucleic acid. It is, of course, contemplated that alternative methods, which are well known in the art, may be employed to prepare PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides. For instance, the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 sequence, or portions thereof, may be produced by direct peptide synthesis using solid-phase techniques [see, e.g., Stewart et al., Solid-Phase Peptide Synthesis, W.H. Freeman Co., San Francisco, Calif. (1969); Merrifield, J. Am. Chem. Soc., 85:2149-2154 (1963)]. In vitro protein synthesis may be performed using manual techniques or by automation. Automated synthesis may be accomplished, for instance, using an Applied Biosystems Peptide Synthesizer (Foster City, Calif.) using manufacturer's instructions. Various portions of the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide may be chemically synthesized separately and combined using chemical or enzymatic methods to produce the full-length PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide. [0442] 1. Isolation of DNA Encoding PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190 PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605 PRO1693 PRO1753 PRO1755, PRO1777 PRO1788, PRO1864, PRO1925 PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917 PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 Polypeptides

[0443] DNA encoding PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides may be obtained from a cDNA library prepared from tissue believed to possess the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 mRNA and to express it at a detectable level. Accordingly, human PRO69122-, PRO204-, PRO214-, PRO222-, PRO234-, PRO265-, PRO309-, PRO332-, PRO342-, PRO356-, PRO540-, PRO618-, PRO944-, PRO994-, PRO1079-, PRO1110-, PRO1122-, PRO1138-, PRO1190-, PRO1272-, PRO1286-, PRO1295-, PRO1309-, PRO1316-, PRO1383-, PRO1384-, PRO1431-, PRO1434-, PRO1475-, PRO1481-, PRO1568-, PRO1573-, PRO1599-, PRO1604-, PRO1605-, PRO1693-, PRO1753-, PRO1755-, PRO1777-, PRO1788-, PRO1864-, PRO1925-, PRO1926-, PRO3566-, PRO4330-, PRO4423-, PRO36935-, PRO4977-, PRO4979-, PRO4980-, PRO4981-, PRO5801-, PRO5995-, PRO6001-, PRO6095-, PRO6182-, PRO7170-, PRO7171-, PRO7436-, PRO9912-, PRO9917-, PRO37337-, PRO37496-, PRO19646-, PRO21718-, PRO19820-, PRO21201-, PRO20026-, PRO20110-, PRO23203- or PRO35250-DNA can be conveniently obtained from a cDNA library prepared from human tissue; such as described in the Examples. The PRO69122-, PRO204-, PRO214-, PRO222-, PRO234-, PRO265-, PRO309-, PRO332-, PRO342-, PRO356-, PRO540-, PRO618-, PRO944-, PRO994-, PRO1079-, PRO1110-, PRO1122-, PRO1138-, PRO1190-, PRO1272-, PRO1286-, PRO1295-, PRO1309-, PRO1316-, PRO1383-, PRO1384-, PRO1431-, PRO1434-, PRO1475-, PRO1481-, PRO1568-, PRO1573-, PRO1599-, PRO1604-, PRO1605-, PRO1693-, PRO1753-, PRO1755-, PRO1777-, PRO1788-, PRO1864-, PRO1925-, PRO1926-, PRO3566-, PRO4330-, PRO4423-, PRO36935-, PRO4977-, PRO4979-, PRO4980-, PRO4981-, PRO5801-, PRO5995-, PRO6001-, PRO6095-, PRO6182-, PRO7170-, PRO7171-, PRO7436-, PRO9912-, PRO9917-, PRO37337-, PRO37496-, PRO19646-, PRO21718-, PRO19820-, PRO21201-, PRO20026-, PRO20110-, PRO23203- or PRO35250-encoding gene may also be obtained from a genomic library or by known synthetic procedures (e.g., automated nucleic acid synthesis).

[0444] Libraries can be screened with probes (such as antibodies to the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide or oligonucleotides of at least about 20-80 bases) designed to identify the gene of interest or the protein encoded by it. Screening the cDNA or genomic library with the selected probe may be conducted using standard procedures, such as described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989). An alternative means to isolate the gene encoding PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 is to use PCR methodology [Sambrook et al., supra; Dieffenbach et al., PCR Primer: A Laboratory Manual (Cold Spring Harbor Laboratory Press, 1995)].

[0445] The Examples below describe techniques for screening a cDNA library. The oligonucleotide sequences selected as probes should be of sufficient length and sufficiently unambiguous that false positives are minimized. The oligonucleotide is preferably labeled such that it can be detected upon hybridization to DNA in the library being screened. Methods of labeling are well known in the art, and include the use of radiolabels like .sup.32P-labeled ATP, biotinylation or enzyme labeling. Hybridization conditions, including moderate stringency and high stringency, are provided in Sambrook et al., supra.

[0446] Sequences identified in such library screening methods can be compared and aligned to other known sequences deposited and available in public databases such as GenBank or other private sequence databases. Sequence identity (at either the amino acid or nucleotide level) within defined regions of the molecule or across the full-length sequence can be determined using methods known in the art and as described herein.

[0447] Nucleic acid having protein coding sequence may be obtained by screening selected cDNA or genomic libraries using the deduced amino acid sequence disclosed herein for the first time, and, if necessary, using conventional primer extension procedures as described in Sambrook et al., supra, to detect precursors and processing intermediates of mRNA that may not have been reverse-transcribed into cDNA.

[0448] 2. Selection and Transformation of Host Cells

[0449] Host cells are transfected or transformed with expression or cloning vectors described herein for PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide production and cultured in conventional nutrient media modified as appropriate for inducing promoters, selecting transformants, or amplifying the genes encoding the desired sequences. The culture conditions, such as media, temperature, pH and the like, can be selected by the skilled artisan without undue experimentation. In general, principles, protocols, and practical techniques for maximizing the productivity of cell cultures can be found in Mammalian Cell Biotechnology: a Practical Approach, M. Butler, ed. (IRL Press, 1991) and Sambrook et al., supra.

[0450] Methods of eukaryotic cell transfection and prokaryotic cell transformation are known to the ordinarily skilled artisan, for example, CaCl.sub.2, CaPO.sub.4, liposome-mediated and electroporation. Depending on the host cell used, transformation is performed using standard techniques appropriate to such cells. The calcium treatment employing calcium chloride, as described in Sambrook et al., supra, or electroporation is generally used for prokaryotes. Infection with Agrobacterium tumefaciens is used for transformation of certain plant cells, as described by Shaw et al., Gene, 23:315 (1983) and WO 89/05859 published 29 Jun. 1989. For mammalian cells without such cell walls, the calcium phosphate precipitation method of Graham and van der Eb, Virology, 52:456-457 (1978) can be employed. General aspects of mammalian cell host system transfections have been described in U.S. Pat. No. 4,399,216. Transformations into yeast are typically carried out according to the method of Van Solingen et al., J. B act., 130:946 (1977) and Hsiao et al., Proc. Natl. Acad. Sci. (USA), 76:3829 (1979). However, other methods for introducing DNA into cells, such as by nuclear microinjection, electroporation, bacterial protoplast fusion with intact cells, or polycations, e.g., polybrene, polyornithine, may also be used. For various techniques for transforming mammalian cells, see Keown et al., Methods in Enzymology, 185:527-537 (1990) and Mansour et al., Nature, 336:348-352 (1988).

[0451] Suitable host cells for cloning or expressing the DNA in the vectors herein include prokaryote, yeast, or higher eukaryote cells. Suitable prokaryotes include but are not limited to eubacteria, such as Gram-negative or Gram-positive organisms, for example, Enterobacteriaceae such as E. coli. Various E. coli strains are publicly available, such as E. coli K12 strain MM294 (ATCC 31,446); E. coli X1776 (ATCC 31,537); E. coli strain W3110 (ATCC 27,325) and K5 772 (ATCC 53,635). Other suitable prokaryotic host cells include Enterobacteriaceae such as Escherichia, e.g., E. coli, Enterobacter, Erwinia, Klebsiella, Proteus, Salmonella, e.g., Salmonella typhimurium, Serratia, e.g., Serratia marcescans, and Shigella, as well as Bacilli such as B. subtilis and B. licheniformis (e.g., B. licheniformis 41P disclosed in DD 266,710 published 12 Apr. 1989), Pseudomonas such as P. aeruginosa, and Streptomyces. These examples are illustrative rather than limiting. Strain W3110 is one particularly preferred host or parent host because it is a common host strain for recombinant DNA product fermentations. Preferably, the host cell secretes minimal amounts of proteolytic enzymes. For example, strain

[0452] W3110 may be modified to effect a genetic mutation in the genes encoding proteins endogenous to the host, with examples of such hosts including E. coli W3110 strain 1A2, which has the complete genotype tonA; E. coli W3110 strain 9E4, which has the complete genotype tonA ptr3; E. coli W3110 strain 27C7 (ATCC 55,244), which has the complete genotype tonA ptr3 phoA E15 (argF-lac)169 degP ompTkan.sup.r; E. coli W3110 strain 37D6, which has the complete genotype tonA ptr3 phoA E15 (argF-lac)169 degP ompT rbs7 ilvG kan.sup.r; E. coli W3110 strain 40B4, which is strain 37D6 with a non-kanamycin resistant degP deletion mutation; and an E. coli strain having mutant periplasmic protease disclosed in U.S. Pat. No. 4,946,783 issued 7 Aug. 1990. Alternatively, in vitro methods of cloning, e.g., PCR or other nucleic acid polymerase reactions, are suitable.

[0453] In addition to prokaryotes, eukaryotic microbes such as filamentous fungi or yeast are suitable cloning or expression hosts for PRO69122-, PRO204-, PRO214-, PRO222-, PRO234-, PRO265-, PRO309-, PRO332-, PRO342-, PRO356-, PRO540-, PRO618-, PRO944-, PRO994-, PRO1079-, PRO1110-, PRO1122-, PRO1138-, PRO1190-, PRO1272-, PRO1286-, PRO1295-, PRO1309-, PRO1316-, PRO1383-, PRO1384-, PRO1431-, PRO1434-, PRO1475-, PRO1481-, PRO1568-, PRO1573-, PRO1599-, PRO1604-, PRO1605-, PRO1693-, PRO1753-, PRO1755-, PRO1777-, PRO1788-, PRO1864-, PRO1925-, PRO1926-, PRO3566-, PRO4330-, PRO4423-, PRO36935-, PRO4977-, PRO4979-, PRO4980-, PRO4981-, PRO5801-, PRO5995-, PRO6001-, PRO6095-, PRO6182-, PRO7170-, PRO7171-, PRO7436-, PRO9912-, PRO9917-, PRO37337-, PRO37496-, PRO19646-, PRO21718-, PRO19820-, PRO21201-, PRO20026-, PRO20110-, PRO23203- or PRO35250-encoding vectors. Saccharomyces cerevisiae is a commonly used lower eukaryotic host microorganism. Others include Schkosaccharomyces pombe (Beach and Nurse, Nature, 290: 140 [1981]; EP 139,383 published 2 May 1985); Kluyveromyces hosts (U.S. Pat. No. 4,943,529; Fleer et al., Bio/Technology, 9:968-975 (1991)) such as, e.g., K. lactis (MW98-8C, CBS683, CBS4574; Louvencourt et al., J. Bacteriol., 154(2):737-742 [1983]), K. fragilis (ATCC 12,424), K. bulgaricus (ATCC 16,045), K. wickeramii (ATCC 24,178), K. waltii (ATCC 56,500), K. drosophilarum (ATCC 36,906; Van den Berg et al., Bio/Technology, 8:135 (1990)), K. thermotolerans, and K. marxianus; yarrowia (EP 402,226); Pichia pastoris (EP 183,070; Sreekrishna et al., J. Basic Microbiol., 28:265-278 [1988]); Candida; Trichoderma reesia (EP 244,234); Neurospora crassa (Case et al., Proc. Natl. Acad. Sci. USA, 76:5259-5263 [1979]); Schwanniomyces such as Schwanniomyces occidentalis (EP 394,538 published 31 Oct. 1990); and filamentous fungi such as, e.g., Neurospora, Penicillium, Tolypocladium (WO 91/00357 published 10 Jan. 1991), and Aspergillus hosts such as A. nidulans (Ballance et al., Biochem. Biophys. Res. Commun., 112:284-289 [1983]; Tilburn et al., Gene, 26:205-221 [1983]; Yelton et al., Proc. Natl. Acad. Sci. USA, 81: 1470-1474 [1984]) and A. niger (Kelly and Hynes, EMBO J., 4:475-479 [1985]). Methylotropic yeasts are suitable herein and include, but are not limited to, yeast capable of growth on methanol selected from the genera consisting of Hansenula, Candida, Kloeckera, Pichia, Saccharomyces, Torulopsis, and Rhodotorula. A list of specific species that are exemplary of this class of yeasts may be found in C. Anthony, The Biochemistry of Methylotrophs, 269 (1982).

[0454] Suitable host cells for the expression of glycosylated PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides are derived from multicellular organisms. Examples of invertebrate cells include insect cells such as Drosophila S2 and Spodoptera Sf9, as well as plant cells. Examples of useful mammalian host cell lines include Chinese hamster ovary (CHO) and COS cells. More specific examples include monkey kidney CV1 line transformed by SV40 (COS-7, ATCC CRL 1651); human embryonic kidney line (293 or 293 cells subcloned for growth in suspension culture, Graham et al., J. Gen Virol., 36:59 (1977)); Chinese hamster ovary cells/-DHFR (CHO, Urlaub and Chasin, Proc. Natl. Acad. Sci. USA, 77:4216 (1980)); mouse sertoli cells (TM4, Mather, Biol. Reprod., 23:243-251 (1980)); human lung cells (W138, ATCC CCL 75); human liver cells (Hep G2, HB 8065); and mouse mammary tumor (MMT 060562, ATCC CCL51). The selection of the appropriate host cell is deemed to be within the skill in the art.

[0455] 3. Selection and Use of a Replicable Vector The nucleic acid (e.g., cDNA or genomic DNA) encoding PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides may be inserted into a replicable vector for cloning (amplification of the DNA) or for expression. Various vectors are publicly available. The vector may, for example, be in the form of a plasmid, cosmid, viral particle, or phage. The appropriate nucleic acid sequence may be inserted into the vector by a variety of procedures. In general, DNA is inserted into an appropriate restriction endonuclease site(s) using techniques known in the art. Vector components generally include, but are not limited to, one or more of a signal sequence, an origin of replication, one or more marker genes, an enhancer element, a promoter, and a transcription termination sequence. Construction of suitable vectors containing one or more of these components employs standard ligation techniques which are known to the skilled artisan.

[0456] The PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide may be produced recombinantly not only directly, but also as a fusion polypeptide with a heterologous polypeptide, which may be a signal sequence or other polypeptide having a specific cleavage site at the N-terminus of the mature protein or polypeptide. In general, the signal sequence may be a component of the vector, or it may be a part of the PRO69122-, PRO204-, PRO214-, PRO222-, PRO234-, PRO265-, PRO309-, PRO332-, PRO342-, PRO356-, PRO540-, PRO618-, PRO944-, PRO994-, PRO1079-, PRO1110-, PRO1122-, PRO1138-, PRO1190-, PRO1272-, PRO1286-, PRO1295-, PRO1309-, PRO1316-, PRO1383-, PRO1384-, PRO1431-, PRO1434-, PRO1475-, PRO1481-, PRO1568-, PRO1573-, PRO1599-, PRO1604-, PRO1605-, PRO1693-, PRO1753-, PRO1755-, PRO1777-, PRO1788-, PRO1864-, PRO1925-, PRO1926-, PRO3566-, PRO4330-, PRO4423-, PRO36935-, PRO4977-, PRO4979-, PRO4980-, PRO4981-, PRO5801-, PRO5995-, PRO6001-, PRO6095-, PRO6182-, PRO7170-, PRO7171-, PRO7436-, PRO9912-, PRO9917-, PRO37337-, PRO37496-, PRO19646-, PRO21718-, PRO19820-, PRO21201-, PRO20026-, PRO20110-, PRO23203- or PRO35250-encoding DNA that is inserted into the vector. The signal sequence may be a prokaryotic signal sequence selected, for example, from the group of the alkaline phosphatase, penicillinase, 1 pp, or heat-stable enterotoxin II leaders. For yeast secretion the signal sequence may be, e.g., the yeast invertase leader, alpha factor leader (including Saccharomyces and Kluyveronzyces .alpha.-factor leaders, the latter described in U.S. Pat. No. 5,010,182), or acid phosphatase leader, the C. albicans glucoamylase leader (EP 362,179 published 4 Apr. 1990), or the signal described in WO 90/13646 published 15 Nov. 1990. In mammalian cell expression, mammalian signal sequences may be used to direct secretion of the protein, such as signal sequences from secreted polypeptides of the same or related species, as well as viral secretory leaders.

[0457] Both expression and cloning vectors contain a nucleic acid sequence that enables the vector to replicate in one or more selected host cells. Such sequences are well known for a variety of bacteria, yeast, and viruses. The origin of replication from the plasmid pBR322 is suitable for most Gram-negative bacteria, the 211 plasmid origin is suitable for yeast, and various viral origins (SV40, polyoma, adenovirus, VSV or BPV) are useful for cloning vectors in mammalian cells.

[0458] Expression and cloning vectors will typically contain a selection gene, also termed a selectable marker. Typical selection genes encode proteins that (a) confer resistance to antibiotics or other toxins, e.g., ampicillin, neomycin, methotrexate, or tetracycline, (b) complement auxotrophic deficiencies, or (c) supply critical nutrients not available from complex media, e.g., the gene encoding D-alanine racemase for Bacilli.

[0459] An example of suitable selectable markers for mammalian cells are those that enable the identification of cells competent to take up the PRO69122-, PRO204-, PRO214-, PRO222-, PRO234-, PRO265-, PRO309-, PRO332-, PRO342-, PRO356-, PRO540-, PRO618-, PRO944-, PRO994-, PRO1079-, PRO1110-, PRO1122-, PRO1138-, PRO1190-, PRO1272-, PRO1286-, PRO1295-, PRO1309-, PRO1316-, PRO1383-, PRO1384-, PRO1431-, PRO1434-, PRO1475-, PRO1481-, PRO1568-, PRO1573-, PRO1599-, PRO1604-, PRO1605-, PRO1693-, PRO1753-, PRO1755-, PRO1777-, PRO1788-, PRO1864-, PRO1925-, PRO1926-, PRO3566-, PRO4330-, PRO4423-, PRO36935-, PRO4977-, PRO4979-, PRO4980-, PRO4981-, PRO5801-, PRO5995-, PRO6001-, PRO6095-, PRO6182-, PRO7170-, PRO7171-, PRO7436-, PRO9912-, PRO9917-, PRO37337-, PRO37496-, PRO19646-, PRO21718-, PRO19820-, PRO21201-, PRO20026-, PRO20110-, PRO23203- or PRO35250-encoding nucleic acid, such as DHFR or thymidine kinase. An appropriate host cell when wild-type DHFR is employed is the CHO cell line deficient in DHFR activity, prepared and propagated as described by Urlaub et al., Proc. Natl. Acad. Sci. USA, 77:4216 (1980). A suitable selection gene for use in yeast is the trp1 gene present in the yeast plasmid YRp7 [Stinchcomb et al., Nature, 282:39 (1979); Kingsman et al., Gene, 7:141 (1979); Tschemper et al., Gene, 10:157 (1980)]. The trp1 gene provides a selection marker for a mutant strain of yeast lacking the ability to grow in tryptophan, for example, ATCC No. 44076 or PEP4-1 [Jones, Genetics, 85:12 (1977)].

[0460] Expression and cloning vectors usually contain a promoter operably linked to the PRO69122-, PRO204-, PRO214-, PRO222-, PRO234-, PRO265-, PRO309-, PRO332-, PRO342-, PRO356-, PRO540-, PRO618-, PRO944-, PRO994-, PRO1079-, PRO1110-, PRO1122-, PRO1138-, PRO1190-, PRO1272-, PRO1286-, PRO1295-, PRO1309-, PRO1316-, PRO1383-, PRO1384-, PRO1431-, PRO1434-, PRO1475-, PRO1481-, PRO1568-, PRO1573-, PRO1599-, PRO1604-, PRO1605-, PRO1693-, PRO1753-, PRO1755-, PRO1777-, PRO1788-, PRO1864-, PRO1925-, PRO1926-, PRO3566-, PRO4330-, PRO4423-, PRO36935-, PRO4977-, PRO4979-, PRO4980-, PRO4981-, PRO5801-, PRO5995-, PRO6001-, PRO6095-, PRO6182-, PRO7170-, PRO7171-, PRO7436-, PRO9912-, PRO9917-, PRO37337-, PRO37496-, PRO19646-, PRO21718-, PRO19820-, PRO21201-, PRO20026-, PRO20110-, PRO23203- or PRO35250-encoding nucleic acid sequence to direct mRNA synthesis. Promoters recognized by a variety of potential host cells are well known. Promoters suitable for use with prokaryotic hosts include the .beta.-lactamase and lactose promoter systems [Chang et al., Nature, 275:615 (1978); Goeddel et al., Nature, 281:544 (1979)], alkaline phosphatase, a tryptophan (trp) promoter system [Goeddel, Nucleic Acids Res., 8:4057 (1980); EP 36,776], and hybrid promoters such as the tac promoter [deBoer et al., Proc. Natl. Acad. Sci. USA, 80:21-25 (1983)]. Promoters for use in bacterial systems also will contain a Shine-Dalgarno (S.D.) sequence operably linked to the DNA encoding PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides.

[0461] Examples of suitable promoting sequences for use with yeast hosts include the promoters for 3-phosphoglycerate kinase [Hitzeman et al., J. Biol. Chem., 255:2073 (1980)] or other glycolytic enzymes [Hess et al., J. Adv. Enzyme Reg., 7:149 (1968); Holland, Biochemistry, 17:4900 (1978)], such as enolase, glyceraldehyde-3-phosphate dehydrogenase, hexokinase, pyruvate decarboxylase, phosphofructokinase, glucose-6-phosphate isomerase, 3-phosphoglycerate mutase, pyruvate kinase, triosephosphate isomerase, phosphoglucose isomerase, and glucokinase.

[0462] Other yeast promoters, which are inducible promoters having the additional advantage of transcription controlled by growth conditions, are the promoter regions for alcohol dehydrogenase 2, isocytochrome C, acid phosphatase, degradative enzymes associated with nitrogen metabolism, metallothionein, glyceraldehyde-3-phosphate dehydrogenase, and enzymes responsible for maltose and galactose utilization. Suitable vectors and promoters for use in yeast expression are further described in EP 73,657.

[0463] PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 transcription from vectors in mammalian host cells is controlled, for example, by promoters obtained from the genomes of viruses such as polyoma virus, fowlpox virus (UK 2,211,504 published July 1989), adenovirus (such as Adenovirus 2), bovine papilloma virus, avian sarcoma virus, cytomegalovirus, a retrovirus, hepatitis-B virus and Simian Virus 40 (SV40), from heterologous mammalian promoters, e.g., the actin promoter or an immunoglobulin promoter, and from heat-shock promoters, provided such promoters are compatible with the host cell systems.

[0464] Transcription of a DNA encoding the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide by higher eukaryotes may be increased by inserting an enhancer sequence into the vector. Enhancers are cis-acting elements of DNA, usually about from 10 to 300 bp, that act on a promoter to increase its transcription. Many enhancer sequences are now known from mammalian genes (globin, elastase, albumin, .alpha.-fetoprotein, and insulin). Typically, however, one will use an enhancer from a eukaryotic cell virus. Examples include the SV40 enhancer on the late side of the replication origin (bp 100-270), the cytomegalovirus early promoter enhancer, the polyoma enhancer on the late side of the replication origin, and adenovirus enhancers. The enhancer may be spliced into the vector at a position 5' or 3' to the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 coding sequence, but is preferably located at a site 5' from the promoter.

[0465] Expression vectors used in eukaryotic host cells (yeast, fungi, insect, plant, animal, human, or nucleated cells from other multicellular organisms) will also contain sequences necessary for the termination of transcription and for stabilizing the mRNA. Such sequences are commonly available from the 5' and, occasionally 3', untranslated regions of eukaryotic or viral DNAs or cDNAs. These regions contain nucleotide segments transcribed as polyadenylated fragments in the untranslated portion of the mRNA encoding PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides.

[0466] Still other methods, vectors, and host cells suitable for adaptation to the synthesis of PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides in recombinant vertebrate cell culture are described in Gething et al., Nature, 293:620-625 (1981); Mantei et al., Nature, 281:40-46 (1979); EP 117,060; and EP 117,058.

[0467] 4. Detecting Gene Amplification/Expression Gene amplification and/or expression may be measured in a sample directly, for example, by conventional Southern blotting, Northern blotting to quantitate the transcription of mRNA [Thomas, Proc. Natl. Acad. Sci. USA, 77:5201-5205 (1980)], dot blotting (DNA analysis), or in situ hybridization, using an appropriately labeled probe, based on the sequences provided herein. Alternatively, antibodies may be employed that can recognize specific duplexes, including DNA duplexes, RNA duplexes, and DNA-RNA hybrid duplexes or DNA-protein duplexes. The antibodies in turn may be labeled and the assay may be carried out where the duplex is bound to a surface, so that upon the formation of duplex on the surface, the presence of antibody bound to the duplex can be detected.

[0468] Gene expression, alternatively, may be measured by immunological methods, such as immunohistochemical staining of cells or tissue sections and assay of cell culture or body fluids, to quantitate directly the expression of gene product. Antibodies useful for immunohistochemical staining and/or assay of sample fluids may be either monoclonal or polyclonal, and may be prepared in any mammal. Conveniently, the antibodies may be prepared against a native sequence PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide or against a synthetic peptide based on the DNA sequences provided herein or against exogenous sequence fused to PRO69122-, PRO204-, PRO214-, PRO222-, PRO234-, PRO265-, PRO309-, PRO332-, PRO342-, PRO356-, PRO540-, PRO618-, PRO944-, PRO994-, PRO1079-, PRO1110-, PRO1122-, PRO1138-, PRO1190-, PRO1272-, PRO1286-, PRO1295-, PRO1309-, PRO1316-, PRO1383-, PRO1384-, PRO1431-, PRO1434-, PRO1475-, PRO1481-, PRO1568-, PRO1573-, PRO1599-, PRO1604-, PRO1605-, PRO1693-, PRO1753-, PRO1755-, PRO1777-, PRO1788-, PRO1864-, PRO1925-, PRO1926-, PRO3566-, PRO4330-, PRO4423-, PRO36935-, PRO4977-, PRO4979-, PRO4980-, PRO4981-, PRO5801-, PRO5995-, PRO6001-, PRO6095-, PRO6182-, PRO7170-, PRO7171-, PRO7436-, PRO9912-, PRO9917-, PRO37337-, PRO37496-, PRO19646-, PRO21718-, PRO19820-, PRO21201-, PRO20026-, PRO20110-, PRO23203- or PRO35250-DNA and encoding a specific antibody epitope.

5. Purification of Polypeptide

[0469] Forms of PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides may be recovered from culture medium or from host cell lysates. If membrane-bound, it can be released from the membrane using a suitable detergent solution (e.g. Triton-X100) or by enzymatic cleavage. Cells employed in expression of PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO6113, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides can be disrupted by various physical or chemical means, such as freeze-thaw cycling, sonication, mechanical disruption, or cell lysing agents.

[0470] It may be desired to purify PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides from recombinant cell proteins or polypeptides. The following procedures are exemplary of suitable purification procedures: by fractionation on an ion-exchange column; ethanol precipitation; reverse phase HPLC; chromatography on silica or on a cation-exchange resin such as DEAF; chromatofocusing; SDS-PAGE; ammonium sulfate precipitation; gel filtration using, for example, Sephadex G-75; protein A Sepharose columns to remove contaminants such as IgG; and metal chelating columns to bind epitope-tagged forms of the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide. Various methods of protein purification may be employed and such methods are known in the art and described for example in Deutscher, Methods in Enzymology, 182 (1990); Scopes, Protein Purification: Principles and Practice, Springer-Verlag, New York (1982). The purification step(s) selected will depend, for example, on the nature of the production process used and the particular PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide produced.

[0471] E. Uses for PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 Polypeptides

[0472] Nucleotide sequences (or their complement) encoding PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides have various applications in the art of molecular biology, including uses as hybridization probes, in chromosome and gene mapping and in the generation of anti-sense RNA and DNA. PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 nucleic acid will also be useful for the preparation of PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides by the recombinant techniques described herein.

[0473] The full-length native sequence PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 gene, or portions thereof, may be used as hybridization probes for a cDNA library to isolate the full-length PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 cDNA or to isolate still other cDNAs (for instance, those encoding naturally-occurring variants of PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides or PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides from other species) which have a desired sequence identity to the native PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 sequence disclosed herein. Optionally, the length of the probes will be about 20 to about 50 bases. The hybridization probes may be derived from at least partially novel regions of the full length native nucleotide sequence wherein those regions may be determined without undue experimentation or from genomic sequences including promoters, enhancer elements and introns of native sequence PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250. By way of example, a screening method will comprise isolating the coding region of the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 gene using the known DNA sequence to synthesize a selected probe of about 40 bases. Hybridization probes may be labeled by a variety of labels, including radionucleotides such as .sup.32P or .sup.35S, or enzymatic labels such as alkaline phosphatase coupled to the probe via avidin/biotin coupling systems. Labeled probes having a sequence complementary to that of the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 gene of the present invention can be used to screen libraries of human cDNA, genomic DNA or mRNA to determine which members of such libraries the probe hybridizes to. Hybridization techniques are described in further detail in the Examples below.

[0474] Any EST sequences disclosed in the present application may similarly be employed as probes, using the methods disclosed herein.

[0475] Other useful fragments of the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 nucleic acids include antisense or sense oligonucleotides comprising a singe-stranded nucleic acid sequence (either RNA or DNA) capable of binding to target PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 mRNA (sense) or PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 DNA (antisense) sequences. Antisense or sense oligonucleotides, according to the present invention, comprise a fragment of the coding region of PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 DNA. Such a fragment generally comprises at least about 14 nucleotides, preferably from about 14 to 30 nucleotides. The ability to derive an antisense or a sense oligonucleotide, based upon a cDNA sequence encoding a given protein is described in, for example, Stein and Cohen (Cancer Res. 48:2659, 1988) and van der Krol et al. (BioTechniques 6:958, 1988).

[0476] Binding of antisense or sense oligonucleotides to target nucleic acid sequences results in the formation of duplexes that block transcription or translation of the target sequence by one of several means, including enhanced degradation of the duplexes, premature termination of transcription or translation, or by other means. The antisense oligonucleotides thus may be used to block expression of PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250. Antisense or sense oligonucleotides further comprise oligonucleotides having modified sugar-phosphodiester backbones (or other sugar linkages, such as those described in WO 91/06629) and wherein such sugar linkages are resistant to endogenous nucleases. Such oligonucleotides with resistant sugar linkages are stable in vivo (i.e., capable of resisting enzymatic degradation) but retain sequence specificity to be able to bind to target nucleotide sequences.

[0477] Other examples of sense or antisense oligonucleotides include those oligonucleotides which are covalently linked to organic moieties, such as those described in WO 90/10048, and other moieties that increases affinity of the oligonucleotide for a target nucleic acid sequence, such as poly-(L-lysine). Further still, intercalating agents, such as ellipticine, and alkylating agents or metal complexes may be attached to sense or antisense oligonucleotides to modify binding specificities of the antisense or sense oligonucleotide for the target nucleotide sequence.

[0478] Antisense or sense oligonucleotides may be introduced into a cell containing the target nucleic acid sequence by any gene transfer method, including, for example, CaPO.sub.4-mediated DNA transfection, electroporation, or by using gene transfer vectors such as Epstein-Barr virus. In a preferred procedure, an antisense or sense oligonucleotide is inserted into a suitable retroviral vector. A cell containing the target nucleic acid sequence is contacted with the recombinant retroviral vector, either in vivo or ex vivo. Suitable retroviral vectors include, but are not limited to, those derived from the murine retrovirus M-MuLV, N2 (a retrovirus derived from M-MuLV), or the double copy vectors designated DCT5A, DCT5B and DCT5C (see WO 90/13641).

[0479] Sense or antisense oligonucleotides also may be introduced into a cell containing the target nucleotide sequence by formation of a conjugate with a ligand binding molecule, as described in WO 91/04753. Suitable ligand binding molecules include, but are not limited to, cell surface receptors, growth factors, other cytokines, or other ligands that bind to cell surface receptors. Preferably, conjugation of the ligand binding molecule does not substantially interfere with the ability of the ligand binding molecule to bind to its corresponding molecule or receptor, or block entry of the sense or antisense oligonucleotide or its conjugated version into the cell.

[0480] Alternatively, a sense or an antisense oligonucleotide may be introduced into a cell containing the target nucleic acid sequence by formation of an oligonucleotide-lipid complex, as described in WO 90/10448. The sense or antisense oligonucleotide-lipid complex is preferably dissociated within the cell by an endogenous lipase.

[0481] Antisense or sense RNA or DNA molecules are generally at least about 5 bases in length, about 10 bases in length, about 15 bases in length, about 20 bases in length, about 25 bases in length, about 30 bases in length, about 35 bases in length, about 40 bases in length, about 45 bases in length, about 50 bases in length, about 55 bases in length, about 60 bases in length, about 65 bases in length, about 70 bases in length, about 75 bases in length, about 80 bases in length, about 85 bases in length, about 90 bases in length, about 95 bases in length, about 100 bases in length, or more.

[0482] The probes may also be employed in PCR techniques to generate a pool of sequences for identification of closely related PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 coding sequences.

[0483] Nucleotide sequences encoding a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide can also be used to construct hybridization probes for mapping the gene which encodes that PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide and for the genetic analysis of individuals with genetic disorders. The nucleotide sequences provided herein may be mapped to a chromosome and specific regions of a chromosome using known techniques, such as in situ hybridization, linkage analysis against known chromosomal markers, and hybridization screening with libraries.

[0484] When the coding sequences for PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 encode a protein which binds to another protein (for example, where the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 is a receptor), the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide can be used in assays to identify the other proteins or molecules involved in the binding interaction. By such methods, inhibitors of the receptor/ligand binding interaction can be identified. Proteins involved in such binding interactions can also be used to screen for peptide or small molecule inhibitors or agonists of the binding interaction. Also, the receptor PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 can be used to isolate correlative ligand(s). Screening assays can be designed to find lead compounds that mimic the biological activity of a native PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide or a receptor for PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides. Such screening assays will include assays amenable to high-throughput screening of chemical libraries, making them particularly suitable for identifying small molecule drug candidates. Small molecules contemplated include synthetic organic or inorganic compounds. The assays can be performed in a variety of formats, including protein-protein binding assays, biochemical screening assays, immunoassays and cell based assays, which are well characterized in the art.

[0485] Nucleic acids which encode PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides or its modified forms can also be used to generate either transgenic animals or "knock out" animals which, in turn, are useful in the development and screening of therapeutically useful reagents. A transgenic animal (e.g., a mouse or rat) is an animal having cells that contain a transgene, which transgene was introduced into the animal or an ancestor of the animal at a prenatal, e.g., an embryonic stage. A transgene is a DNA which is integrated into the genome of a cell from which a transgenic animal develops. The invention provides cDNA encoding a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide which can be used to clone genomic DNA encoding a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide in accordance with established techniques and the genomic sequences used to generate transgenic animals that contain cells which express DNA encoding PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides. Any technique known in the art may be used to introduce a target gene transgene into animals to produce the founder lines of transgenic animals. Such techniques include, but are not limited to pronuclear microinjection (U.S. Pat. Nos. 4,873,191, 4,736,866 and 4,870,009); retrovirus mediated gene transfer into germ lines (Van der Putten, et al., Proc. Natl. Acad. Sci., USA, 82:6148-6152 (1985)); gene targeting in embryonic stem cells (Thompson, et al., Cell, 56:313-321 (1989)); nonspecific insertional inactivation using a gene trap vector (U.S. Pat. No. 6,436,707); electroporation of embryos (Lo, Mol. Cell. Biol., 3:1803-1814 (1983)); and sperm-mediated gene transfer (Lavitrano, et al., Cell, 57:717-723 (1989)); etc. Typically, particular cells would be targeted for a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 transgene incorporation with tissue-specific enhancers. Transgenic animals that include a copy of a transgene encoding a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide introduced into the germ line of the animal at an embryonic stage can be used to examine the effect of increased expression of DNA encoding PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides. Such animals can be used as tester animals for reagents thought to confer protection from, for example, pathological conditions associated with its overexpression. In accordance with this facet of the invention, an animal is treated with the reagent and a reduced incidence of the pathological condition, compared to untreated animals bearing the transgene, would indicate a potential therapeutic intervention for the pathological condition. Alternatively, non-human homologues of PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides can be used to construct a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 "knockout" animal which has a defective or altered gene encoding PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 proteins as a result of homologous recombination between the endogenous gene encoding PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides and altered genomic DNA encoding PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides introduced into an embryonic stem cell of the animal. Preferably the knock out animal is a mammal. More preferably, the mammal is a rodent such as a rat or mouse. For example, cDNA encoding PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides can be used to clone genomic DNA encoding PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides in accordance with established techniques. A portion of the genomic DNA encoding the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide can be deleted or replaced with another gene, such as a gene encoding a selectable marker which can be used to monitor integration. Typically, several kilobases of unaltered flanking DNA (both at the 5' and 3' ends) are included in the vector [see e.g., Thomas and Capecchi, Cell, 51:503 (1987) for a description of homologous recombination vectors]. The vector is introduced into an embryonic stem cell line (e.g., by electroporation) and cells in which the introduced DNA has homologously recombined with the endogenous DNA are selected [see e.g., Li et al., Cell, 69:915 (1992)]. The selected cells are then injected into a blastocyst of an animal (e.g., a mouse or rat) to form aggregation chimeras [see e.g., Bradley, in Teratocarcinomas and Embryonic Stem Cells: A Practical Approach, E. J. Robertson, ed. (IRL, Oxford, 1987), pp. 113-152]. A chimeric embryo can then be implanted into a suitable pseudopregnant female foster animal and the embryo brought to term to create a "knock out" animal. Progeny harboring the homologously recombined DNA in their germ cells can be identified by standard techniques and used to breed animals in which all cells of the animal contain the homologously recombined DNA. Knockout animals can be characterized for instance, for their ability to defend against certain pathological conditions and for their development of pathological conditions due to absence of the gene encoding the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide.

[0486] In addition, knockout mice can be highly informative in the discovery of gene function and pharmaceutical utility for a drug target, as well as in the determination of the potential on-target side effects associated with a given target. Gene function and physiology are so well conserved between mice and humans, since they are both mammals and contain similar numbers of genes, which are highly conserved between the species. It has recently been well documented, for example, that 98% of genes on mouse chromosome 16 have a human ortholog (Mural et al., Science 296:1661-71 (2002)).

[0487] Although gene targeting in embryonic stem (ES) cells has enabled the construction of mice with null mutations in many genes associated with human disease, not all genetic diseases are attributable to null mutations. One can design valuable mouse models of human diseases by establishing a method for gene replacement (knock-in) which will disrupt the mouse locus and introduce a human counterpart with mutation, Subsequently one can conduct in vivo drug studies targeting the human protein (Kitamoto et. Al., Biochemical and Biophysical Res. Commun., 222:742-47 (1996)).

[0488] Nucleic acid encoding the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides may also be used in gene therapy. In gene therapy applications, genes are introduced into cells in order to achieve in vivo synthesis of a therapeutically effective genetic product, for example for replacement of a defective gene. "Gene therapy" includes both conventional gene therapy where a lasting effect is achieved by a single treatment, and the administration of gene therapeutic agents, which involves the one time or repeated administration of a therapeutically effective DNA or mRNA. Antisense RNAs and DNAs can be used as therapeutic agents for blocking the expression of certain genes in vivo. It has already been shown that short antisense oligonucleotides can be imported into cells where they act as inhibitors, despite their low intracellular concentrations caused by their restricted uptake by the cell membrane. (Zamecnik et al., Proc. Natl. Acad. Sci. USA 83:4143-4146 [1986]). The oligonucleotides can be modified to enhance their uptake, e.g. by substituting their negatively charged phosphodiester groups by uncharged groups.

[0489] There are a variety of techniques available for introducing nucleic acids into viable cells. The techniques vary depending upon whether the nucleic acid is transferred into cultured cells in vitro, or in vivo in the cells of the intended host. Techniques suitable for the transfer of nucleic acid into mammalian cells in vitro include the use of liposomes, electroporation, microinjection, cell fusion, DEAE-dextran, the calcium phosphate precipitation method, etc. The currently preferred in vivo gene transfer techniques include transfection with viral (typically retroviral) vectors and viral coat protein-liposome mediated transfection (Dzau et al., Trends in Biotechnology 11, 205-210 [1993]). In some situations it is desirable to provide the nucleic acid source with an agent that targets the target cells, such as an antibody specific for a cell surface membrane protein or the target cell, a ligand for a receptor on the target cell, etc. Where liposomes are employed, proteins which bind to a cell surface membrane protein associated with endocytosis may be used for targeting and/or to facilitate uptake, e.g. capsid proteins or fragments thereof tropic for a particular cell type, antibodies for proteins which undergo internalization in cycling, proteins that target intracellular localization and enhance intracellular half-life. The technique of receptor-mediated endocytosis is described, for example, by Wu et al., J. Biol. Chem. 262, 4429-4432 (1987); and Wagner et al., Proc. Natl. Acad. Sci. USA 87, 3410-3414 (1990). For review of gene marking and gene therapy protocols see Anderson et al., Science 256, 808-813 (1992).

[0490] The PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides described herein may also be employed as molecular weight markers for protein electrophoresis purposes and the isolated nucleic acid sequences may be used for recombinantly expressing those markers.

[0491] The nucleic acid molecules encoding the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides or fragments thereof described herein are useful for chromosome identification. In this regard, there exists an ongoing need to identify new chromosome markers, since relatively few chromosome marking reagents, based upon actual sequence data are presently available. Each PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 nucleic acid molecule of the present invention can be used as a chromosome marker.

[0492] The PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides and nucleic acid molecules of the present invention may also be used diagnostically for tissue typing, wherein the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides of the present invention may be differentially expressed in one tissue as compared to another, preferably in a diseased tissue as compared to a normal tissue of the same tissue type. PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 nucleic acid molecules will find use for generating probes for PCR, Northern analysis, Southern analysis and Western analysis.

[0493] The PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides described herein may also be employed as therapeutic agents. The PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides of the present invention can be formulated according to known methods to prepare pharmaceutically useful compositions, whereby the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 product hereof is combined in admixture with a pharmaceutically acceptable carrier vehicle. Therapeutic formulations are prepared for storage by mixing the active ingredient having the desired degree of purity with optional physiologically acceptable carriers, excipients or stabilizers (Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)), in the form of lyophilized formulations or aqueous solutions. Acceptable carriers, excipients or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate and other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone, amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and/or nonionic surfactants such as TWEEN.TM., PLURONICS.TM. or PEG.

[0494] The formulations to be used for in vivo administration must be sterile. This is readily accomplished by filtration through sterile filtration membranes, prior to or following lyophilization and reconstitution.

[0495] Therapeutic compositions herein generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.

[0496] The route of administration is in accord with known methods, e.g. injection or infusion by intravenous, intraperitoneal, intracerebral, intramuscular, intraocular, intraarterial or intralesional routes, topical administration, or by sustained release systems.

[0497] Dosages and desired drug concentrations of pharmaceutical compositions of the present invention may vary depending on the particular use envisioned. The determination of the appropriate dosage or route of administration is well within the skill of an ordinary physician. Animal experiments provide reliable guidance for the determination of effective doses for human therapy. Interspecies scaling of effective doses can be performed following the principles laid down by Mordenti, J. and Chappell, W. "The use of interspecies scaling in toxicokinetics" In Toxicokinetics and New Drug Development, Yacobi et al., Eds., Pergamon Press, New York 1989, pp. 42-96.

[0498] When in vivo administration of a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide or agonist or antagonist thereof is employed, normal dosage amounts may vary from about 10 ng/kg to up to 100 mg/kg of mammal body weight or more per day, preferably about 1 .mu.g/kg/day to 10 mg/kg/day, depending upon the route of administration. Guidance as to particular dosages and methods of delivery is provided in the literature; see, for example, U.S. Pat. No. 4,657,760; 5,206,344; or 5,225,212. It is anticipated that different formulations will be effective for different treatment compounds and different disorders, that administration targeting one organ or tissue, for example, may necessitate delivery in a manner different from that to another organ or tissue.

[0499] Where sustained-release administration of a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide is desired in a formulation with release characteristics suitable for the treatment of any disease or disorder requiring administration of the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, microencapsulation of the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide is contemplated. Microencapsulation of recombinant proteins for sustained release has been successfully performed with human growth hormone (rhGH), interferon- (rhIFN-), interleukin-2, and MN rgp120. Johnson et al., Nat. Med., 2:795-799 (1996); Yasuda, Biomed. Ther., 27:1221-1223 (1993); Hora et al., Bio/Technology, 8:755-758 (1990); Cleland, "Design and Production of Single Immunization Vaccines Using Polylactide Polyglycolide Microsphere Systems," in Vaccine Design: The Subunit and Adjuvant Approach, Powell and Newman, eds, (Plenum Press: New York, 1995), pp. 439-462; WO 97/03692, WO 96/40072, WO 96/07399; and U.S. Pat. No. 5,654,010.

[0500] The sustained-release formulations of these proteins were developed using poly-lactic-coglycolic acid (PLGA) polymer due to its biocompatibility and wide range of biodegradable properties. The degradation products of PLGA, lactic and glycolic acids, can be cleared quickly within the human body. Moreover, the degradability of this polymer can be adjusted from months to years depending on its molecular weight and composition. Lewis, "Controlled release of bioactive agents from lactide/glycolide polymer," in: M. Chasin and R. Langer (Eds.), Biodegradable Polymers as Drug Delivery Systems (Marcel Dekker: New York, 1990), pp. 1-41.

[0501] This invention encompasses methods of screening compounds to identify those that mimic the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide (agonists) or prevent the effect of the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide (antagonists). Agonists that mimic a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide would be especially valuable therapeutically in those instances where a negative phenotype is observed based on findings with the non-human transgenic animal whose genome comprises a disruption of the gene which encodes for the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide. Antagonists that prevent the effects of a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide would be especially valuable therapeutically in those instances where a positive phenotype is observed based upon observations with the non-human transgenic knockout animal. Screening assays for antagonist drug candidates are designed to identify compounds that bind or complex with the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide encoded by the genes identified herein, or otherwise interfere with the interaction of the encoded polypeptide with other cellular proteins. Such screening assays will include assays amenable to high-throughput screening of chemical libraries, making them particularly suitable for identifying small molecule drug candidates.

[0502] The assays can be performed in a variety of formats, including protein-protein binding assays, biochemical screening assays, immunoassays, and cell-based assays, which are well characterized in the art.

[0503] All assays for antagonists are common in that they call for contacting the drug candidate with a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide encoded by a nucleic acid identified herein under conditions and for a time sufficient to allow these two components to interact.

[0504] In binding assays, the interaction is binding and the complex formed can be isolated or detected in the reaction mixture. The PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide encoded by the gene identified herein or the drug candidate is immobilized on a solid phase, e.g., on a microtiter plate, by covalent or non-covalent attachments. Non-covalent attachment generally is accomplished by coating the solid surface with a solution of the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide and drying. Alternatively, an immobilized antibody, e.g., a monoclonal antibody, specific for the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide to be immobilized can be used to anchor it to a solid surface. The assay is performed by adding the non-immobilized component, which may be labeled by a detectable label, to the immobilized component, e.g., the coated surface containing the anchored component. When the reaction is complete, the non-reacted components are removed, e.g., by washing, and complexes anchored on the solid surface are detected. When the originally non-immobilized component carries a detectable label, the detection of label immobilized on the surface indicates that complexing occurred. Where the originally non-immobilized component does not carry a label, complexing can be detected, for example, by using a labeled antibody specifically binding the immobilized complex.

[0505] If the candidate compound interacts with but does not bind to a particular PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide encoded by a gene identified herein, its interaction with that polypeptide can be assayed by methods well known for detecting protein-protein interactions. Such assays include traditional approaches, such as, e.g., cross-linking, co-immunoprecipitation, and co-purification through gradients or chromatographic columns. In addition, protein-protein interactions can be monitored by using a yeast-based genetic system described by Fields and co-workers (Fields and Song, Nature (London), 340:245-246 (1989); Chien et al., Proc. Natl. Acad. Sci. USA, 88:9578-9582 (1991)) as disclosed by Chevray and Nathans, Proc. Natl. Acad. Sci. USA, 89: 5789-5793 (1991). Many transcriptional activators, such as yeast GAL4, consist of two physically discrete modular domains, one acting as the DNA-binding domain, the other one functioning as the transcription-activation domain. The yeast expression system described in the foregoing publications (generally referred to as the "two-hybrid system") takes advantage of this property, and employs two hybrid proteins, one in which the target protein is fused to the DNA-binding domain of GAL4, and another, in which candidate activating proteins are fused to the activation domain. The expression of a GAL1-lacZ reporter gene under control of a GAL4-activated promoter depends on reconstitution of GAL4 activity via protein-protein interaction. Colonies containing interacting polypeptides are detected with a chromogenic substrate for (3-galactosidase. A complete kit (MATCHMAKER') for identifying protein-protein interactions between two specific proteins using the two-hybrid technique is commercially available from Clontech. This system can also be extended to map protein domains involved in specific protein interactions as well as to pinpoint amino acid residues that are crucial for these interactions.

[0506] Compounds that interfere with the interaction of a gene encoding a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide identified herein and other intra- or extracellular components can be tested as follows: usually a reaction mixture is prepared containing the product of the gene and the intra- or extracellular component under conditions and for a time allowing for the interaction and binding of the two products. To test the ability of a candidate compound to inhibit binding, the reaction is run in the absence and in the presence of the test compound. In addition, a placebo may be added to a third reaction mixture, to serve as positive control. The binding (complex formation) between the test compound and the intra- or extracellular component present in the mixture is monitored as described hereinabove. The formation of a complex in the control reaction(s) but not in the reaction mixture containing the test compound indicates that the test compound interferes with the interaction of the test compound and its reaction partner.

[0507] To assay for antagonists, the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide may be added to a cell along with the compound to be screened for a particular activity and the ability of the compound to inhibit the activity of interest in the presence of the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide indicates that the compound is an antagonist to the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide. Alternatively, antagonists may be detected by combining the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496; PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide and a potential antagonist with membrane-bound PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide receptors or recombinant receptors under appropriate conditions for a competitive inhibition assay. The PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide can be labeled, such as by radioactivity, such that the number of PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide molecules bound to the receptor can be used to determine the effectiveness of the potential antagonist. The gene encoding the receptor can be identified by numerous methods known to those of skill in the art, for example, ligand panning and FACS sorting. Coligan et al., Current Protocols in Immun, 1(2): Chapter 5 (1991). Preferably, expression cloning is employed wherein polyadenylated RNA is prepared from a cell responsive to the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide and a cDNA library created from this RNA is divided into pools and used to transfect COS cells or other cells that are not responsive to the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide. Transfected cells that are grown on glass slides are exposed to labeled PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide. The PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide can be labeled by a variety of means including iodination or inclusion of a recognition site for a site-specific protein kinase. Following fixation and incubation, the slides are subjected to autoradiographic analysis. Positive pools are identified and sub-pools are prepared and re-transfected using an interactive sub-pooling and re-screening process, eventually yielding a single clone that encodes the putative receptor.

[0508] As an alternative approach for receptor identification, the labeled PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide can be photoaffinity-linked with cell membrane or extract preparations that express the receptor molecule. Cross-linked material is resolved by PAGE and exposed to X-ray film The labeled complex containing the receptor can be excised, resolved into peptide fragments, and subjected to protein micro-sequencing. The amino acid sequence obtained from micro-sequencing would be used to design a set of degenerate oligonucleotide probes to screen a cDNA library to identify the gene encoding the putative receptor.

[0509] Another approach in assessing the effect of an antagonist to a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, would be administering a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO1110, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 antagonist to a wild-type mouse in order to mimic a known knockout phenotype. Thus, one would initially knockout the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 gene of interest and observe the resultant phenotype as a consequence of knocking out or disrupting the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO1110, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 gene. Subsequently, one could then assess the effectiveness of an antagonist to the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide by administering an antagonist to the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide to a wild-type mouse. An effective antagonist would be expected to mimic the phenotypic effect that was initially observed in the knockout animal.

[0510] Likewise, one could assess the effect of an agonist to a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, by administering a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 agonist to a non-human transgenic mouse in order to ameliorate a known negative knockout phenotype. Thus, one would initially knockout the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 gene of interest and observe the resultant phenotype as a consequence of knocking out or disrupting the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 gene. Subsequently, one could then assess the effectiveness of an agonist to the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO1110, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide by administering an agonist to the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide to a the non-human transgenic mouse. An effective agonist would be expected to ameliorate the negative phenotypic effect that was initially observed in the knockout animal.

[0511] In another assay for antagonists, mammalian cells or a membrane preparation expressing the receptor would be incubated with a labeled PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide in the presence of the candidate compound. The ability of the compound to enhance or block this interaction could then be measured.

[0512] More specific examples of potential antagonists include an oligonucleotide that binds to the fusions of immunoglobulin with the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, and, in particular, antibodies including, without limitation, poly- and monoclonal antibodies and antibody fragments, single-chain antibodies, anti-idiotypic antibodies, and chimeric or humanized versions of such antibodies or fragments, as well as human antibodies and antibody fragments. Alternatively, a potential antagonist may be a closely related protein, for example, a mutated form of the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide that recognizes the receptor but imparts no effect, thereby competitively inhibiting the action of the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide.

[0513] Another potential PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide antagonist is an antisense RNA or DNA construct prepared using antisense technology, where, e.g., an antisense RNA or DNA molecule acts to block directly the translation of mRNA by hybridizing to targeted mRNA and preventing protein translation. Antisense technology can be used to control gene expression through triple-helix formation or antisense DNA or RNA, both of which methods are based on binding of a polynucleotide to DNA or RNA. For example, the 5' coding portion of the polynucleotide sequence, which encodes the mature PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides herein, is used to design an antisense RNA oligonucleotide of from about 10 to 40 base pairs in length. A DNA oligonucleotide is designed to be complementary to a region of the gene involved in transcription (triple helix--see Lee et al., Nucl. Acids Res., 6:3073 (1979); Cooney et al., Science, 241: 456 (1988); Dervan et al., Science, 251:1360 (1991)), thereby preventing transcription and the production of the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide. The antisense RNA oligonucleotide hybridizes to the mRNA in vivo and blocks translation of the mRNA molecule into the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide (antisense--Okano, Neurochem., 56:560 (1991); Oligodeoxynucleotides as Antisense Inhibitors of Gene Expression (CRC Press: Boca Raton, Fla., 1988). The oligonucleotides described above can also be delivered to cells such that the antisense RNA or DNA may be expressed in vivo to inhibit production of the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide. When antisense DNA is used, oligodeoxyribonucleotides derived from the translation-initiation site, e.g., between about -10 and +10 positions of the target gene nucleotide sequence, are preferred.

[0514] Potential antagonists include small molecules that bind to the active site, the receptor binding site, or growth factor or other relevant binding site of the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, thereby blocking the normal biological activity of the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide. Examples of small molecules include, but are not limited to, small peptides or peptide-like molecules, preferably soluble peptides, and synthetic non-peptidyl organic or inorganic compounds.

[0515] Ribozymes are enzymatic RNA molecules capable of catalyzing the specific cleavage of RNA. Ribozymes act by sequence-specific hybridization to the complementary target RNA, followed by endonucleolytic cleavage. Specific ribozyme cleavage sites within a potential RNA target can be identified by known techniques. For further details see, e.g., Rossi, Current Biology, 4:469-471 (1994), and PCT publication No. WO 97/33551 (published Sep. 18, 1997).

[0516] Nucleic acid molecules in triple-helix formation used to inhibit transcription should be single-stranded and composed of deoxynucleotides. The base composition of these oligonucleotides is designed such that it promotes triple-helix formation via Hoogsteen base-pairing rules, which generally require sizeable stretches of purines or pyrimidines on one strand of a duplex. For further details see, e.g., PCT publication No. WO 97/33551, supra.

[0517] These small molecules can be identified by any one or more of the screening assays discussed hereinabove and/or by any other screening techniques well known for those skilled in the art.

[0518] Diagnostic and therapeutic uses of the herein disclosed molecules may also be based upon the positive functional assay hits disclosed and described below.

[0519] F. Anti-PRO69122, Anti-PRO204, Anti-PRO214, Anti-PRO222, Anti-PRO234, Anti-PRO265, Anti-PRO309, Anti-PRO332, Anti-PRO342, Anti-PRO356, Anti-PRO540, Anti-PRO618, Anti-PRO944, Anti-PRO994, Anti-PRO1079, Anti-PRO1110, Anti-PRO1122, Anti-PRO1138, Anti-PRO1190, Anti-PRO1272, Anti-PRO1286, Anti-PRO1295, Anti-PRO1309, Anti-PRO1316, Anti-PRO1383, Anti-PRO1384, Anti-PRO1431, Anti-PRO1434, Anti-PRO1475, Anti-PRO1481, Anti-PRO1568, Anti-PRO1573, Anti-PRO1599, Anti-PRO1604, Anti-PRO1605, Anti-PRO1693, Anti-PRO1753, Anti-PRO1755, Anti-PRO1777, Anti-PRO1788, Anti-PRO1864, Anti-PRO1925, Anti-PRO1926, Anti-PRO3566, Anti-PRO4330, Anti-PRO4423, Anti-PRO36935, Anti-PRO4977, Anti-PRO4979, Anti-PRO4980, Anti-PRO4981, Anti-PRO5801, Anti-PRO5995, Anti-PRO6001, Anti-PRO6095, Anti-PRO6182, Anti-PRO7170, Anti-PRO7171, Anti-PRO7436, Anti-PRO9912, Anti-PRO9917, Anti-PRO37337, Anti-PRO37496, Anti-PRO19646, Anti-PRO21718, Anti-PRO19820, Anti-PRO21201, Anti-PRO20026, Anti-PRO20110, Anti-PRO23203 or Anti-PRO35250 Antibodies

[0520] The present invention provides anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibodies which may find use herein as therapeutic and/or diagnostic agents. Exemplary antibodies include polyclonal, monoclonal, humanized, bispecific, and heteroconjugate antibodies.

[0521] 1. Polyclonal Antibodies

[0522] Polyclonal antibodies are preferably raised in animals by multiple subcutaneous (sc) or intraperitoneal (ip) injections of the relevant antigen and an adjuvant. It may be useful to conjugate the relevant antigen (especially when synthetic peptides are used) to a protein that is immunogenic in the species to be immunized. For example, the antigen can be conjugated to keyhole limpet hemocyanin (KLH), serum albumin, bovine thyroglobulin, or soybean trypsin inhibitor, using a bifunctional or derivatizing agent, e.g., maleimidobenzoyl sulfosuccinimide ester (conjugation through cysteine residues), N-hydroxysuccinimide (through lysine residues), glutaraldehyde, succinic anhydride, SOCl.sub.2, or R.sup.1N.dbd.C.dbd.NR, where R and R.sup.1 are different alkyl groups.

[0523] Animals are immunized against the antigen, immunogenic conjugates, or derivatives by combining, e.g., 100 .mu.g or 5 .mu.g of the protein or conjugate (for rabbits or mice, respectively) with 3 volumes of Freund's complete adjuvant and injecting the solution intradermally at multiple sites. One month later, the animals are boosted with 1/5 to 1/10 the original amount of peptide or conjugate in Freund's complete adjuvant by subcutaneous injection at multiple sites. Seven to 14 days later, the animals are bled and the serum is assayed for antibody titer Animals are boosted until the titer plateaus. Conjugates also can be made in recombinant cell culture as protein fusions. Also, aggregating agents such as alum are suitably used to enhance the immune response.

[0524] 2. Monoclonal Antibodies

[0525] Monoclonal antibodies may be made using the hybridoma method first described by Kohler et al., Nature, 256:495 (1975), or may be made by recombinant DNA methods (U.S. Pat. No. 4,816,567).

[0526] In the hybridoma method, a mouse or other appropriate host animal, such as a hamster, is immunized as described above to elicit lymphocytes that produce or are capable of producing antibodies that will specifically bind to the protein used for immunization. Alternatively, lymphocytes may be immunized in vitro. After immunization, lymphocytes are isolated and then fused with a myeloma cell line using a suitable fusing agent, such as polyethylene glycol, to form a hybridoma cell (Goding, Monoclonal Antibodies: Principles and Practice, pp. 59-103 (Academic Press, 1986)).

[0527] The hybridoma cells thus prepared are seeded and grown in a suitable culture medium which medium preferably contains one or more substances that inhibit the growth or survival of the unfused, parental myeloma cells (also referred to as fusion partner). For example, if the parental myeloma cells lack the enzyme hypoxanthine guanine phosphoribosyl transferase (HGPRT or HPRT), the selective culture medium for the hybridomas typically will include hypoxanthine, aminopterin, and thymidine (HAT medium), which substances prevent the growth of HGPRT-deficient cells.

[0528] Preferred fusion partner myeloma cells are those that fuse efficiently, support stable high-level production of antibody by the selected antibody-producing cells, and are sensitive to a selective medium that selects against the unfused parental cells. Preferred myeloma cell lines are murine myeloma lines, such as those derived from MOPC-21 and MPC-11 mouse tumors available from the Salk Institute Cell Distribution Center, San Diego, Calif. USA, and SP-2 and derivatives e.g., X63-Ag8-653 cells available from the American Type Culture Collection, Manassas, Va., USA. Human myeloma and mouse-human heteromyeloma cell lines also have been described for the production of human monoclonal antibodies (Kozbor, J. Immunol., 133:3001 (1984); and Brodeur et al., Monoclonal Antibody Production Techniques and Applications, pp. 51-63 (Marcel Dekker, Inc., New York, 1987)).

[0529] Culture medium in which hybridoma cells are growing is assayed for production of monoclonal antibodies directed against the antigen. Preferably, the binding specificity of monoclonal antibodies produced by hybridoma cells is determined by immunoprecipitation or by an in vitro binding assay, such as radioimmunoassay (RIA) or enzyme-linked immunosorbent assay (ELISA).

[0530] The binding affinity of the monoclonal antibody can, for example, be determined by the Scatchard analysis described in Munson et al., Anal. Biochem., 107:220 (1980).

[0531] Once hybridoma cells that produce antibodies of the desired specificity, affinity, and/or activity are identified, the clones may be sub cloned by limiting dilution procedures and grown by standard methods (Goding, Monoclonal Antibodies: Principles and Practice, pp. 59-103 (Academic Press, 1986)). Suitable culture media for this purpose include, for example, D-MEM or RPMI-1640 medium. In addition, the hybridoma cells may be grown in vivo as ascites tumors in an animal e.g., by i.p. injection of the cells into mice.

[0532] The monoclonal antibodies secreted by the subclones are suitably separated from the culture medium, ascites fluid, or serum by conventional antibody purification procedures such as, for example, affinity chromatography (e.g., using protein A or protein G-Sepharose) or ion-exchange chromatography, hydroxylapatite chromatography, gel electrophoresis, dialysis, etc.

[0533] DNA encoding the monoclonal antibodies is readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of murine antibodies). The hybridoma cells serve as a preferred source of such DNA. Once isolated, the DNA may be placed into expression vectors, which are then transfected into host cells such as E. coli cells, simian COS cells, Chinese Hamster Ovary (CHO) cells, or myeloma cells that do not otherwise produce antibody protein, to obtain the synthesis of monoclonal antibodies in the recombinant host cells. Review articles on recombinant expression in bacteria of DNA encoding the antibody include Skerra et al., Curr. Opinion in Immunol., 5:256-262 (1993) and Pluckthun, Immunol. Revs. 130:151-188 (1992).

[0534] Monoclonal antibodies or antibody fragments can be isolated from antibody phage libraries generated using the techniques described in McCafferty et al., Nature, 348:552-554 (1990). Clackson et al., Nature, 352:624-628 (1991) and Marks et al., J. Mol. Biol., 222:581-597 (1991) describe the isolation of murine and human antibodies, respectively, using phage libraries. Subsequent publications describe the production of high affinity (nM range) human antibodies by chain shuffling (Marks et al., Bio/Technology, 10:779-783 (1992)), as well as combinatorial infection and in vivo recombination as a strategy for constructing very large phage libraries (Waterhouse et al., Nuc. Acids. Res. 21:2265-2266 (1993)). Thus, these techniques are viable alternatives to traditional monoclonal antibody hybridoma techniques for isolation of monoclonal antibodies.

[0535] The DNA that encodes the antibody may be modified to produce chimeric or fusion antibody polypeptides, for example, by substituting human heavy chain and light chain constant domain (C.sub.H and C.sub.L) sequences for the homologous murine sequences (U.S. Pat. No. 4,816,567; and Morrison, et al., Proc. Natl. Acad. Sci. USA, 81:6851 (1984)), or by fusing the immunoglobulin coding sequence with all or part of the coding sequence for a non-immunoglobulin polypeptide (heterologous polypeptide). The non-immunoglobulin polypeptide sequences can substitute for the constant domains of an antibody, or they are substituted for the variable domains of one antigen-combining site of an antibody to create a chimeric bivalent antibody comprising one antigen-combining site having specificity for an antigen and another antigen-combining site having specificity for a different antigen.

[0536] 3. Human and Humanized Antibodies

[0537] The anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibodies of the invention may further comprise humanized antibodies or human antibodies. Humanized forms of non-human (e.g., murine) antibodies are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab', F(ab').sub.2 or other antigen-binding subsequences of antibodies) which contain minimal sequence derived from non-human immunoglobulin. Humanized antibodies include human immunoglobulins (recipient antibody) in which residues from a complementary determining region (CDR) of the recipient are replaced by residues from a CDR of a non-human species (donor antibody) such as mouse, rat or rabbit having the desired specificity, affinity and capacity. In some instances, Fv framework residues of the human immunoglobulin are replaced by corresponding non-human residues. Humanized antibodies may also comprise residues which are found neither in the recipient antibody nor in the imported CDR or framework sequences. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin consensus sequence. The humanized antibody optimally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin [Jones et al., Nature, 321:522-525 (1986); Riechmann et al., Nature, 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol., 2:593-596 (1992)].

[0538] Methods for humanizing non-human antibodies are well known in the art. Generally, a humanized antibody has one or more amino acid residues introduced into it from a source which is non-human. These non-human amino acid residues are often referred to as "import" residues, which are typically taken from an "import" variable domain. Humanization can be essentially performed following the method of Winter and co-workers [Jones et al., Nature, 321:522-525 (1986); Riechmann et al., Nature, 332:323-327 (1988); Verhoeyen et al., Science, 239:1534-1536 (1988)], by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. Accordingly, such "humanized" antibodies are chimeric antibodies (U.S. Pat. No. 4,816,567), wherein substantially less than an intact human variable domain has been substituted by the corresponding sequence from a non-human species. In practice, humanized antibodies are typically human antibodies in which some CDR residues and possibly some FR residues are substituted by residues from analogous sites in rodent antibodies.

[0539] The choice of human variable domains, both light and heavy, to be used in making the humanized antibodies is very important to reduce antigenicity and HAMA response (human anti-mouse antibody) when the antibody is intended for human therapeutic use. According to the so-called "best-fit" method, the sequence of the variable domain of a rodent antibody is screened against the entire library of known human variable domain sequences. The human V domain sequence which is closest to that of the rodent is identified and the human framework region (FR) within it accepted for the humanized antibody (Sims et al., J. Immunol. 151:2296 (1993); Chothia et al., J. Mol. Biol., 196:901 (1987)). Another method uses a particular framework region derived from the consensus sequence of all human antibodies of a particular subgroup of light or heavy chains. The same framework may be used for several different humanized antibodies (Carter et al., Proc. Natl. Acad. Sci. USA, 89:4285 (1992); Presta et al., J. Immunol. 151:2623 (1993)).

[0540] It is further important that antibodies be humanized with retention of high binding affinity for the antigen and other favorable biological properties. To achieve this goal, according to a preferred method, humanized antibodies are prepared by a process of analysis of the parental sequences and various conceptual humanized products using three-dimensional models of the parental and humanized sequences. Three-dimensional immunoglobulin models are commonly available and are familiar to those skilled in the art. Computer programs are available which illustrate and display probable three-dimensional conformational structures of selected candidate immunoglobulin sequences. Inspection of these displays permits analysis of the likely role of the residues in the functioning of the candidate immunoglobulin sequence, i.e., the analysis of residues that influence the ability of the candidate immunoglobulin to bind its antigen. In this way, FR residues can be selected and combined from the recipient and import sequences so that the desired antibody characteristic, such as increased affinity for the target antigen(s), is achieved. In general, the hypervariable region residues are directly and most substantially involved in influencing antigen binding.

[0541] Various forms of a humanized anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibody are contemplated. For example, the humanized antibody may be an antibody fragment, such as a Fab, which is optionally conjugated with one or more cytotoxic agent(s) in order to generate an immunoconjugate. Alternatively, the humanized antibody may be an intact antibody, such as an intact IgG1 antibody.

[0542] As an alternative to humanization, human antibodies can be generated. For example, it is now possible to produce transgenic animals (e.g., mice) that are capable, upon immunization, of producing a full repertoire of human antibodies in the absence of endogenous immunoglobulin production. For example, it has been described that the homozygous deletion of the antibody heavy-chain joining region go gene in chimeric and germ-line mutant mice results in complete inhibition of endogenous antibody production. Transfer of the human germ-line immunoglobulin gene array into such germ-line mutant mice will result in the production of human antibodies upon antigen challenge. See, e.g., Jakobovits et al., Proc. Natl. Acad. Sci. USA, 90:2551 (1993); Jakobovits et al., Nature, 362:255-258 (1993); Bruggemann et al., Year in Immuno. 7:33 (1993); U.S. Pat. Nos. 5,545,806, 5,569,825, 5,591,669 (all of GenPharm); 5,545,807; and WO 97/17852.

[0543] Alternatively, phage display technology (McCafferty et al., Nature 348:552-553 [1990]) can be used to produce human antibodies and antibody fragments in vitro, from immunoglobulin variable (V) domain gene repertoires from unimmunized donors. According to this technique, antibody V domain genes are cloned in-frame into either a major or minor coat protein gene of a filamentous bacteriophage, such as M13 or fd, and displayed as functional antibody fragments on the surface of the phage particle. Because the filamentous particle contains a single-stranded DNA copy of the phage genome, selections based on the functional properties of the antibody also result in selection of the gene encoding the antibody exhibiting those properties. Thus, the phage mimics some of the properties of the B-cell. Phage display can be performed in a variety of formats, reviewed in, e.g., Johnson, Kevin S, and Chiswell, David J., Current Opinion in Structural Biology 3:564-571 (1993). Several sources of V-gene segments can be used for phage display. Clackson et al., Nature, 352:624-628 (1991) isolated a diverse array of anti-oxazolone antibodies from a small random combinatorial library of V genes derived from the spleens of immunized mice. A repertoire of V genes from unimmunized human donors can be constructed and antibodies to a diverse array of antigens (including self-antigens) can be isolated essentially following the techniques described by Marks et al., J. Mol. Biol. 222:581-597 (1991), or Griffith et al., EMBO J. 12:725-734 (1993). See, also, U.S. Pat. Nos. 5,565,332 and 5,573,905.

[0544] As discussed above, human antibodies may also be generated by in vitro activated B cells (see U.S. Pat. Nos. 5,567,610 and 5,229,275).

[0545] 4. Antibody Fragments

[0546] In certain circumstances there are advantages of using antibody fragments, rather than whole antibodies. The smaller size of the fragments allows for rapid clearance, and may lead to improved access to solid tumors.

[0547] Various techniques have been developed for the production of antibody fragments. Traditionally, these fragments were derived via proteolytic digestion of intact antibodies (see, e.g., Morimoto et al., Journal of Biochemical and Biophysical Methods 24:107-117 (1992); and Brennan et al., Science, 229:81 (1985)). However, these fragments can now be produced directly by recombinant host cells. Fab, Fv and ScFv antibody fragments can all be expressed in and secreted from E. coli, thus allowing the facile production of large amounts of these fragments. Antibody fragments can be isolated from the antibody phage libraries discussed above. Alternatively, Fab'-SH fragments can be directly recovered from E. coli and chemically coupled to form F(ab').sub.2 fragments (Carter et al., Bio/Technology 10:163-167 (1992)). According to another approach, F(ab').sub.2 fragments can be isolated directly from recombinant host cell culture. Fab and F(ab').sub.2 fragment with increased in vivo half-life comprising a salvage receptor binding epitope residues are described in U.S. Pat. No. 5,869,046. Other techniques for the production of antibody fragments will be apparent to the skilled practitioner. The antibody of choice is a single chain Fv fragment (scFv). See WO 93/16185; U.S. Pat. No. 5,571,894; and U.S. Pat. No. 5,587,458. Fv and sFv are the only species with intact combining sites that are devoid of constant regions; thus, they are suitable for reduced nonspecific binding during in vivo use. sFv fusion proteins may be constructed to yield fusion of an effector protein at either the amino or the carboxy terminus of an sFv. See Antibody Engineering, ed. Borrebaeck, supra. The antibody fragment may also be a "linear antibody", e.g., as described in U.S. Pat. No. 5,641,870 for example. Such linear antibody fragments may be monospecific or bispecific.

[0548] 5. Bispecific Antibodies

[0549] Bispecific antibodies are antibodies that have binding specificities for at least two different epitopes. Exemplary bispecific antibodies may bind to two different epitopes of a PRO69122, PRO204, PRO214; PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 protein as described herein. Other such antibodies may combine a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 binding site with a binding site for another protein. Alternatively, an anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 arm may be combined with an arm which binds to a triggering molecule on a leukocyte such as a T-cell receptor molecule (e.g. CD3), or Fc receptors for IgG (Fc.gamma.R), such as Fc.gamma.RI (CD64), Fc.gamma.RII (CD32) and Fc.gamma.RIII (CD16), so as to focus and localize cellular defense mechanisms to the PRO69122-, PRO204-, PRO214-, PRO222-, PRO234-, PRO265-, PRO309-, PRO332-, PRO342-, PRO356-, PRO540-, PRO618-, PRO944-, PRO994-, PRO1079-, PRO1110-, PRO1122-, PRO1138-, PRO1190-, PRO1272-, PRO1286-, PRO1295-, PRO1309-, PRO1316-, PRO1383-, PRO1384-, PRO1431-, PRO1434-, PRO1475-, PRO1481-, PRO1568-, PRO1573-, PRO1599-, PRO1604-, PRO1605-, PRO1693-, PRO1753-, PRO1755-, PRO1777-, PRO1788-, PRO1864-, PRO1925-, PRO1926-, PRO3566-, PRO4330-, PRO4423-, PRO36935-, PRO4977-, PRO4979-, PRO4980-, PRO4981-, PRO5801-, PRO5995-, PRO6001-, PRO6095-, PRO6182-, PRO7170-, PRO7171-, PRO7436-, PRO9912-, PRO9917-, PRO37337-, PRO37496-, PRO19646-, PRO21718-, PRO19820-, PRO21201-, PRO20026-, PRO20110-, PRO23203- or PRO35250-expressing cell. Bispecific antibodies may also be used to localize cytotoxic agents to cells which express a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide. These antibodies possess a PRO69122-, PRO204-, PRO214-, PRO222-, PRO234-, PRO265-, PRO309-, PRO332-, PRO342-, PRO356-, PRO540-, PRO618-, PRO944-, PRO994-, PRO1079-, PRO1110-, PRO1122-, PRO1138-, PRO1190-, PRO1272-, PRO1286-, PRO1295-, PRO1309-, PRO1316-, PRO1383-, PRO1384-, PRO1431-, PRO1434-, PRO1475-, PRO1481-, PRO1568-, PRO1573-, PRO1599-, PRO1604-, PRO1605-, PRO1693-, PRO1753-, PRO1755-, PRO1777-, PRO1788-, PRO1864-, PRO1925-, PRO1926-, PRO3566-, PRO4330-, PRO4423-, PRO36935-, PRO4977-, PRO4979-, PRO4980-, PRO4981-, PRO5801-, PRO5995-, PRO6001-, PRO6095-, PRO6182-, PRO7170-, PRO7171-, PRO7436-, PRO9912-, PRO9917-, PRO37337-, PRO37496-, PRO19646-, PRO21718-, PRO19820-, PRO21201-, PRO20026-, PRO20110-, PRO23203- or PRO35250-binding arm and an arm which binds the cytotoxic agent (e.g., saporin, anti-interferon-.alpha., vinca alkaloid, ricin A chain, methotrexate or radioactive isotope hapten). Bispecific antibodies can be prepared as full length antibodies or antibody fragments (e.g., F(ab).sub.2 bispecific antibodies).

[0550] WO 96/16673 describes a bispecific anti-ErbB2/anti-Fc.gamma.RIII antibody and U.S. Pat. No. 5,837,234 discloses a bispecific anti-ErbB2/anti-Fc.gamma.RI antibody. A bispecific anti-ErbB2/Fca antibody is shown in WO98/02463. U.S. Pat. No. 5,821,337 teaches a bispecific anti-ErbB2/anti-CD3 antibody.

[0551] Methods for making bispecific antibodies are known in the art. Traditional production of full length bispecific antibodies is based on the co-expression of two immunoglobulin heavy chain-light chain pairs, where the two chains have different specificities (Millstein et al., Nature 305:537-539 (1983)). Because of the random assortment of immunoglobulin heavy and light chains, these hybridomas (quadromas) produce a potential mixture of 10 different antibody molecules, of which only one has the correct bispecific structure. Purification of the correct molecule, which is usually done by affinity chromatography steps, is rather cumbersome, and the product yields are low. Similar procedures are disclosed in WO 93/08829, and in Traunecker et al., EMBO J. 10:3655-3659 (1991).

[0552] According to a different approach, antibody variable domains with the desired binding specificity (antibody-antigen combining sites) are fused to immunoglobulin constant domain sequences. Preferably, the fusion is with an Ig heavy chain constant domain, comprising at least part of the hinge, C.sub.H2, and C.sub.H3 regions. It is preferred to have the first heavy-chain constant region (C.sub.H1) containing the site necessary for light chain bonding, present in at least one of the fusions. DNAs encoding the immunoglobulin heavy chain fusions and, if desired, the immunoglobulin light chain, are inserted into separate expression vectors, and are co-transfected into a suitable host cell. This provides for greater flexibility in adjusting the mutual proportions of the three polypeptide fragments when unequal ratios of the three polypeptide chains used in the construction provide the optimum yield of the desired bispecific antibody. It is, however, possible to insert the coding sequences for two or all three polypeptide chains into a single expression vector when the expression of at least two polypeptide chains in equal ratios results in high yields or when the ratios have no significant affect on the yield of the desired chain combination.

[0553] The invention provides bispecific antibodies which are composed of a hybrid immunoglobulin heavy chain with a first binding specificity in one arm, and a hybrid immunoglobulin heavy chain-light chain pair (providing a second binding specificity) in the other arm. It was found that this asymmetric structure facilitates the separation of the desired bispecific compound from unwanted immunoglobulin chain combinations, as the presence of an immunoglobulin light chain in only one half of the bispecific molecule provides for a facile way of separation. This approach is disclosed in WO 94/04690. For further details of generating bispecific antibodies see, for example, Suresh et al., Methods in Enzymology 121:210 (1986).

[0554] According to another approach described in U.S. Pat. No. 5,731,168, the interface between a pair of antibody molecules can be engineered to maximize the percentage of heterodimers which are recovered from recombinant cell culture. The preferred interface comprises at least a part of the C.sub.H3 domain. In this method, one or more small amino acid side chains from the interface of the first antibody molecule are replaced with larger side chains (e.g., tyrosine or tryptophan). Compensatory "cavities" of identical or similar size to the large side chain(s) are created on the interface of the second antibody molecule by replacing large amino acid side chains with smaller ones (e.g., alanine or threonine). This provides a mechanism for increasing the yield of the heterodimer over other unwanted end-products such as homodimers.

[0555] Bispecific antibodies include cross-linked or "heteroconjugate" antibodies. For example, one of the antibodies in the heteroconjugate can be coupled to avidin, the other to biotin. Such antibodies have, for example, been proposed to target immune system cells to unwanted cells (U.S. Pat. No. 4,676,980), and for treatment of HIV infection (WO 91/00360, WO 92/200373, and EP 03089). Heteroconjugate antibodies may be made using any convenient cross-linking methods. Suitable cross-linking agents are well known in the art, and are disclosed in U.S. Pat. No. 4,676,980, along with a number of cross-linking techniques.

[0556] Techniques for generating bispecific antibodies from antibody fragments have also been described in the literature. For example, bispecific antibodies can be prepared using chemical linkage. Brennan et al., Science 229:81 (1985) describe a procedure wherein intact antibodies are proteolytically cleaved to generate F(ab').sub.2 fragments. These fragments are reduced in the presence of the dithiol complexing agent, sodium arsenite, to stabilize vicinal dithiols and prevent intermolecular disulfide formation. The Fab' fragments generated are then converted to thionitrobenzoate (TNB) derivatives. One of the Fab'-TNB derivatives is then reconverted to the Fab'-thiol by reduction with mere aptoethylamine and is mixed with an equimolar amount of the other Fab'-TNB derivative to form the bispecific antibody. The bispecific antibodies produced can be used as agents for the selective immobilization of enzymes.

[0557] Recent progress has facilitated the direct recovery of Fab'-SH fragments from E. coli, which can be chemically coupled to form bispecific antibodies. Shalaby et al., J. Exp. Med. 175: 217-225 (1992) describe the production of a fully humanized bispecific antibody F(ab').sub.2 molecule. Each Fab' fragment was separately secreted from E. coli and subjected to directed chemical coupling in vitro to form the bispecific antibody. The bispecific antibody thus formed was able to bind to cells overexpressing the ErbB2 receptor and normal human T cells, as well as trigger the lytic activity of human cytotoxic lymphocytes against human breast tumor targets. Various techniques for making and isolating bispecific antibody fragments directly from recombinant cell culture have also been described. For example, bispecific antibodies have been produced using leucine zippers. Kostelny et al., J. Immunol. 148(5):1547-1553 (1992). The leucine zipper peptides from the Fos and Jun proteins were linked to the Fab' portions of two different antibodies by gene fusion. The antibody homodimers were reduced at the hinge region to form monomers and then re-oxidized to form the antibody heterodimers. This method can also be utilized for the production of antibody homodimers. The "diabody" technology described by Hollinger et al., Proc. Natl. Acad. Sci. USA 90:6444-6448 (1993) has provided an alternative mechanism for making bispecific antibody fragments. The fragments comprise a V.sub.H connected to a V.sub.L by a linker which is too short to allow pairing between the two domains on the same chain. Accordingly, the V.sub.H and V.sub.L domains of one fragment are forced to pair with the complementary V.sub.L and V.sub.H domains of another fragment, thereby forming two antigen-binding sites. Another strategy for making bispecific antibody fragments by the use of single-chain Fv (sFv) dimers has also been reported. See Gruber et al., J. Immunol., 152:5368 (1994).

[0558] Antibodies with more than two valencies are contemplated. For example, trispecific antibodies can be prepared. Tutt et al., J. Immunol. 147:60 (1991).

[0559] 6. Heteroconjugate Antibodies

[0560] Heteroconjugate antibodies are also within the scope of the present invention. Heteroconjugate antibodies are composed of two covalently joined antibodies. Such antibodies have, for example, been proposed to target immune system cells to unwanted cells [U.S. Pat. No. 4,676,980], and for treatment of HIV infection [WO 91/00360; WO 92/200373; EP 03089]. It is contemplated that the antibodies may be prepared in vitro using known methods in synthetic protein chemistry, including those involving crosslinking agents. For example, immunotoxins may be constructed using a disulfide exchange reaction or by forming a thioether bond. Examples of suitable reagents for this purpose include iminothiolate and methyl-4-mercaptobutyrimidate and those disclosed, for example, in U.S. Pat. No. 4,676,980.

[0561] 7. Multivalent Antibodies

[0562] A multivalent antibody may be internalized (and/or catabolized) faster than a bivalent antibody by a cell expressing an antigen to which the antibodies bind. The antibodies of the present invention can be multivalent antibodies (which are other than of the IgM class) with three or more antigen binding sites (e.g. tetravalent antibodies), which can be readily produced by recombinant expression of nucleic acid encoding the polypeptide chains of the antibody. The multivalent antibody can comprise a dimerization domain and three or more antigen binding sites. The preferred dimerization domain comprises (or consists of) an Fc region or a hinge region. In this scenario, the antibody will comprise an Fc region and three or more antigen binding sites amino-terminal to the Fc region. The preferred multivalent antibody herein comprises (or consists of) three to about eight, but preferably four, antigen binding sites. The multivalent antibody comprises at least one polypeptide chain (and preferably two polypeptide chains), wherein the polypeptide chain(s) comprise two or more variable domains. For instance, the polypeptide chain(s) may comprise VD1-(X1).sub.n-VD2-(X2).sub.n-Fc, wherein VD1 is a first variable domain, VD2 is a second variable domain, Fc is one polypeptide chain of an Fc region, X1 and X2 represent an amino acid or polypeptide, and n is 0 or 1. For instance, the polypeptide chain(s) may comprise: VH-CH1-flexible linker-VH-CH1-Fc region chain; or VH-CH1-VH-CH1-Fc region chain. The multivalent antibody herein preferably further comprises at least two (and preferably four) light chain variable domain polypeptides. The multivalent antibody herein may, for instance, comprise from about two to about eight light chain variable domain polypeptides. The light chain variable domain polypeptides contemplated here comprise a light chain variable domain and, optionally, further comprise a CL domain.

[0563] 8. Effector Function Engineering

[0564] It may be desirable to modify the antibody of the invention with respect to effector function, e.g., so as to enhance antigen-dependent cell-mediated cytotoxicity (ADCC) and/or complement dependent cytotoxicity (CDC) of the antibody. This may be achieved by introducing one or more amino acid substitutions in an Fc region of the antibody. Alternatively or additionally, cysteine residue(s) may be introduced in the Fc region, thereby allowing interchain disulfide bond formation in this region. The homodimeric antibody thus generated may have improved internalization capability and/or increased complement-mediated cell killing and antibody-dependent cellular cytotoxicity (ADCC). See Caron et al., J. Exp Med. 176:1191-1195 (1992) and Shopes, B. J. Immunol. 148:2918-2922 (1992). Homodimeric antibodies with enhanced anti-tumor activity may also be prepared using heterobifunctional cross-linkers as described in Wolff et al., Cancer Research 53:2560-2565 (1993). Alternatively, an antibody can be engineered which has dual Fc regions and may thereby have enhanced complement lysis and ADCC capabilities. See Stevenson et al., Anti-Cancer Drug Design 3:219-230 (1989). To increase the serum half life of the antibody, one may incorporate a salvage receptor binding epitope into the antibody (especially an antibody fragment) as described in U.S. Pat. No. 5,739,277, for example. As used herein, the term "salvage receptor binding epitope" refers to an epitope of the Fc region of an IgG molecule (e.g., IgG.sub.1, IgG.sub.2, IgG.sub.3, or IgG.sub.4) that is responsible for increasing the in vivo serum half-life of the IgG molecule.

[0565] 9. Immunoconjugates

[0566] The invention also pertains to immunoconjugates comprising an antibody conjugated to a cytotoxic agent such as a chemotherapeutic agent, a growth inhibitory agent, a toxin (e.g., an enzymatically active toxin of bacterial, fungal, plant, or animal origin, or fragments thereof), or a radioactive isotope (i.e., a radioconjugate).

[0567] Chemotherapeutic agents useful in the generation of such immunoconjugates have been described above. Enzymatically active toxins and fragments thereof that can be used include diphtheria A chain, nonbinding active fragments of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, and the tricothecenes. A variety of radionuclides are available for the production of radioconjugated antibodies. Examples include .sup.122Bi, .sup.131I, .sup.131In, .sup.90Y, and .sup.186Re. Conjugates of the antibody and cytotoxic agent are made using a variety of bifunctional protein-coupling agents such as N-succinimidyl-3-(2-pyridyldithiol) propionate (SPDP), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCL), active esters (such as disuccinimidyl suberate), aldehydes (such as glutareldehyde), bis-azido compounds (such as bis(p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (such as bis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such as tolyene 2,6-diisocyanate), and bis-active fluorine compounds (such as 1,5-difluoro-2,4-dinitrobenzene). For example, a ricin immunotoxin can be prepared as described in Vitetta et al., Science, 238: 1098 (1987). Carbon-14-labeled 1-isothiocyanatobenzyl-3-methyldiethylene triaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugation of radionucleotide to the antibody. See WO94/11026.

[0568] Conjugates of an antibody and one or more small molecule toxins, such as a calicheamicin, maytansinoids, a trichothene, and CC1065, and the derivatives of these toxins that have toxin activity, are also contemplated herein.

Maytansine and Maytansinoids

[0569] The invention provides an anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibody (full length or fragments) which is conjugated to one or more maytansinoid molecules.

[0570] Maytansinoids are mitototic inhibitors which act by inhibiting tubulin polymerization. Maytansine was first isolated from the east African shrub Maytenus serrata (U.S. Pat. No. 3,896,111). Subsequently, it was discovered that certain microbes also produce maytansinoids, such as maytansinol and C-3 maytansinol esters (U.S. Pat. No. 4,151,042). Synthetic maytansinol and derivatives and analogues thereof are disclosed, for example, in U.S. Pat. Nos. 4,137,230; 4,248,870; 4,256,746; 4,260,608; 4,265,814; 4,294,757; 4,307,016; 4,308,268; 4,308,269; 4,309,428; 4,313,946; 4,315,929; 4,317,821; 4,322,348; 4,331,598; 4,361,650; 4,364,866; 4,424,219; 4,450,254; 4,362,663; and 4,371,533, the disclosures of which are hereby expressly incorporated by reference.

Maytansinoid-Antibody Conjugates

[0571] In an attempt to improve their therapeutic index, maytansine and maytansinoids have been conjugated to antibodies specifically binding to tumor cell antigens. Immunoconjugates containing maytansinoids and their therapeutic use are disclosed, for example, in U.S. Pat. Nos. 5,208,020, 5,416,064 and European Patent EP 0 425 235 B1, the disclosures of which are hereby expressly incorporated by reference. Liu et al., Proc. Natl. Acad. Sci. USA 93:8618-8623 (1996) described immunoconjugates comprising a maytansinoid designated DM1 linked to the monoclonal antibody C242 directed against human colorectal cancer. The conjugate was found to be highly cytotoxic towards cultured colon cancer cells, and showed antitumor activity in an in vivo tumor growth assay. Chari et al., Cancer Research 52:127-131 (1992) describe immunoconjugates in which a maytansinoid was conjugated via a disulfide linker to the murine antibody A7 binding to an antigen on human colon cancer cell lines, or to another murine monoclonal antibody TA.1 that binds the HER-2/neu oncogene. The cytotoxicity of the TA.1-maytansonoid conjugate was tested in vitro on the human breast cancer cell line SK-BR-3, which expresses 3.times.10.sup.5 HER-2 surface antigens per cell. The drug conjugate achieved a degree of cytotoxicity similar to the free maytansonid drug, which could be increased by increasing the number of maytansinoid molecules per antibody molecule. The A7-maytansinoid conjugate showed low systemic cytotoxicity in mice.

Anti-PRO69122, Anti-PRO204, Anti-PRO214, Anti-PRO222, Anti-PRO234, Anti-PRO265, Anti-PRO309, Anti-PRO332, Anti-PRO342, Anti-PRO356, Anti-PRO540, Anti-PRO618, Anti-PRO944, Anti-PRO994, Anti-PRO1079, Anti-PRO1110, Anti-PRO1122, Anti-PRO1138, Anti-PRO1190, Anti-PRO1272, Anti-PRO1286, Anti-PRO1295, Anti-PRO1309, Anti-PRO1316, Anti-PRO1383, Anti-PRO1384, Anti-PRO1431, Anti-PRO1434, Anti-PRO1475, Anti-PRO1481, Anti-PRO1568, Anti-PRO1573, Anti-PRO1599, Anti-PRO1604, Anti-PRO1605, PRO1693, Anti-PRO1753, Anti-PRO1755, Anti-PRO1777, Anti-PRO1788, Anti-PRO1864, Anti-PRO1925, Anti-PRO1926, Anti-PRO3566, Anti-PRO4330, Anti-PRO4423, Anti-PRO36935, Anti-PRO4977, Anti-PRO4979, Anti-PRO4980, Anti-PRO4981, Anti-PRO5801, Anti-PRO5995, Anti-PRO6001, Anti-PRO6095, Anti-PRO6182, Anti-PRO7170, Anti-PRO7171, Anti-PRO7436, Anti-PRO9912, Anti-PRO9917, Anti-PRO37337, Anti-PRO37496, Anti-PRO19646, Anti-PRO21718, Anti-PRO19820, Anti-PRO21201, Anti-PRO20026, Anti-PRO20110, Anti-PRO23203 or Anti-PRO35250 Antibody-Maytansinoid Conjugates (Immunoconjugates)

[0572] Anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibody-maytansinoid conjugates are prepared by chemically linking an anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibody to a maytansinoid molecule without significantly diminishing the biological activity of either the antibody or the maytansinoid molecule. An average of 3-4 maytansinoid molecules conjugated per antibody molecule has shown efficacy in enhancing cytotoxicity of target cells without negatively affecting the function or solubility of the antibody, although even one molecule of toxin/antibody would be expected to enhance cytotoxicity over the use of naked antibody. Maytansinoids are well known in the art and can be synthesized by known techniques or isolated from natural sources. Suitable maytansinoids are disclosed, for example, in U.S. Pat. No. 5,208,020 and in the other patents and nonpatent publications referred to hereinabove. Preferred maytansinoids are maytansinol and maytansinol analogues modified in the aromatic ring or at other positions of the maytansinol molecule, such as various maytansinol esters.

[0573] There are many linking groups known in the art for making antibody-maytansinoid conjugates, including, for example, those disclosed in U.S. Pat. No. 5,208,020 or EP Patent 0 425 235 B1, and Chari et al., Cancer Research 52:127-131 (1992). The linking groups include disufide groups, thioether groups, acid labile groups, photolabile groups, peptidase labile groups, or esterase labile groups, as disclosed in the above-identified patents, disulfide and thioether groups being preferred.

[0574] Conjugates of the antibody and maytansinoid may be made using a variety of bifunctional protein coupling agents such as N-succinimidyl-3-(2-pyridyldithio) propionate (SPDP), succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate, iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCL), active esters (such as disuccinimidyl suberate), aldehydes (such as glutareldehyde), bis-azido compounds (such as bis(p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (such as bis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such as toluene 2,6-diisocyanate), and bis-active fluorine compounds (such as 1,5-difluoro-2,4-dinitrobenzene). Particularly preferred coupling agents include N-succinimidyl-3-(2-pyridyldithio) propionate (SPDP) (Carlsson et al., Biochem. J. 173:723-737 [1978]) and N-succinimidyl-4-(2-pyridylthio)pentanoate (SPP) to provide for a disulfide linkage.

[0575] The linker may be attached to the maytansinoid molecule at various positions, depending on the type of the link. For example, an ester linkage may be formed by reaction with a hydroxyl group using conventional coupling techniques. The reaction may occur at the C-3 position having a hydroxyl group, the C-14 position modified with hyrdoxymethyl, the C-15 position modified with a hydroxyl group, and the C-20 position having a hydroxyl group. The linkage is formed at the C-3 position of maytansinol or a maytansinol analogue.

Calicheamicin

[0576] Another immunoconjugate of interest comprises an anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibody conjugated to one or more calicheamicin molecules. The calicheamicin family of antibiotics are capable of producing double-stranded DNA breaks at sub-picomolar concentrations. For the preparation of conjugates of the calicheamicin family, see U.S. Pat. Nos. 5,712,374, 5,714,586, 5,739,116, 5,767,285, 5,770,701, 5,770,710, 5,773,001, 5,877,296 (all to American Cyanamid Company). Structural analogues of calicheamicin which may be used include, but are not limited to, .gamma..sub.1.sup.I, .alpha..sub.2.sup.I, .alpha..sub.3.sup.I, N-acetyl-.gamma..sub.1.sup.I, PSAG and .theta..sup.I.sub.1 (Hinman et al., Cancer Research 53:3336-3342 (1993), Lode et al., Cancer Research 58:2925-2928 (1998) and the aforementioned U.S. patents to American Cyanamid). Another anti-tumor drug that the antibody can be conjugated is QFA which is an antifolate. Both calicheamicin and QFA have intracellular sites of action and do not readily cross the plasma membrane. Therefore, cellular uptake of these agents through antibody mediated internalization greatly enhances their cytotoxic effects.

Other Cytotoxic Agents

[0577] Other antitumor agents that can be conjugated to the anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibodies of the invention include BCNU, streptozoicin, vincristine and 5-fluorouracil, the family of agents known collectively LL-E33288 complex described in U.S. Pat. Nos. 5,053,394, 5,770,710, as well as esperamicins (U.S. Pat. No. 5,877,296).

[0578] Enzymatically active toxins and fragments thereof which can be used include diphtheria A chain, nonbinding active fragments of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin and the tricothecenes. See, for example, WO 93/21232 published Oct. 28, 1993.

[0579] The present invention further contemplates an immunoconjugate formed between an antibody and a compound with nucleolytic activity (e.g., a ribonuclease or a DNA endonuclease such as a deoxyribonuclease; DNase).

[0580] For selective destruction of the tumor, the antibody may comprise a highly radioactive atom. A variety of radioactive isotopes are available for the production of radioconjugated anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibodies. Examples include At.sup.211, I.sup.131, I.sup.125, Y.sup.90, Re.sup.186, Re.sup.188, Sm.sup.153, Bi.sup.212, P.sup.32, Pb.sup.212 and radioactive isotopes of Lu. When the conjugate is used for diagnosis, it may comprise a radioactive atom for scintigraphic studies, for example tc.sup.99m or I.sup.123, or a spin label for nuclear magnetic resonance (NMR) imaging (also known as magnetic resonance imaging, mri), such as iodine-123 again, iodine-131, indium-111, fluorine-19, carbon-13, nitrogen-15, oxygen-17, gadolinium, manganese or iron.

[0581] The radio- or other labels may be incorporated in the conjugate in known ways. For example, the peptide may be biosynthesized or may be synthesized by chemical amino acid synthesis using suitable amino acid precursors involving, for example, fluorine-19 in place of hydrogen. Labels such as tc.sup.99m or I.sup.123, Re.sup.188 and In.sup.111 can be attached via a cysteine residue in the peptide. Yttrium-90 can be attached via a lysine residue. The IODOGEN method (Fraker et al (1978) Biochem. Biophys. Res. Commun. 80: 49-57 can be used to incorporate iodine-123. "Monoclonal Antibodies in Immunoscintigraphy" (Chatal, CRC Press 1989) describes other methods in detail.

[0582] Conjugates of the antibody and cytotoxic agent may be made using a variety of bifunctional protein coupling agents such as N-succinimidyl-3-(2-pyridyldithio) propionate (SPDP), succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate, iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCL), active esters (such as disuccinimidyl suberate), aldehydes (such as glutareldehyde), bis-azido compounds (such as his (p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (such as bis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such as tolyene 2,6-diisocyanate), and bis-active fluorine compounds (such as 1,5-difluoro-2,4-dinitrobenzene). For example, a ricin immunotoxin can be prepared as described in Vitetta et al., Science 238:1098 (1987). Carbon-14-labeled 1-isothiocyanatobenzyl-3-methyldiethylene triaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugation of radionucleotide to the antibody. See WO94/11026. The linker may be a "cleavable linker" facilitating release of the cytotoxic drug in the cell. For example, an acid-labile linker, peptidase-sensitive linker, photolabile linker, dimethyl linker or disulfide-containing linker (Chari et al., Cancer Research 52:127-131 (1992); U.S. Pat. No. 5,208,020) may be used.

[0583] Alternatively, a fusion protein comprising the anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibody and cytotoxic agent may be made, e.g., by recombinant techniques or peptide synthesis. The length of DNA may comprise respective regions encoding the two portions of the conjugate either adjacent one another or separated by a region encoding a linker peptide which does not destroy the desired properties of the conjugate.

[0584] The invention provides that the antibody may be conjugated to a "receptor" (such streptavidin) for utilization in tumor pre-targeting wherein the antibody-receptor conjugate is administered to the patient, followed by removal of unbound conjugate from the circulation using a clearing agent and then administration of a "ligand" (e.g., avidin) which is conjugated to a cytotoxic agent (e.g., a radionucleotide).

[0585] 10. Immunoliposomes

[0586] The anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110 anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibodies disclosed herein may also be formulated as immunoliposomes. A "liposome" is a small vesicle composed of various types of lipids, phospholipids and/or surfactant which is useful for delivery of a drug to a mammal. The components of the liposome are commonly arranged in a bilayer formation, similar to the lipid arrangement of biological membranes. Liposomes containing the antibody are prepared by methods known in the art, such as described in Epstein et al., Proc. Natl. Acad. Sci. USA 82:3688 (1985); Hwang et al., Proc. Natl. Acad. Sci. USA 77:4030 (1980); U.S. Pat. Nos. 4,485,045 and 4,544,545; and WO97/38731 published

[0587] Oct. 23, 1997. Liposomes with enhanced circulation time are disclosed in U.S. Pat. No. 5,013,556.

[0588] Particularly useful liposomes can be generated by the reverse phase evaporation method with a lipid composition comprising phosphatidylcholine, cholesterol and PEG-derivatized phosphatidylethanolamine (PEG-PE). Liposomes are extruded through filters of defined pore size to yield liposomes with the desired diameter. Fab' fragments of the antibody of the present invention can be conjugated to the liposomes as described in Martin et al., J. Biol. Chem. 257:286-288 (1982) via a disulfide interchange reaction. A chemotherapeutic agent is optionally contained within the liposome. See Gabizon et al., J. National Cancer Inst. 81(19):1484 (1989).

[0589] 11. Pharmaceutical Compositions of Antibodies

[0590] Antibodies specifically binding a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide identified herein, as well as other molecules identified by the screening assays disclosed hereinbefore, can be administered for the treatment of various disorders in the form of pharmaceutical compositions.

[0591] If the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide is intracellular and whole antibodies are used as inhibitors, internalizing antibodies are preferred. However, lipofections or liposomes can also be used to deliver the antibody, or an antibody fragment, into cells. Where antibody fragments are used, the smallest inhibitory fragment that specifically binds to the binding domain of the target protein is preferred. For example, based upon the variable-region sequences of an antibody, peptide molecules can be designed that retain the ability to bind the target protein sequence. Such peptides can be synthesized chemically and/or produced by recombinant DNA technology. See, e.g., Marasco et al., Proc. Natl. Acad. Sci. USA, 90: 7889-7893 (1993). The formulation herein may also contain more than one active compound as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other. Alternatively, or in addition, the composition may comprise an agent that enhances its function, such as, for example, a cytotoxic agent, cytokine, chemotherapeutic agent, or growth-inhibitory agent. Such molecules are suitably present in combination in amounts that are effective for the purpose intended.

[0592] The active ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles, and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences, supra.

[0593] The formulations to be used for in vivo administration must be sterile. This is readily accomplished by filtration through sterile filtration membranes.

[0594] Sustained-release preparations may be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and .gamma. ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT.TM. (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid. While polymers such as ethylene-vinyl acetate and lactic acid-glycolic acid enable release of molecules for over 100 days, certain hydrogels release proteins for shorter time periods. When encapsulated antibodies remain in the body for a long time, they may denature or aggregate as a result of exposure to moisture at 37.degree. C., resulting in a loss of biological activity and possible changes in immunogenicity. Rational strategies can be devised for stabilization depending on the mechanism involved. For example, if the aggregation mechanism is discovered to be intermolecular S--S bond formation through thio-disulfide interchange, stabilization may be achieved by modifying sulfhydryl residues, lyophilizing from acidic solutions, controlling moisture content, using appropriate additives, and developing specific polymer matrix compositions.

G. Uses for Anti-PRO69122, Anti-PRO204, Anti-PRO214, Anti-PRO222, Anti-PRO234, Anti-PRO265, Anti-PRO309, Anti-PRO332, Anti-PRO342, Anti-PRO356, Anti-PRO540, Anti-PRO618, Anti-PRO944, Anti-PRO994, Anti-PRO1079, Anti-PRO1110, Anti-PRO1122, Anti-PRO1138, Anti-PRO1190, Anti-PRO1272, Anti-PRO1286, Anti-PRO1295, Anti-PRO1309, Anti-PRO1316, Anti-PRO1383, Anti-PRO1384, Anti-PRO1431, Anti-PRO1434, Anti-PRO1475, Anti-PRO1481, Anti-PRO1568, Anti-PRO1573, Anti-PRO1599, Anti-PRO1604, Anti-PRO1605, Anti-PRO1693, Anti-PRO1753, Anti-PRO1755, Anti-PRO1777, Anti-PRO1788, Anti-PRO1864, Anti-PRO1925, Anti-PRO1926, Anti-PRO3566, Anti-PRO4330, Anti-PRO4423, Anti-PRO36935, Anti-PRO4977, Anti-PRO4979, Anti-PRO4980, Anti-PRO4981, Anti-PRO5801, Anti-PRO5995, Anti-PRO6001, Anti-PRO6095, Anti-PRO6182, Anti-PRO7170, Anti-PRO7171, Anti-PRO7436, Anti-PRO9912, Anti-PRO9917, Anti-PRO37337, Anti-PRO37496, Anti-PRO19646, Anti-PRO21718, Anti-PRO19820, Anti-PRO21201, Anti-PRO20026, Anti-PRO20110, Anti-PRO23203 or Anti-PRO35250 Antibodies

[0595] The anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibodies of the invention have various therapeutic and/or diagnostic utilities for a neurological disorder; a cardiovascular, endothelial or angiogenic disorder; an immunological disorder; an ontological disorder, an embryonic developmental disorder or lethality, or a metabolic abnormality. For example, anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibodies may be used in diagnostic assays for PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250, e.g., detecting its expression (and in some cases, differential expression) in specific cells, tissues, or serum. Various diagnostic assay techniques known in the art may be used, such as competitive binding assays, direct or indirect sandwich assays and immunoprecipitation assays conducted in either heterogeneous or homogeneous phases [Zola, Monoclonal Antibodies: A Manual of Techniques, CRC Press, Inc. (1987) pp. 147-158]. The antibodies used in the diagnostic assays can be labeled with a detectable moiety. The detectable moiety should be capable of producing, either directly or indirectly, a detectable signal. For example, the detectable moiety may be a radioisotope, such as .sup.3H, .sup.14C, .sup.32P, .sup.35S, or .sup.125I, a fluorescent or chemiluminescent compound, such as fluorescein isothiocyanate, rhodamine, or luciferin, or an enzyme, such as alkaline phosphatase, beta-galactosidase or horseradish peroxidase. Any method known in the art for conjugating the antibody to the detectable moiety may be employed, including those methods described by Hunter et al., Nature, 144:945 (1962); David et al., Biochemistry, 13:1014 (1974); Pain et al., J. Immunol. Meth., 40:219 (1981); and Nygren, J. Histochem. and Cytochem., 30:407 (1982).

[0596] Anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibodies also are useful for the affinity purification of PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides from recombinant cell culture or natural sources. In this process, the antibodies against PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO1110, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides are immobilized on a suitable support, such a Sephadex resin or filter paper, using methods well known in the art. The immobilized antibody then is contacted with a sample containing the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide to be purified, and thereafter the support is washed with a suitable solvent that will remove substantially all the material in the sample except the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, which is bound to the immobilized antibody. Finally, the support is washed with another suitable solvent that will release the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide from the antibody.

[0597] The following examples are offered for illustrative purposes only, and are not intended to limit the scope of the present invention in any way.

[0598] All patent and literature references cited in the present specification are hereby incorporated by reference in their entirety.

EXAMPLES

[0599] Commercially available reagents referred to in the examples were used according to manufacturer's instructions unless otherwise indicated. The source of those cells identified in the following examples, and throughout the specification, by ATCC accession numbers is the American Type Culture Collection, Manassas, Va.

Example 1

Extracellular Domain Homology Screening to Identify Novel Polypeptides and cDNA Encoding Therefor

[0600] The extracellular domain (ECD) sequences (including the secretion signal sequence, if any) from about 950 known secreted proteins from the Swiss-Prot public database were used to search EST databases. The EST databases included public databases (e.g., Dayhoff, GenBank), and proprietary databases (e.g. LIFESEQ.TM., Incyte Pharmaceuticals, Palo Alto, Calif.). The search was performed using the computer program BLAST or BLAST-2 (Altschul et al., Methods in Enzymology, 266:460-480 (1996)) as a comparison of the ECD protein sequences to a 6 frame translation of the EST sequences. Those comparisons with a BLAST score of 70 (or in some cases 90) or greater that did not encode known proteins were clustered and assembled into consensus DNA sequences with the program "phrap" (Phil Green, University of Washington, Seattle, Wash.).

[0601] Using this extracellular domain homology screen, consensus DNA sequences were assembled relative to the other identified EST sequences using phrap. In addition, the consensus DNA sequences obtained were often (but not always) extended using repeated cycles of BLAST or BLAST-2 and phrap to extend the consensus sequence as far as possible using the sources of EST sequences discussed above.

[0602] Based upon the consensus sequences obtained as described above, oligonucleotides were then synthesized and used to identify by PCR a cDNA library that contained the sequence of interest and for use as probes to isolate a clone of the full-length coding sequence for a PRO polypeptide. Forward and reverse PCR primers generally range from 20 to 30 nucleotides and are often designed to give a PCR product of about 100-1000 bp in length. The probe sequences are typically 40-55 bp in length. In some cases, additional oligonucleotides are synthesized when the consensus sequence is greater than about 1-1.5 kbp. In order to screen several libraries for a full-length clone, DNA from the libraries was screened by PCR amplification, as per Ausubel et al., Current Protocols in Molecular Biology, with the PCR primer pair. A positive library was then used to isolate clones encoding the gene of interest using the probe oligonucleotide and one of the primer pairs.

[0603] The cDNA libraries used to isolate the cDNA clones were constructed by standard methods using commercially available reagents such as those from Invitrogen, San Diego, Calif. The cDNA was primed with oligo dT containing a NotI site, linked with blunt to SalI hemikinased adaptors, cleaved with NotI, sized appropriately by gel electrophoresis, and cloned in a defined orientation into a suitable cloning vector (such as pRKB or pRKD; pRK5B is a precursor of pRK5D that does not contain the SfiI site; see, Holmes et al., Science, 253:1278-1280 (1991)) in the unique XhoI and NotI sites.

Example 2

Isolation of cDNA clones by Amylase Screening

[0604] 1. Preparation of Oligo dT Primed cDNA Library

[0605] mRNA was isolated from a human tissue of interest using reagents and protocols from Invitrogen, San Diego, Calif. (Fast Track 2). This RNA was used to generate an oligo dT primed cDNA library in the vector pRK5D using reagents and protocols from Life Technologies, Gaithersburg, Md. (Super Script Plasmid System). In this procedure, the double stranded cDNA was sized to greater than 1000 bp and the SalI/NotI linkered cDNA was cloned into XhoI/NotI cleaved vector. pRK5D is a cloning vector that has an sp6 transcription initiation site followed by an SfiI restriction enzyme site preceding the XhoI/NotI cDNA cloning sites.

[0606] 2. Preparation of Random Primed cDNA Library

[0607] A secondary cDNA library was generated in order to preferentially represent the 5' ends of the primary cDNA clones. Sp6 RNA was generated from the primary library (described above), and this RNA was used to generate a random primed cDNA library in the vector pSST-AMY.0 using reagents and protocols from Life Technologies (Super Script Plasmid System, referenced above). In this procedure the double stranded cDNA was sized to 500-1000 bp, linkered with blunt to Nod adaptors, cleaved with SfiI, and cloned into SfiI/NotI cleaved vector. pSST-AMY.0 is a cloning vector that has a yeast alcohol dehydrogenase promoter preceding the cDNA cloning sites and the mouse amylase sequence (the mature sequence without the secretion signal) followed by the yeast alcohol dehydrogenase terminator, after the cloning sites. Thus, cDNAs cloned into this vector that are fused in frame with amylase sequence will lead to the secretion of amylase from appropriately transfected yeast colonies.

[0608] 3. Transformation and Detection

[0609] DNA from the library described in paragraph 2 above was chilled on ice to which was added electrocompetent DH10B bacteria (Life Technologies, 20 ml). The bacteria and vector mixture was then electroporated as recommended by the manufacturer. Subsequently, SOC media (Life Technologies, 1 ml) was added and the mixture was incubated at 37.degree. C. for 30 minutes. The transformants were then plated onto 20 standard 150 mm LB plates containing ampicillin and incubated for 16 hours (37.degree. C.). Positive colonies were scraped off the plates and the DNA was isolated from the bacterial pellet using standard protocols, e.g. CsCl-gradient. The purified DNA was then carried on to the yeast protocols below.

[0610] The yeast methods were divided into three categories: (1) Transformation of yeast with the plasmid/cDNA combined vector; (2) Detection and isolation of yeast clones secreting amylase; and (3) PCR amplification of the insert directly from the yeast colony and purification of the DNA for sequencing and further analysis.

[0611] The yeast strain used was HD56-5A (ATCC-90785). This strain has the following genotype: MAT alpha, ura3-52, leu2-3, leu2-112, his3-11, his3-15, MAL.sup.+, SUC.sup.+, GAL.sup.+. Preferably, yeast mutants can be employed that have deficient post-translational pathways. Such mutants may have translocation deficient alleles in sec71, sec72, sec62, with truncated sec71 being most preferred. Alternatively, antagonists (including antisense nucleotides and/or ligands) which interfere with the normal operation of these genes, other proteins implicated in this post translation pathway (e.g., SEC61p, SEC72p, SEC62p, SEC63p, TDJ1p or SSA1p-4-p) or the complex formation of these proteins may also be preferably employed in combination with the amylase-expressing yeast.

[0612] Transformation was performed based on the protocol outlined by Gietz et al., Nucl. Acid. Res., 20:1425 (1992). Transformed cells were then inoculated from agar into YEPD complex media broth (100 ml) and grown overnight at 30.degree. C. The YEPD broth was prepared as described in Kaiser et al., Methods in Yeast Genetics, Cold Spring Harbor Press, Cold Spring Harbor, N.Y., p. 207 (1994). The overnight culture was then diluted to about 2.times.10.sup.6 cells/ml (approx. OD.sub.600=0.1) into fresh YEPD broth (500 ml) and regrown to 1.times.10.sup.7 cells/ml (approx. OD.sub.600=0.4-0.5).

[0613] The cells were then harvested and prepared for transformation by transfer into GS3 rotor bottles in a Sorval GS3 rotor at 5,000 rpm for 5 minutes, the supernatant discarded, and then resuspended into sterile water, and centrifuged again in 50 ml falcon tubes at 3,500 rpm in a Beckman GS-6KR centrifuge. The supernatant was discarded and the cells were subsequently washed with LiAc/TE (10 ml, 10 mM Tris-HCl, 1 mM EDTA pH 7.5, 100 mM Li.sub.2OOCCH.sub.3), and resuspended into LiAc/TE (2.5 ml).

[0614] Transformation took place by mixing the prepared cells (100 .mu.l) with freshly denatured single stranded salmon testes DNA (Lofstrand Labs, Gaithersburg, Md.) and transforming DNA (1 .mu.g, vol.<10 .mu.l) in microfuge tubes. The mixture was mixed briefly by vortexing, then 40% PEG/TE (600 .mu.l, 40% polyethylene glycol-4000, mM Tris-HCl, 1 mM EDTA, 100 mM Li.sub.2OOCCH.sub.3, pH 7.5) was added. This mixture was gently mixed and incubated at 30.degree. C. while agitating for 30 minutes. The cells were then heat shocked at 42.degree. C. for 15 minutes, and the reaction vessel centrifuged in a microfuge at 12,000 rpm for 5-10 seconds, decanted and resuspended into TE (500 .mu.l, 10 mM Tris-HCl, 1 mM EDTA pH 7.5) followed by recentrifugation. The cells were then diluted into TE (1 ml) and aliquots (200 .mu.l) were spread onto the selective media previously prepared in 150 mm growth plates (VWR).

[0615] Alternatively, instead of multiple small reactions, the transformation was performed using a single, large scale reaction, wherein reagent amounts were scaled up accordingly.

[0616] The selective media used was a synthetic complete dextrose agar lacking uracil (SCD-Ura) prepared as described in Kaiser et al., Methods in Yeast Genetics, Cold Spring Harbor Press, Cold Spring Harbor, N.Y., p. 208-210 (1994). Transformants were grown at 30.degree. C. for 2-3 days.

[0617] The detection of colonies secreting amylase was performed by including red starch in the selective growth media. Starch was coupled to the red dye (Reactive Red-120, Sigma) as per the procedure described by Biely et al., Anal. Biochem., 172:176-179 (1988). The coupled starch was incorporated into the SCD-Ura agar plates at a final concentration of 0.15% (w/v), and was buffered with potassium phosphate to a pH of 7.0 (50-100 mM final concentration).

[0618] The positive colonies were picked and streaked across fresh selective media (onto 150 mm plates) in order to obtain well isolated and identifiable single colonies. Well isolated single colonies positive for amylase secretion were detected by direct incorporation of red starch into buffered SCD-Ura agar. Positive colonies were determined by their ability to break down starch resulting in a clear halo around the positive colony visualized directly.

[0619] 4. Isolation of DNA by PCR Amplification When a positive colony was isolated, a portion of it was picked by a toothpick and diluted into sterile water (30 .mu.l) in a 96 well plate. At this time, the positive colonies were either frozen and stored for subsequent analysis or immediately amplified. An aliquot of cells (5 .mu.l) was used as a template for the PCR reaction in a 25 .mu.l volume containing: 0.5 .mu.l Klentaq (Clontech, Palo Alto, Calif.); 4.0 .mu.l 10 mM dNTP's (Perkin Elmer-Cetus); 2.5 .mu.l Kentaq buffer (Clontech); 0.25 .mu.l forward oligo 1; 0.25 .mu.l reverse oligo 2; 12.5 .mu.l distilled water. The sequence of the forward oligonucleotide 1 was:

TABLE-US-00007 (SEQ ID NO: 143) 5'-TGTAAAACGACGGCCAGTTAAATAGACCTGCAATTATTAATCT-3'

The sequence of reverse oligonucleotide 2 was:

TABLE-US-00008 (SEQ ID NO: 144) 5'-CAGGAAACAGCTATGACCACCTGCACACCTGCAAATCCATT-3'

PCR was then performed as follows:

TABLE-US-00009 a. Denature 92.degree. C., 5 minutes b. 3 cycles of: Denature 92.degree. C., 30 seconds Anneal 59.degree. C., 30 seconds Extend 72.degree. C., 60 seconds c. 3 cycles of: Denature 92.degree. C., 30 seconds Anneal 57.degree. C., 30 seconds Extend 72.degree. C., 60 seconds d. 25 cycles of: Denature 92.degree. C., 30 seconds Anneal 55.degree. C., 30 seconds Extend 72.degree. C., 60 seconds e. Hold 4.degree. C.

[0620] The underlined regions of the oligonucleotides annealed to the ADH promoter region and the amylase region, respectively, and amplified a 307 bp region from vector pSST-AMY.0 when no insert was present. Typically, the first 18 nucleotides of the 5' end of these oligonucleotides contained annealing sites for the sequencing primers. Thus, the total product of the PCR reaction from an empty vector was 343 bp. However, signal sequence-fused cDNA resulted in considerably longer nucleotide sequences.

[0621] Following the PCR, an aliquot of the reaction (5 .mu.l) was examined by agarose gel electrophoresis in a 1% agarose gel using a Tris-Borate-EDTA (TBE) buffering system as described by Sambrook et al., supra. Clones resulting in a single strong PCR product larger than 400 bp were further analyzed by DNA sequencing after purification with a 96 Qiaquick PCR clean-up column (Qiagen Inc., Chatsworth, Calif.).

Example 3

Isolation of cDNA Clones Using Signal Algorithm Analysis

[0622] Various polypeptide-encoding nucleic acid sequences were identified by applying a proprietary signal sequence finding algorithm developed by Genentech, Inc. (South San Francisco, Calif.) upon ESTs as well as clustered and assembled EST fragments from public (e.g., GenBank) and/or private (LIFESEQ.RTM., Incyte Pharmaceuticals, Inc., Palo Alto, Calif.) databases. The signal sequence algorithm computes a secretion signal score based on the character of the DNA nucleotides surrounding the first and optionally the second methionine codon(s) (ATG) at the 5'-end of the sequence or sequence fragment under consideration. The nucleotides following the first ATG must code for at least 35 unambiguous amino acids without any stop codons. If the first ATG has the required amino acids, the second is not examined. If neither meets the requirement, the candidate sequence is not scored. In order to determine whether the EST sequence contains an authentic signal sequence, the DNA and corresponding amino acid sequences surrounding the ATG codon are scored using a set of seven sensors (evaluation parameters) known to be associated with secretion signals. Use of this algorithm resulted in the identification of numerous polypeptide-encoding nucleic acid sequences.

[0623] Using the techniques described in Examples 1 to 3 above, numerous full-length cDNA clones were identified as encoding PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides as disclosed herein. These cDNAs were then deposited under the terms of the Budapest Treaty with the American Type Culture Collection, 10801 University Blvd., Manassas, Va. 20110-2209, USA (ATCC) as shown in Table 7 below. In addition, the sequence of DNA284870 encoding PRO69122 polypeptides was identified from GenBank accession no.: AF052059; the sequence of DNA38649 encoding PRO342 polypeptides was identified from GenBank accession no.: AY358342; the sequence of DNA336539 encoding PRO36935 polypeptides was identified from GenBank accession no.: Z29083 the sequence of DNA222844 encoding PRO4979 polypeptides (also known as PRO38844 polypeptides) was identified from GenBank accession no.: AB098597; the sequence of DNA98380 encoding PRO6001 polypeptides was identified from GenBank accession no.: AY358785; the sequence of DNA226874 encoding PRO37337 polypeptides was identified from GenBank accession no.: Y07909; the sequence of DNA227033 encoding PRO37496 polypeptides was identified from GenBank accession no.: BC003006; and the sequence of DNA188342 encoding PRO21718 polypeptides was identified from GenBank accession no.: AF146761.

TABLE-US-00010 TABLE 7 Material ATCC Dep. No. Deposit Date DNA30871-1157 209380 Oct. 16, 1997 DNA32286-1191 209385 Oct. 16, 1997 DNA33107-1135 209251 Sep. 16, 1997 DNA35557-1137 209255 Sep. 16, 1998 DNA36350-1158 209378 Oct. 16, 1997 DNA61601-1223 209713 Mar. 31, 1998 DNA40982-1235 209433 Nov. 7, 1997 DNA47470-1130P1 209422 Oct. 28, 1997 DNA44189-1322 209699 Mar. 26, 1998 DNA49152-1324 209813 Apr. 28, 1998 DNA52185-1370 209861 May 14, 1998 DNA58855-1422 203018 Jun. 23, 1998 DNA56050-1455 203011 Jun. 23, 1998 DNA58727-1474 203171 Sep. 1, 1998 DNA62377-1381-1 203552 Dec. 22, 1998 DNA58850-1495 209956 Jun. 9, 1998 DNA59586-1520 203288 Sep. 29, 1998 DNA64896-1539 203238 Sep. 9, 1998 DNA64903-1553 203223 Sep. 15, 1998 DNA59218-1559 203287 Sep. 29, 1998 DNA59588-1571 203106 Aug. 11, 1998 DNA60608-1577 203126 Aug. 18, 1998 DNA58743-1609 203154 Aug. 25, 1998 DNA71159-1617 203135 Aug. 18, 1998 DNA73401-1633 203273 Sep. 22, 1998 DNA68818-2536 203657 Feb. 9, 1999 DNA61185-1646 203464 Nov. 17, 1998 DNA58732-1650 203290 Sep. 29, 1998 DNA68880-1676 203319 Oct. 6, 1998 DNA73735-1681 203356 Oct. 20, 1998 DNA62845-1684 203361 Oct. 20, 1998 DNA71286-1687 203357 Oct. 20, 1998 DNA77648-1688 203408 Oct. 27, 1998 DNA77301-1708 203407 Oct. 27, 1998 DNA68883-1691 203535 Dec. 15, 1998 DNA76396-1698 203471 Nov. 17, 1998 DNA77652-2505 203480 Nov. 17, 1998 DNA71235-1706 203584 Jan. 12, 1999 DNA45409-2511 203579 Jan. 12, 1999 DNA82302-2529 203534 Dec. 15, 1998 DNA82340-2530 203547 Dec. 22, 1998 DNA59844-2542 203650 Feb. 9, 1999 DNA90842-2574 203845 Mar. 16, 1999 DNA96893-2621 PTA-12 May 4, 1999 DNA62849-2647 PTA-205 Jun. 8, 1999 DNA97003-2649 PTA-43 May 11, 1999 DNA94849-2960 PTA-2306 Jul. 25, 2000 DNA115291-2681 PTA-202 Jun. 8, 1999 DNA96988-2685 PTA-384 Jul. 20, 1999 DNA105680-2710 PTA-483 Aug. 3, 1999 DNA110700-2716 PTA-512 Aug. 10, 1999 DNA108722-2743 PTA-552 Aug. 17, 1999 DNA108670-2744 PTA-546 Aug. 17, 1999 DNA119535-2756 PTA-613 Aug. 31, 1999 DNA108700-2802 PTA-1093 Dec. 22, 1999 DNA119474-2803 PTA-1097 Dec. 22, 1999 DNA145841-2868 PTA-1678 Apr. 11, 2000 DNA149911-2885 PTA-1776 Apr. 25, 2000 DNA168028-2956 PTA-2304 Jul. 25, 2000 DNA154095-2998 PTA-2591 Oct. 10, 2000 DNA185171-2994 PTA-2513 Sep. 26, 2000 DNA171732-3100 PTA-3329 Apr. 24, 2001

[0624] These deposits were made under the provisions of the Budapest Treaty on the International Recognition of the Deposit of Microorganisms for the Purpose of Patent Procedure and the Regulations thereunder (Budapest Treaty). This assures maintenance of a viable culture of the deposit for 30 years from the date of deposit. The deposits will be made available by ATCC under the terms of the Budapest Treaty, and subject to an agreement between Genentech, Inc. and ATCC, which assures permanent and unrestricted availability of the progeny of the culture of the deposit to the public upon issuance of the pertinent U.S. patent or upon laying open to the public of any U.S. or foreign patent application, whichever comes first, and assures availability of the progeny to one determined by the U.S. Commissioner of Patents and Trademarks to be entitled thereto according to 35 USC .sctn.122 and the Commissioner's rules pursuant thereto (including 37 CFR .sctn.1.14 with particular reference to 8860G 638).

[0625] The assignee of the present application has agreed that if a culture of the materials on deposit should die or be lost or destroyed when cultivated under suitable conditions, the materials will be promptly, replaced on notification with another of the same. Availability of the deposited material is not to be construed as a license to practice the invention in contravention of the rights granted under the authority of any government in accordance with its patent laws.

Example 4

Isolation of cDNA Clones Encoding Human PRO204 Polypeptides [UNQ178]

[0626] An expressed sequence tag (EST) DNA database (LIFESEQ.RTM., Incyte Pharmaceuticals, Palo Alto, Calif.) was searched and an EST was identified. Human fetal retina cDNA libraries were screened with PCR oligonucleotide primers and confirmed by hybridization with synthetic oligonucleotide probe which was based upon the EST sequence.

TABLE-US-00011 hybridization probe: (SEQ ID NO: 145) 5'-GGCATGCAGCAGCTGGACATTTGCGAGGGCTTTTGCTGGCTG-3' forward PCR primer: (SEQ ID NO: 146) 5'-CTGCTGCAGAGTTGCACGAAC-3' reverse PCR primer 1: (SEQ ID NO: 147) 5'-CAGTTGTTGTTGTCACAGAGAAG-3' reverse PCR primer 2: (SEQ ID NO: 148) 5'-AGTTCGTGCAACTCTGCAGCAG-3'

[0627] A cDNA clone was identified and sequenced in entirety. The entire nucleotide sequence of the identified clone DNA3087-1157 is shown in FIG. 3 (SEQ ID NO:3). Clone DNA30871-1157 (SEQ ID NO:3) contains a single open reading frame with an apparent translation initiation site at nucleotide positions 376-378 and ending at the stop codon (TAA) found at nucleotide positions 1498-1500 (FIG. 3; SEQ ID NO:3), as indicated by bolded underline. The predicted PRO204 polypeptide precursor (i.e., UNQ178, SEQ ID NO:4) is 374 amino acids long, has a calculated molecular weight of 39,285 daltons, a pI of 6.06 and is shown in FIG. 4. A cDNA containing DNA encoding UNQ178 (SEQ ID NO:3) has been deposited with the ATTC on Oct. 16, 1997 and has been assigned deposit number 209380.

Example 5

Isolation of cDNA Clones Encoding Human PRO214 Polypeptides [UNQ188]

[0628] A consensus DNA sequence was assembled using phrap as described in Example 1 above. This consensus DNA sequence is designated herein as DNA28744. Based on this consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence.

[0629] In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pair identified below. A positive library was then used to isolate clones encoding the PRO214 gene using the probe oligonucleotide and one of the PCR primers.

[0630] RNA for construction of the cDNA libraries was isolated from human fetal lung tissue.

[0631] A cDNA clone was sequenced in its entirety. The full length nucleotide sequence of DNA32286-1191 is shown in FIG. 5 (SEQ ID NO:5). DNA32286-1191 contains a single open reading frame with an apparent translational initiation site at nucleotide position 103 (FIG. 5; SEQ ID NO:5). The predicted polypeptide precursor is 420 amino acids long (FIG. 6; SEQ ID NO:6).

[0632] Based on a BLAST and FastA sequence alignment analysis of the full-length sequence, PRO214 polypeptide shows amino acid sequence identity to HT protein and/or Fibulin (49% and 38%, respectively).

[0633] The oligonucleotide sequences used in the above procedure were the following:

TABLE-US-00012 28744.p (OLI555) (SEQ ID NO: 149) 5'-CCTGGCTATCAGCAGGTGGGCTCCAAGTGTCTCGATGTGGATGAGT GTGA-3' 28744.f (OLI556) (SEQ ID NO: 150) 5'-ATTCTGCGTGAACACTGAGGGC-3' 28744.r (OLI557) (SEQ ID NO: 151) 5'-ATCTGCTTGTAGCCCTCGGCAC-3'

Example 6

Isolation of cDNA Clones Encoding Human PRO222 Polypeptides [UNQ196]

[0634] A consensus DNA sequence was assembled relative to the other identified EST sequences as described in Example 1 above, wherein the consensus sequence is designated herein as DNA28771. Based on the DNA28771 consensus sequence, oligonucleotides were synthesized to identify by PCR a cDNA library that contained the sequence of interest and for use as probes to isolate a clone of the full-length coding sequence for PRO222.

[0635] A pair of PCR primers (forward and reverse) were synthesized:

TABLE-US-00013 (SEQ ID NO: 152) forward PCR primer 5'-ATCTCCTATCGCTGCTTTCCCGG-3' (SEQ ID NO: 153) reverse PCR primer 5'-AGCCAGGATCGCAGTAAAACTCC-3'

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA28771 sequence which had the following nucleotide sequence:

TABLE-US-00014 hybridization probe (SEQ ID NO: 154) 5'-ATTTAAACTTGATGGGTCTGCGTATCTTGAGTGCTTACAAAACCTT ATCT-3'

[0636] In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PRO222 gene using the probe oligonucleotide and one of the PCR primers.

[0637] RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue.

[0638] DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO222 [herein designated as DNA33107-1135] and the derived protein sequence for PRO222.

[0639] The entire nucleotide sequence of DNA33107-1135 is shown in FIG. 7 (SEQ ID NO:7). Clone

[0640] DNA33107-1135 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 159-161 and ending at the stop codon at nucleotide positions 1629-1631 (FIG. 7; SEQ ID NO:7). The predicted polypeptide precursor is 490 amino acids long (FIG. 8; SEQ ID NO:8). Clone DNA33107-1135 has been deposited with ATCC on Sep. 16, 1997 and is assigned ATCC deposit no. ATCC 209251.

[0641] Based on a BLAST and FastA sequence alignment analysis of the full-length sequence, PRO222 shows amino acid sequence identity to mouse complement factor h precursor (25-26%), complement receptor (27-29%), mouse complement C3b receptor type 2 long form precursor (25-47%) and human hypothetical protein kiaa0247 (40%).

Example 7

Isolation of cDNA Clones Encoding Human PRO234 Polypeptides [UNQ208]

[0642] A consensus DNA sequence was assembled (DNA30926) using phrap as described in Example 1 above. Based on this consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence.

[0643] RNA for the construction of the cDNA libraries was isolated using standard isolation protocols, e.g., Ausubel et al., Current Protocols in Molecular Biology, from tissue or cell line sources or it was purchased from commercial sources (e.g., Clontech). The cDNA libraries used to isolate the cDNA clones were constructed by standard methods (e.g., Ausubel et al.) using commercially available reagents (e.g., Invitrogen). This library was derived from 22 week old fetal brain tissue.

[0644] A cDNA clone was sequenced in its entirety and is herein designated DNA35557-1137 (SEQ ID NO:9). The entire nucleotide sequence of DNA355557-1137 is shown in FIG. 9 (SEQ ID NO:9). The predicted polypeptide precursor is 382 amino acids long (designated PRO234; SEQ ID NO:10; FIG. 10) and has a calculated molecular weight of approximately 43.1 kDa.

[0645] The oligonucleotide sequences used in the above procedure were the following:

TABLE-US-00015 30926.p (OLI826) (SEQ ID NO: 155): 5'-GTTCATTGAAAACCTCTTGCCATCTGATGGTGACTTCTGGATTGGG CTCA-3' 30926.f (OLI827) (SEQ ID NO: 156): 5'-AAGCCAAAGAAGCCTGCAGGAGGG-3' 30926.r (OLI828) (SEQ ID NO: 157): 5'-CAGTCCAAGCATAAAGGTCCTGGC-3'

Example 8

Isolation of cDNA Clones Encoding Human PRO265 Polypeptides [UNQ232]

[0646] A consensus DNA sequence was assembled relative to other EST sequences as described in Example 1 above using phrap. This consensus sequence is herein designated DNA33679. Based on the DNA33679 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO265.

[0647] PCR primers (two forward and one reverse) were synthesized:

TABLE-US-00016 forward PCR primer A: (SEQ ID NO: 158) 5'-CGGTCTACCTGTATGGCAACC-3'; forward PCR primer B: (SEQ ID NO: 159) 5'-GCAGGACAACCAGATAAACCAC-3'; reverse PCR primer (SEQ ID NO: 160) 5'-ACGCAGATTTGAGAAGGCTGTC-3'

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA33679 sequence which had the following nucleotide sequence

TABLE-US-00017 hybridization probe (SEQ ID NO: 161) 5'-TTCACGGGCTGCTCTTGCCCAGCTCTTGAAGCTTGAAGAGCTGCA C-3'

[0648] In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with PCR primer pairs identified above. A positive library was then used to isolate clones encoding the PRO265 gene using the probe oligonucleotide and one of the PCR primers.

[0649] RNA for construction of the cDNA libraries was isolated from human a fetal brain library.

[0650] DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO265 [herein designated as DNA36350-1158] (SEQ ID NO:11) and the derived protein sequence for PRO265.

[0651] The entire nucleotide sequence of DNA36350-1158 is shown in FIG. 11 (SEQ ID NO:11). Clone DNA36350-1158 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 352-354 and ending at the stop codon at positions 2332-2334 (FIG. 11). The predicted polypeptide precursor is 660 amino acids long (FIG. 12; SEQ ID NO:12). Clone DNA36350-1158 has been deposited with ATCC on Oct. 16, 1997 and is assigned ATCC deposit no. ATCC 209378.

[0652] Analysis of the amino acid sequence of the full-length PRO265 polypeptide suggests that portions of it possess significant homology to the fibromodulin and the fibromodulin precursor, thereby indicating that PRO265 may be a novel member of the leucine rich repeat family, particularly related to fibromodulin.

Example 9

Isolation of cDNA Clones Encoding Human PRO309 Polypeptides [UNQ272]

[0653] An expressed sequence tag (EST) DNA database (LIFESEQ.TM., Incyte Pharmaceuticals, Palo Alto, Calif.) was searched and an EST was identified which was in a fetal pancreas library which shared significant identity which the adaptor protein Shc. A full length cDNA corresponding to the isolated EST was cloned from a human fetal kidney library using an in vivo cloning technique (Nsp1) in pRK5. There is a single long open reading frame which encodes a 576 amino acid protein. The C-terminus of Nsp1 has no significant identity to any known mammalian proteins. This C-terminal sequence was then used to re-screen the EST database, wherein was found an additional fragment. From this sequence was constructed cloning and enrichment primers, and the corresponding full length sequence was isolated for Nsp3 using an in vivo cloning technique from a human placenta library in pRK5. The probes used for the cloning of the full length sequences were the following:

TABLE-US-00018 Nsp1: Cloning: (SEQ ID NO: 162) ACTGAGGCCTGTTGAAAGTGCAGAGCTCAG Enrichment Primer: (SEQ ID NO: 163) GCTGAAGAAGAGCTTCAG Nsp3: Cloning: (SEQ ID NO: 164) GGCCAGCATGATGGACATGGTGTGGAACCTTTCCAGCAGGTCTAGGCGT A Enrichment Primer: (SEQ ID NO: 165) GGTGCAGCCCAGGATGTC

[0654] Nsp3 has an SH2 domain and a potential SH3 interaction domain (PS region). The proteins lack apparent kinase or phosphatase domains. cDNA clones Nsp1 Nsp3 were sequenced in their entirety. The entire nucleotide sequence of DNA61601-1223 [FIG. 13; SEQ ID NO:13] encoding PRO309 polypeptides [FIG. 14; SEQ ID NO:14] has been deposited with ATCC Mar. 31, 1998 and is assigned ATCC deposit number 209713.

Example 10

Isolation of cDNA Clones Encoding Human PRO332 Polypeptides [UNQ293]

[0655] Based upon an ECD homology search performed as described in Example 1 above, a consensus DNA sequence designated herein as DNA36688 was assembled. Based on the DNA36688 consensus sequence, oligonucleotides were synthesized to identify by PCR a cDNA library that contained the sequence of interest and for use as probes to isolate a clone of the full-length coding sequence for PRO332.

[0656] A pair of PCR primers (forward and reverse) were synthesized:

TABLE-US-00019 5'-GCATTGGCCGCGAGACTTTGCC-3' (SEQ ID NO: 166) 5'-GCGGCCACGGTCCTTGGAAATG-3' (SEQ ID NO: 167)

[0657] A probe was also synthesized:

TABLE-US-00020 (SEQ ID NO: 168) 5'-TGGAGGAGCTCAACCTCAGCTACAACCGCATCACCAGCCCACAG G-3'

[0658] In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PRO332 gene using the probe oligonucleotide and one of the PCR primers.

[0659] RNA for construction of the cDNA libraries was isolated from a human fetal liver library (LIB229).

[0660] DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for DNA40982-1235 and the derived protein sequence for PRO332.

[0661] The entire nucleotide sequence of DNA40982-1235 is shown in FIG. 15 (SEQ ID NO:15). Clone DNA40982-1235 contains a single open reading frame (with an apparent translational initiation site at nucleotide positions 342-344, as indicated in FIG. 15). The predicted polypeptide precursor is 642 amino acids long (FIG. 16; SEQ ID NO:16), and has a calculated molecular weight of 72,067 (pI: 6.60). Clone DNA40982-1235 has been deposited with ATCC Nov. 7, 1997 and is assigned ATCC deposit no. ATCC 209433.

[0662] Based on a BLAST and FastA sequence alignment analysis of the full-length sequence, PRO332 shows about 30-40% amino acid sequence identity with a series of known proteoglycan sequences, including, for example, fibromodulin and fibromodulin precursor sequences of various species (FMOD BOVIN, FMOD CHICK, FMOD RAT, FMOD MOUSE, FMOD HUMAN, PR36773), osteomodulin sequences (AB000114 1, AB007848 1), decorin sequences (CFU83141 1, OCU03394 1, PR42266, PR42267, PR42260, PR89439), keratan sulfate proteoglycans (BTU48360 1, AF022890 1), corneal proteoglycan (AF022256 1), and bone/cartilage proteoglycans and proteoglycane precursors (PGS1 BOVIN, PGS2 MOUSE, PGS2 HUMAN).

Example 11

Isolation of cDNA Clones Encoding Human PRO356 (NL4) Polypeptides [UNQ313]

[0663] An expressed sequence tag (EST) DNA database (LIFESEQ.RTM., Incyte Pharmaceuticals, Palo Alto, Calif.) was searched and an EST (#2939340) was identified which showed homology to human TIE-2 L1 and TIE-2 L2.

[0664] Based on the EST, a pair of PCR primers (forward and reverse), and a probe were synthesized:

TABLE-US-00021 (SEQ ID NO: 169) NL4,5-1: 5'-TTCAGCACCAAGGACAAGGACAATGACAACT-3' (SEQ ID NO: 170) NL4,3-1: 5'-TGTGCACACTTGTCCAAGCAGTTGTCATTGTC-3' (SEQ ID NO: 171) NL4,3-3: 5'-GTAGTACACTCCATTGAGGTTGG-3'.

[0665] Oligo dT primed cDNA libraries were prepared from uterus mRNA purchased from Clontech, Inc. (Palo Alto, Calif., USA, catalog #6537-1) in the vector pRK5D using reagents and protocols from Life Technologies, Gaithersburg, Md. (Super Script Plasmid System). pRK5D is a cloning vector that has an sp6 transcription initiation site followed by an SfiI restriction enzyme site preceding the XhoI/NotI cDNA cloning sites. The cDNA was primed with oligo dT containing a Nod site, linked with blunt to SalI hemikinased adaptors, cleaved with Nod, sized to greater than 1000 bp appropriately by gel electrophoresis, and cloned in a defined orientation into XhoI/NotI-cleaved pRK5D.

[0666] In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PRO356 gene using the probe oligonucleotide and one of the PCR primers.

[0667] DNA sequencing of the clones isolated as described above gave a full-length DNA sequence DNA47470-1130P1 (SEQ ID NO:19; FIG. 19) and the derived PRO356 protein (SEQ ID NO:20; FIG. 20) shown in FIGS. 19 & 20 respectively.

[0668] The entire nucleotide sequence of DNA47470-1130P1 is shown in FIG. 19 (SEQ ID NO:19). Clone

[0669] DNA47470-1130P1 (SEQ ID NO:19) contains a single open reading frame with an apparent translation initiation site at nucleotide positions 215-217, and a TAA stop codon at nucleotide positions 1038-1040, as indicated by bolded underline. The predicted PRO356 polypeptide shown in FIG. 20 is 346 amino acids long (SEQ ID NO:20), has a calculated molecular weight of 40,018 daltons and a pI of 8.19. A cDNA clone containing DNA47470-1130P1 (SEQ ID NO:19) has been deposited with ATCC on Oct. 28, 1997 and is assigned ATCC deposit no. 209422.

[0670] Further analysis of the PRO356 polypeptide of FIG. 20 (SEQ ID NO:20) reveals: a signal peptide at amino acid residues 1 to about 26, N-glycosylation sites at about residues 58-62, 253-257 and 267-271, glycosyaminoglycan attachment sites at residues 167-171, a cAMP- and cGMP-dependent protein kinase phosphorylation site at about residues 176-180, N-myristoylation sites at about residues 168-174, 196-202, 241-247, 252-258, 256-262, 327-333, a cell attachment sequence at about residues 199-202, and fibrinogen beta and gamma chains C-terminal domain proteins at about residues 160-198, 201-210, 219-256, 266-279, 283-313.

Example 12

Isolation of cDNA Clones Encoding Human PRO540 Polypeptides [UNQ341]

[0671] A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA39631. Based on the DNA39631 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO540.

[0672] Forward and reverse PCR primers were synthesized:

TABLE-US-00022 (SEQ ID NO: 172) forward PCR primer 5'-CTGGGGCTACACACGGGGTGAGG-3' (SEQ ID NO: 173) reverse PCR primer 5'-GGTGCCGCTGCAGAAAGTAGAGCG-3'

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA40654 sequence which had the following nucleotide sequence

TABLE-US-00023 hybridization probe (SEQ ID NO: 174) 5'-GCCCCAAATGAAAACGGGCCCTACTTCCTGGCCCTCCGCGAGAT G-3'

[0673] In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with one of the PCR primer pairs identified above. A positive library was then used to isolate clones encoding the PRO540 gene using the probe oligonucleotide and one of the PCR primers. RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue (LIB227).

[0674] DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO540 [herein designated as UNQ341 (DNA44189-1322)] (SEQ ID NO:21) and the derived protein sequence for PRO540.

[0675] The entire nucleotide sequence of UNQ341 (DNA44189-1322) is shown in FIG. 21 (SEQ ID NO:21). Clone UNQ341 (DNA44189-1322) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 21-23 and ending at the stop codon at nucleotide positions 1257-1259 (FIG. 21). The predicted polypeptide precursor is 412 amino acids long (FIG. 22; SEQ ID NO:22). The full-length PRO540 protein shown in FIG. 22 has an estimated molecular weight of about 46,658 daltons and a pI of about 6.65. Important regions of the amino acid sequence of PRO540 include the signal peptide, potential N-glycosylation sites, a potential lipid substrate binding site, a sequence typical of lipases and serine proteins, and a beta-transducin family Trp-Asp repeat. Clone UNQ341 (DNA44189-1322) has been deposited with ATCC on Mar. 26, 1998 and is assigned ATCC deposit no. 209699.

Example 13

Isolation of cDNA Clones Encoding Human PRO618 Polypeptides [UNQ354]

[0676] A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA30900. Based on the DNA30900 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO618.

[0677] Forward and reverse PCR primers were synthesized:

TABLE-US-00024 forward PCR primer (SEQ ID NO: 175) 5'-TAACAGCTGCCCACTGCTTCCAGG-3' reverse PCR primer (SEQ ID NO: 176) 5'-TAATCCAGCAGTGCAGGCCGGG-3'

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA30900 sequence which had the following nucleotide sequence

TABLE-US-00025 hybridization probe (SEQ ID NO: 177) 5'-ATGGCCTCCACGGTGCTGTGGACCGTGTTCCTGGGCAAGGTGTGGC AGAA-3'

[0678] Screening of the above described library gave rise to the partial cDNA clone designated herein DNA3559. Extension of this sequence using repeated cycles of BLAST and phrap gave rise to a nucleotide sequence designated herein as DNA43335. Primers based upon the DNA43335 consensus sequence were then prepared as follows.

TABLE-US-00026 forward PCR primer (SEQ ID NO: 178) 5'-TGCCTATGCACTGAGGAGGCAGAAG-3' reverse PCR primer (SEQ ID NO: 179) 5'-AGGCAGGGACACAGAGTCCATTCAC-3'

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA43335 sequence which had the following nucleotide sequence

TABLE-US-00027 hybridization probe (SEQ ID NO: 180) 5'-AGTATGATTTGCCGTGCACCCAGGGCCAGTGGACGATCCAGAACAG GAGG-3'

[0679] In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with one of the PCR primer pairs identified above. A positive library was then used to isolate full length clones encoding the PRO618 gene using the second probe oligonucleotide and one of the second set of PCR primers. RNA for construction of the cDNA libraries was isolated from human fetal liver tissue (LIB 229).

[0680] DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO618 [herein designated as UNQ354 (DNA49152-1324)] (SEQ ID NO:23) and the derived protein sequence for PRO618.

[0681] The entire nucleotide sequence of UNQ354 (DNA49152-1324) is shown in FIG. 23 (SEQ ID NO:23). Clone UNQ354 (DNA49152-1324) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 73-75 and ending at the stop codon at nucleotide positions 2479-2481 (FIG. 23). The predicted polypeptide precursor is 802 amino acids long (FIG. 24; SEQ ID NO:24). The full-length PRO618 protein shown in FIG. 24 has an estimated molecular weight of about 88,846 daltons and a pI of about 6.41. Important regions of the amino acid sequence of PRO618 include type II transmembrane domain, a sequence typical of a protease, trypsin family, histidine active site, multiple N-glycosylation sites, two sequences typical of a Kringle domain, two regions having sequence similarity to Kallikrein light chain, and a region having sequence similarity to low-density lipoprotein receptor. Clone UNQ354 (DNA49152-1324) has been deposited with ATCC on Apr. 28, 1998 and is assigned ATCC deposit no. 209813.

Example 14

Isolation of cDNA Clones Encoding Human PRO944 Polypeptides [UNQ481]

[0682] A consensus sequence was obtained relative to a variety of EST sequences as described in Example 1 above, wherein the consensus sequence obtained is herein designated DNA47374. A variety of proprietary Genentech EST sequences were employed in the assembly. Based on the DNA47374 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO944.

[0683] A pair of PCR primers (forward and reverse) were synthesized:

TABLE-US-00028 forward PCR primer (SEQ ID NO: 181) 5'-CGAGCGAGTCATGGCCAACGC-3' reverse PCR primer (SEQ ID NO: 182) 5'-GTGTCACACGTAGTCTTTCCCGCTGG-3'

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA47374 sequence which had the following nucleotide sequence

TABLE-US-00029 hybridization probe (SEQ ID NO: 183) 5'-CTGCAGCTGTTGGGCTTCATTCTCGCCTTCCTGGGATGGATCG-3'

[0684] In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PRO944 gene using the probe oligonucleotide and one of the PCR primers. RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue (LIB227).

[0685] DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO944 [herein designated as UNQ481 (DNA52185-1370)] (SEQ ID NO:25) and the derived protein sequence for PRO944.

[0686] The entire nucleotide sequence of UNQ481 (DNA52185-1370) is shown in FIG. 25 (SEQ ID NO:25). Clone UNQ481 (DNA52185-1370) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 219-221 and ending at the stop codon at nucleotide positions 852-854 (FIG. 25). The predicted polypeptide precursor is 211 amino acids long (FIG. 26; SEQ ID NO:26). The full-length PRO944 protein shown in FIG. 26 has an estimated molecular weight of about 22,744 daltons and a pI of about 8.51. Analysis of the full-length PRO944 sequence shown in FIG. 26 (SEQ ID NO:26) evidences the presence of the following: a signal peptide from about amino acid 1 to about amino acid 21, transmembrane domains from about amino acid 82 to about amino acid 102, from about amino acid 118 to about amino acid 142 and from about amino acid 161 to about amino acid 187, a potential N-glycosylation site from about amino acid 72 to about amino acid 75, a sequence block having homology to PMP-22/EMP/MP20 family of proteins from about amino acid 70 to about amino acid 111 and a sequence block having homology to ABC-2 type transport system integral membrane protein from about amino acid 119 to about amino acid 133. Clone UNQ481 (DNA52185-1370) has been deposited with ATCC on May 14, 1998 and is assigned ATCC deposit no. 209861.

[0687] Analysis of the amino acid sequence of the full-length PRO944 polypeptide suggests that it possesses significant sequence similarity to the CPE-R protein, thereby indicating that PRO944 may be a novel CPE-R homolog. More specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35) evidenced significant homology between the PRO944 amino acid sequence and the following Dayhoff sequences, AB000713.sub.--1, AB000714.sub.--1, AF035814.sub.--1, AF000959.sub.--1, HSU89916.sub.--1, EMP2_HUMAN, JC5732, CELF53B3.sub.--6, PM22_MOUSE and CGU49797.sub.--1.

Example 15

Isolation of cDNA Clones Encoding Human PRO994 Polypeptides [UNQ518]

[0688] Use of the signal sequence algorithm described in Example 3 above allowed identification of an EST cluster sequence from the Incyte database, designated 157555. This EST cluster sequence was then compared to a variety of expressed sequence tag (EST) databases which included public EST databases (e.g., GenBank) and a proprietary EST DNA database (LIFESEQ.RTM., Incyte Pharmaceuticals, Palo Alto, Calif.) to identify existing homologies. The homology search was performed using the computer program BLAST or BLAST2 (Altshul et al., Methods in Enzymology 266:460-480 (1996)). Those comparisons resulting in a BLAST score of 70 (or in some cases 90) or greater that did not encode known proteins were clustered and assembled into a consensus DNA sequence with the program "phrap" (Phil Green, University of Washington, Seattle, Wash.). The consensus sequence obtained therefrom is herein designated DNA55728.

[0689] In light of an observed sequence homology between the DNA55728 consensus sequence and an EST sequence encompassed within the Incyte EST clone no. 2860366, the Incyte EST clone 2860366 was purchased and the cDNA insert was obtained and sequenced. It was found that this insert encoded a full-length protein. The sequence of this cDNA insert is shown in FIG. 27 and is herein designated as DNA58855-1422.

[0690] Clone DNA58855-1422 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 31-33 and ending at the stop codon at nucleotide positions 718-720 (FIG. 27; SEQ ID

[0691] NO:27). The predicted polypeptide precursor is 229 amino acids long (FIG. 28; SEQ ID NO:28). The full-length PRO994 protein shown in FIG. 28 has an estimated molecular weight of about 25,109 daltons and a pI of about 6.83. Analysis of the full-length PRO994 sequence shown in FIG. 28 (SEQ ID NO:28) evidences the presence of the following: transmembrane domains from about amino acid 10 to about amino acid 31, from about amino acid 50 to about amino acid 72, from about amino acid 87 to about amino acid 110 and from about amino acid 191 to about amino acid 213, potential N-glycosylation sites from about amino acid 80 to about amino acid 83, from about amino acid 132 to about amino acid 135, from about amino acid 148 to about amino acid 151 and from about amino acid 163 to about amino acid 166 and an amino acid block having homology to TNFR/NGFR cysteine-rich region proteins from about amino acid 4 to about amino acid 11. Clone DNA58855-1422 has been deposited with ATCC on Jun. 23, 1998 and is assigned ATCC deposit no. 203018.

[0692] An analysis of the Dayhoff database (version 35.45 SwissProt 35), using a WU-BLAST2 sequence alignment analysis of the full-length sequence shown in FIG. 28 (SEQ ID NO:28), evidenced significant homology between the PRO994 amino acid sequence and the following Dayhoff sequences: AF027204.sub.--1, TAL6_HUMAN, ILT4_HUMAN, JC6205, MMU57570.sub.--1, S40363, ETU56093.sub.--1, S42858, P_R66849 and P_R74751.

Example 16

Isolation of cDNA Clones Encoding Human PRO1079 Polypeptides [UNQ536]

[0693] A consensus DNA sequence was assembled relative to other EST sequences using phrap as described in Example 1 above, and is herein designated DNA52714. Based on information provided by the assembly, the clone for Merck EST no. H06898 was obtained and sequenced, thereby giving the nucleotide sequence designated herein as DNA56050-1455. The entire nucleotide sequence of DNA56050-1455 is shown in FIG. 29 (SEQ ID NO:29). Clone DNA56050-1455 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 183-185 and ending at the stop codon at nucleotide positions 861-863 (FIG. 29). The predicted polypeptide precursor is 226 amino acids long (FIG. 30; SEQ ID NO:30). The full-length PRO1079 protein shown in FIG. 30 has an estimated molecular weight of about 24,611 Daltons and a pI of about 4.85. Analysis of the full-length PRO1079 sequence shown in FIG. 30 (SEQ ID NO:30) evidences the presence of the following features: a signal peptide at about amino acid 1-29; potential N-myristoylation sites at about amino acids 10-15, and 51-56; homology to photosystem I psaG and psaK proteins at about amino acids 2 to 20; and homology to prolyl endopeptidase family serine proteins at about amino acids 150 to 163.

[0694] Analysis of the amino acid sequence of the full-length PRO1079 polypeptide using the Dayhoff database (version 35.45 SwissProt 35) evidenced some sequence identity between the PRO1079 amino acid sequence and the following Dayhoff sequences: CEK10C3.sub.--4, MMU50734.sub.--1, D69503, AF051149.sub.--1, and VSMP_CVMS.

[0695] Clone UNQ536 (DNA56050-1455) was deposited with the ATCC on Jun. 23, 1998, and is assigned ATCC deposit no. 203011.

Example 17

Isolation of cDNA Clones Encoding Human PRO1110 Polypeptides [UNQ553]

[0696] A cDNA clone (DNA58727-1474) encoding a native human PRO1110 polypeptide was identified by a yeast screen, in a human fetal kidney cDNA library that preferentially represents the 5' ends of the primary cDNA clones. The yeast screen employed identified a single EST clone designated herein as DNA45566. The DNA45566 sequence was then compared to various EST databases including public EST databases (e.g., GenBank), and a proprietary EST database (LIFESEQ.RTM., Incyte Pharmaceuticals, Palo Alto, Calif.) to identify homologous EST sequences. The comparison was performed using the computer program BLAST or BLAST2 [Altschul et al., Methods in Enzymology, 266:460-480 (1996)]. Those comparisons resulting in a BLAST score of 70 (or in some cases, 90) or greater that did not encode known proteins were clustered and assembled into a consensus DNA sequence with the program "phrap" (Phil Green, University of Washington, Seattle, Wash.). This consensus sequence is herein designated DNA46965. Oligonucleotide primers based upon the DNA46965 sequence were then synthesized and employed to screen a human SK-Lu-1 adenocarcinoma cDNA library (LIB 247) which resulted in the identification of the DNA58727-1474 clone shown in FIG. 31.

[0697] The full-length DNA58727-1474 clone shown in FIG. 31 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 131-133 and ending at the stop codon at nucleotide positions 1097-1099 (FIG. 31; SEQ ID NO:31). The predicted polypeptide precursor is 322 amino acids long (FIG. 32; SEQ ID NO:32). The full-length PRO1110 protein shown in FIG. 32 has an estimated molecular weight of about 35,274 daltons and a pI of about 8.57. Analysis of the full-length PRO1110 sequence shown in FIG. 32 (SEQ ID NO:32) evidences the presence of the following: transmembrane domains from about amino acid 41 to about amino acid 60, from about amino acid 66 to about amino acid 85, from about amino acid 101 to about amino acid 120, from about amino acid 137 to about amino acid 153, from about amino acid 171 to about amino acid 192, from about amino acid 205 to about amino acid 226, from about amino acid 235 to about amino acid 255 and from about amino acid 294 to about amino acid 312, a potential N-glycosylation site from about amino acid 6 to about amino acid 69, and a glycosaminoglycan attachment site from about amino acid 18 to about amino acid 21. Clone DNA58727-1474 has been deposited with ATCC on Sep. 1, 1998 and is assigned ATCC deposit no. 203171.

[0698] An analysis of the Dayhoff database (version 35.45 SwissProt 35), using a WU-BLAST2 sequence alignment analysis of the full-length sequence shown in FIG. 32 (SEQ ID NO:32), evidenced significant homology between the PRO1110 amino acid sequence and the following Dayhoff sequences: MMMYELUPR.sub.--1, P_R99799, MAL_HUMAN, P_P80929, RNMALGENE.sub.--1, 568406, PLLP_RAT, MMMALPROT.sub.--1, I38891 and S55622.

Example 18

Isolation of cDNA Clones Encoding Human PRO1122 Polypeptides [UNQ561]

[0699] An expressed sequence tag (EST) DNA database (LIFESEQ.RTM., Incyte Pharmaceuticals, Palo Alto, Calif.) was searched and an EST was identified. The EST was Incyte 1347523 also called DNA49665. Based on DNA49665, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolated a clone of the full-length coding sequence for the PRO1122. [e.g., Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989); Dieffenbach et al., PCR Primer: A Laboratory Manual (Cold Spring Harbor Laboratory Press, 1995)].

[0700] Forward and reverse PCR primers generally range from 20 to 30 nucleotides and are often designed to give a PCR product of about 100-1000 bp in length. The probes sequences are typically 40-55 bp in length. In some cases, additional oligonucleotides are synthesized when the consensus sequence is greater than about 1-1.5 kpb. In order to screen several libraries for a full-length clone, DNA from the libraries was screened by PCR amplification, as per Ausuble et al., Current Protocols in Molecular Biology, with the PCR primer pair. A positive library was then used to isolate clones encoding the gene of interest using the probe oligonucleotide and one of the primer pairs.

[0701] PCR primers (forward, reverse and hybridization) were synthesized:

TABLE-US-00030 forward PCR primer: (SEQ ID NO: 184) 5'-ATCCACAGAAGCTGGCCTTCGCCG-3' reverse PCR primer: (SEQ ID NO: 185) 5'-GGGACGTGGATGAACTCGGTGTGG-3' hybridization probe: (SEQ ID NO: 186) 5'-TATCCACAGAAGCTGGCCTTCGCCGAGTGCCTGTGCAGAG-3'.

[0702] In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PRO1122 gene using the probe oligonucleotide and one of the PCR primers.

[0703] RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue. The cDNA libraries used to isolate the cDNA clones were constructed using standard methods using commercially available reagents such as those from Invitrogen, San Diego, Calif. The cDNA was primed with oligo dT containing a Nod site, linked with blunt to SalI hemikinased adaptors, cleaved with NotI, sized appropriately by gel electrophoresis, and cloned in a defined orientation into a suitable cloning vector (such as pRKB or pRKD; pRK5B is a precursor of pRK5D that does not contain the SfiI site; see, Holmes et al., Science, 235: 1278-1280 (1991)) in the unique XhoI and NotI sites.

[0704] DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO1122 [herein designated as DNA62377-1381-1] (SEQ ID NO:33) and the derived protein PRO1122 sequence (UNQ561) (SEQ ID NO:34).

[0705] The entire nucleotide sequence of DNA62377-1381-1 (SEQ ID NO:33) is shown in FIG. 33 (SEQ ID NO:33). Clone DNA62377-1381-1 (SEQ ID NO:33) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 50-52 and ending at the stop codon at nucleotide positions 641-643 of SEQ ID NO:33 (FIG. 33). The predicted polypeptide precursor is 197 amino acids long (FIG. 34; SEQ ID NO:34). The full-length PRO1122 protein shown in FIG. 34 (UNQ561) (SEQ ID NO:34) has an estimated molecular weight of about 21765 daltons and a pI of about 8.53. Clone DNA62377-1381-1 has been deposited with the ATCC on Dec. 22, 1998 and has been assigned deposit number 203552. It is understood that in the event or a sequencing irregularity or error in the sequences provided herein, the correct sequence is the sequence deposited. Furthermore, all sequences provided herein are the result of known sequencing techniques.

[0706] Analysis of the amino acid sequence of the isolated full-length PRO1122 (UNQ561) suggests that it possesses similarity with IL-17, thereby indicating that PRO1122 (UNQ561) may be a novel cytokine and is herein designated IL-17C. FIG. 34 (SEQ ID NO:34) also shows the approximate locations of the signal peptide, leucine zipper pattern, and a region having sequence identity with IL-17.

Example 19

Isolation of cDNA Clones Encoding Human PRO1138 Polypeptides [UNQ576]

[0707] Use of the signal sequence algorithm described in Example 3 above allowed identification of a single Incyte EST sequence, Incyte cluster sequence no. 165212. This cluster sequence was then compared to a variety of expressed sequence tag (EST) databases which included public EST databases (e.g., GenBank) and a proprietary EST DNA database (LIFESEQ.RTM., Incyte Pharmaceuticals, Palo Alto, Calif.) to identify existing homologies. The homology search was performed using the computer program BLAST or BLAST2 (Altshul et al., Methods in Enzymology 266:460-480 (1996)). Those comparisons resulting in a BLAST score of 70 (or in some cases 90) or greater that did not encode known proteins were clustered and assembled into a consensus DNA sequence with the program "phrap" (Phil Green, University of Washington, Seattle, Wash.). The consensus sequence obtained therefrom is herein designated as DNA54224. The assembly included a proprietary Genentech EST designated herein as DNA49140.

[0708] In light of an observed sequence homology between the DNA54224 consensus sequence and an EST sequence encompassed within the Incyte EST clone no. 3836613, the Incyte EST clone 3836613 was purchased and the cDNA insert was obtained and sequenced. It was found that this insert encoded a full-length protein. The sequence of this cDNA insert is shown in FIG. 35 and is the full-length DNA sequence for PRO1138. Clone DNA58850-1495 was deposited with the ATCC on Jun. 9, 1998, and is assigned ATCC deposit no. 209956.

[0709] The entire nucleotide sequence of DNA58850-1495 is shown in FIG. 35 (SEQ ID NO:35). Clone DNA58850-1495 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 38-40 and, ending at the stop codon at nucleotide positions 1043-1045 (FIG. 35). The predicted polypeptide precursor is 335 amino acids long (FIG. 36; SEQ ID NO:36). The full-length PRO1138 protein shown in FIG. 36 has an estimated molecular weight of about 37,421 Daltons and a pI of about 6.36. Analysis of the full-length PRO1138 sequence shown in FIG. 36 (SEQ ID NO:36) evidences the presence of the following features: a signal peptide at about amino acid 1 to about amino acid 22; a transmembrane domain at about amino acids 224 to about 250; a leucine zipper pattern at about amino acids 229 to about 250; and potential N-glycosylation sites at about amino acids 98-101, 142-145, 148-151, 172-175, 176-179, 204-207, and 291-295.

[0710] Analysis of the amino acid sequence of the full-length PRO1138 polypeptide suggests that it possesses significant sequence similarity to the CD84, thereby indicating that PRO1138 may be a novel member of the Ig superfamily of polypeptides. More particularly, analysis of the amino acid sequence of the full-length PRO1138 polypeptide using the Dayhoff database (version 35.45 SwissProt 35) evidenced homology between the PRO1138 amino acid sequence and the following Dayhoff sequences: HSU82988.sub.--1, HUMLY9.sub.--1, P_R97631, P_R97628, P_R97629, P_R97630, CD48_RAT, CD2_HUMAN, P_P93996, and HUMBGP.sub.--1.

[0711] Clone DNA58850-1495 was deposited with ATCC on Jun. 9, 1998, and is assigned ATCC deposit no. 209956.

Example 20

Isolation of cDNA Clones Encoding Human PRO1190 Polypeptides [UNQ604]

[0712] The method described in Example 1 above allowed the identification of a single Merck/Washington University EST sequence, EST no. AA339802, which is designated herein as "DNA53943". Based on the DNA53943 sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO1190.

[0713] PCR primers (forward and reverse) were synthesized:

TABLE-US-00031 forward PCR primer: (SEQ ID NO: 187) (53943.f1) GGGAAACACAGCAGTCATTGCCTGC reverse PCR primer: (SEQ ID NO: 188) (53943.r1) GCACACGTAGCCTGTCGCTGGAGC

[0714] Additionally, a synthetic oligonucleotide hybridization probe was constructed from the DNA53943 sequence which had the following nucleotide sequence:

TABLE-US-00032 hybridization probe: (SEQ ID NO: 189) (53943.p1) CACCCCAAAGCCCAGGTCCGGTACAGCGTCAAACAAGA GTGG

[0715] In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PRO1190 gene using the probe oligonucleotide and one of the PCR primers. RNA for construction of the cDNA libraries was isolated from human bone marrow.

[0716] DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO1190 (designated herein as DNA59586-1520 [FIG. 37, SEQ ID NO:37]; and the derived protein sequence for PRO1190.

[0717] The entire coding sequence of PRO1190 is shown in FIG. 37 (SEQ ID NO:37). Clone DNA59586-1520 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 340-342 and an apparent stop codon at nucleotide positions 3685-3687. The predicted polypeptide precursor is 1115 amino acids long. The full-length PRO1190 protein shown in FIG. 38 (SEQ ID NO:38) has an estimated molecular weight of about 121,188 daltons and a pI of about 7.07. Other features of the PRO1190 protein include: two transmembrane domains at amino acids 16-30 and 854-879; a cytochrome P450 cysteine heme-iron ligand signature at amino acids 1051-1060; an N-6 adenine-specific DNA methylases signature at amino acids 1045-1051; and potential N-glycosylation sites at amino acids 65-68, 76-79, 98-101, 189-192, 275-278, 518-521, 726-729, and 760-763. Clone DNA59586-1520 was deposited with the ATCC on Sep. 29, 1998, and is assigned ATCC deposit no. 203288.

[0718] An analysis of the Dayhoff database (version 35.45 SwissProt 35), using a WU-BLAST2 sequence alignment analysis of the full-length sequence shown in FIG. 38 (SEQ ID NO:38), revealed homology between the PRO1190 amino acid sequence and the following Dayhoff sequences: AF004840.sub.--1, AF004841.sub.--1, AF026465.sub.--1, HSU72391.sub.--1, P_R13144, AXO1_HUMAN, GEN13349, I58164, D87212.sub.--1, A53449, and D86983.sub.--1, and KIAA0230.

Example 21

Isolation of cDNA Clones Encoding Human PRO1272 Polypeptides [UNQ642]

[0719] Use of the signal sequence algorithm described in Example 3 above allowed identification of an EST cluster sequence from the Incyte database. This EST cluster sequence was then compared to a variety of expressed sequence tag (EST) databases which included public EST databases (e.g., GenBank) and a proprietary EST DNA database (LIFESEQ.RTM., Incyte Pharmaceuticals, Palo Alto, Calif.) to identify existing homologies. The homology search was performed using the computer program BLAST or BLAST2 (Altshul et al., Methods in Enzymology 266:460-480 (1996)). Those comparisons resulting in a BLAST score of 70 (or in some cases 90) or greater that did not encode known proteins were clustered and assembled into a consensus DNA sequence with the program "phrap" (Phil Green, University of Washington, Seattle, Wash.). The consensus sequence obtained therefrom is herein designated DNA58753.

[0720] In light of an observed sequence homology between the DNA58753 sequence and an EST sequence contained within the EST clone 3049165, the Incyte clone (from a lung library) including EST 3049165 was purchased and the cDNA insert was obtained and sequenced. The sequence of this cDNA insert is shown in FIG. 39 and is herein designated as DNA64896-1539.

[0721] The full length clone shown in FIG. 39 contained a single open reading frame with an apparent translational initiation site at nucleotide positions 58-60 and ending at the stop codon found at nucleotide positions 556-558 (FIG. 39; SEQ ID NO:39). The predicted polypeptide precursor (FIG. 40, SEQ ID NO:40) is 166 amino acids long. The signal peptide is at about amino acids 1-23 of SEQ ID NO:40. PRO1272 has a calculated molecular weight of approximately 19,171 daltons and an estimated pI of approximately 8.26. Clone DNA64896-1539 was deposited with the ATCC on Sep. 9, 1998 and is assigned ATCC deposit no. 203238.

[0722] An analysis of the Dayhoff database (version 35.45 SwissProt 35), using a WU-BLAST2 sequence alignment analysis of the full-length sequence shown in FIG. 40 (SEQ ID NO:40), revealed sequence identity between the PRO1272 amino acid sequence and the following Dayhoff sequences (information from database incorporated herein): AF025474.sub.--1, D69100, AE000757.sub.--10, H69466, CELC50E3.sub.--12, XLRANBP1.sub.--1, YD67_SCHPO, B69459, H36856, and FRU40755.sub.--1.

Example 22

Isolation of cDNA Clones Encoding Human PRO1286 Polypeptides [UNQ655]

[0723] Use of the signal sequence algorithm described in Example 3 above allowed identification of an EST cluster sequence from the LIFESEQ.RTM. database, designated EST Cluster No. 86809. This EST cluster sequence was then compared to a variety of expressed sequence tag (EST) databases which included public EST databases (e.g., GenBank) and a proprietary EST DNA database (LIFESEQ.RTM., Incyte Pharmaceuticals, Palo Alto, Calif.) to identify existing homologies. The homology search was performed using the computer program BLAST or BLAST2 (Altshul et al., Methods in Enzymology 266:460-480 (1996)). Those comparisons resulting in a BLAST score of 70 (or in some cases 90) or greater that did not encode known proteins were clustered and assembled into a consensus DNA sequence with the program "phrap" (Phil Green, University of Washington, Seattle, Wash.). ESTs in the assembly included those identified from tumors, cell lines, or diseased tissue. One or more of the ESTs was obtained from a cDNA library constructed from RNA isolated from diseased colon tissue. The consensus sequence obtained therefrom is herein designated DNA58822.

[0724] In light of the sequence homology between the DNA58822 sequence and an EST sequence contained within EST no. 1695434, EST clone no. 1695434 was purchased and the cDNA insert was obtained and sequenced. The sequence of this cDNA insert is shown in FIG. 41 and is herein designated DNA64903-1553 (SEQ ID NO:41).

[0725] The full length clone shown in FIG. 41 contained a single open reading frame with an apparent translational initiation site at nucleotide positions 93-95 and ending at the stop codon found at nucleotide positions 372-374 (FIG. 41; SEQ ID NO:41). The predicted polypeptide precursor (FIG. 42, SEQ ID NO:42) is 93 amino acids long, with a signal sequence at about amino acids 1-18. PRO1286 has a calculated molecular weight of approximately 10,111 daltons and an estimated pI of approximately 9.70.

[0726] An analysis of the Dayhoff database (version 35.45 SwissProt 35), using a WU-BLAST2 sequence alignment analysis of the full-length sequence shown in FIG. 42 (SEQ ID NO:42), revealed some homology between the PRO1286 amino acid sequence and the following Dayhoff sequences: SR5C_ARATH, CELC17H12.sub.--11, MCPD_ENTAE, JQ2283, INVO_LEMCA, P_R07309, ADEVBCAGN.sub.--4, AF020947.sub.--1, CELT23H2.sub.--1, and MDH_STRAR.

[0727] Clone DNA64903-1553 was deposited with the ATCC on Sep. 15, 1998 and is assigned ATCC deposit no. 203223.

Example 23

Isolation of cDNA Clones Encoding Human PRO1295 Polypeptides [UNQ664]

[0728] Use of the signal sequence algorithm described in Example 3 above allowed identification of an EST cluster sequence from the Incyte database. This EST cluster sequence was then compared to a variety of expressed sequence tag (EST) databases which included public EST databases (e.g., GenBank) and a proprietary EST DNA database (LIFESEQ.RTM., Incyte Pharmaceuticals, Palo Alto, Calif.) to identify existing homologies. One or more of the ESTs was derived from a thymus tissue library. The homology search was performed using the computer program BLAST or BLAST2 (Altshul at al., Methods in Enzymology 266:460-480 (1996)). Those comparisons resulting in a BLAST score of 70 (or in some cases 90) or greater that did not encode known proteins were clustered and assembled into a consensus DNA sequence with the program "phrap" (Phil Green, University of Washington, Seattle, Wash.). The consensus sequence obtained therefrom is herein designated DNA56262.

[0729] In light of the sequence homology between the DNA56262 sequence and an EST contained within the Incyte EST 3743334, the clone including this EST was purchased and the cDNA insert was obtained and sequenced. The sequence of this cDNA insert is shown in FIG. 43 and is herein designated as DNA59218-1559.

[0730] The full length clone shown in FIG. 43 contained a single open reading frame with an apparent translational initiation site at nucleotide positions 207-209 and ending at the stop codon found at nucleotide positions 1047-1049 (FIG. 43; SEQ ID NO:43). The predicted polypeptide precursor (FIG. 44, SEQ ID NO:44) is 280 amino acids long. The signal peptide is at about amino acids 1-18 of SEQ ID NO:44. A targeting signal and N-glycosylation site are also indicated in FIG. 44. PRO1295 has a calculated molecular weight of approximately 30,163 daltons and an estimated pI of approximately 6.87. Clone DNA59218-1559 was deposited with the ATCC on Sep. 29, 1998 and is assigned ATCC deposit no. 203287.

[0731] An analysis of the Dayhoff database (version 35.45 SwissProt 35), using a WU-BLAST2 sequence alignment analysis of the full-length sequence shown in FIG. 44 (SEQ ID NO:44), revealed sequence identity between the PRO1295 amino acid sequence and the following Dayhoff sequences (data incorporated herein): AB011099.sub.--1, ILVE_MYCTU, ATTECR.sub.--2, AF010496.sub.--27, P_R15346, S37191, PER_DROMS, L2MU_ADECC and P_W34238.

Example 24

Isolation of cDNA Clones Encoding Human PRO1309 Polypeptides [UNQ675]

[0732] An expressed sequence tag (EST) DNA database (LIFESEQ.RTM., Incyte Pharmaceuticals, Palo Alto, Calif.) was searched and an EST was identified which showed homology to SLIT.

[0733] RNA for construction of cDNA libraries was isolated from human fetal brain tissue. The cDNA libraries used to isolate the cDNA clones encoding human PRO1309 were constructed by standard methods using commercially available reagents such as those from Invitrogen, San Diego, Calif. The cDNA was primed with oligo dT containing a NotI site, linked with blunt to SalI hemikinased adaptors, cleaved with NotI, sized appropriately by gel electrophoresis, and cloned in a defined orientation into a suitable cloning vector (such as pRKB or pRKD; pRK5B is a precursor of pRK5D that does not contain the SfiI site; see, Holmes et al., Science, 253:1278-1280 (1991)) in the unique XhoI and NotI.

[0734] The cDNA libraries (prepared as described above), were screened by hybridization with a synthetic oligonucleotide probe derived from the above described Incyte EST sequence:

TABLE-US-00033 (SEQ ID NO: 190) 5'-TCCGTGCAGGGGGACGCCTTTCAGAAACTGCGCCGAGTTAAGGAA C-3'.

[0735] A cDNA clone was isolated and sequenced in entirety. The entire nucleotide sequence of DNA59588-1571 is shown in FIG. 45 (SEQ ID NO:45). Clone DNA59588-1571 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 720-722 and a stop codon at nucleotide positions 2286-2288 (FIG. 45; SEQ ID NO:45). The predicted polypeptide precursor is 522 amino acids long (FIG. 46; SEQ ID NO:46). The signal peptide is approximately at 1-34 and the transmembrane domain is at approximately 428-450 of SEQ ID NO:278. Clone DNA59588-1571 has been deposited with ATCC on Aug. 11, 1998 and is assigned ATCC deposit no. 203106. The full-length PRO1309 protein shown in FIG. 46 has an estimated molecular weight of about 58,614 daltons and a pI of about 7.42.

[0736] An analysis of the Dayhoff database (version 35.45 SwissProt 35), using a WU-BLAST2 sequence alignment analysis of the full-length sequence shown in FIG. 46 (SEQ ID NO:46), revealed sequence identity between the PRO1309 amino acid sequence and the following Dayhoff sequences: AB007876.sub.--1, GPV_MOUSE, ALS_RAT, P_R85889, LUM_CHICK, AB014462.sub.--1, PGS1_CANFA, CEM88.sub.--7, A58532 and GEN11209.

Example 25

Isolation of cDNA Clones Encoding Human PRO1316 Polypeptides [UNQ682]

[0737] The extracellular domain (ECD) which includes the signal sequence, if any, of publicly available databases known to contain secreted sequences were used to search various publicly available EST (Expressed Sequenced Tag) databases (GenBank, Merck/Wash. U). The search was performed using the computer program BLAST or BLAST2 [Altschul et al., Methods in Enzymology 266: 460-480 (1996)] as a comparison of the ECD protein sequences to a 6 frame translation of the EST sequences. Those comparisons resulting in a BLAST score of 70 (or in some cases 90) or greater that did not did not encode known proteins were clustered and assembled into consensus DNA sequences with the program "phrap" (Phil Green, University of Washington, Seattle, Wash.).

[0738] The above search resulted in the identification of the EST, designated W55979 which showed homology with the secreted protein Dkk-1. The clone corresponding to EST W55979 (clone NbHH19W) was purchased from Merck/Washington University and the cDNA insert was obtained and sequenced in its entirety.

[0739] The nucleic acid sequence corresponding to the full length PRO1316 (designated DNA60608-1577) encoded by the purchased clone, is shown in FIG. 47 (SEQ ID NO:47). DNA60608-1577 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 211-213, and a stop codon at nucleotide positions 988-990 (FIG. 47; SEQ ID NO:47). The predicted polypeptide precursor is 259 amino acids long (FIG. 48; SEQ ID NO:48). Additional regions of significant interest include the nucleotide residues encoding the signal peptide (211-283), an N-glycosylation site (364-366), and the Zn(2)-Cys(6) binuclear cluster domain (505-655). Clone DNA60608-1577 has been deposited with ATCC on Aug. 18, 1998 and is assigned

[0740] ATCC deposit no. 203126. The full-length PRO1316 protein shown in FIG. 48 has an estimated molecular weight of about 28,447 daltons and a pI of about 9.48.

[0741] Based on a BLAST and FastA sequence alignment analysis (using the ALIGN computer program) of the full-length sequence, PRO1316 shows significant amino acid sequence identity to the dickkopf family of proteins. Additionally, DNA60608 has shown homology to AF030433.sub.--1, COL_RABIT, YQI6_CAEEL, ITB6_HUMAN, CONO_LYMST, S41033, D63483.sub.--1, D86864.sub.--1 and AB001978.sub.--1.

Example 26

Isolation of cDNA Clones Encoding Human PRO1383 Polypeptides [UNQ719]

[0742] A consensus DNA sequence was assembled relative to other EST sequences using phrap as described in Example 1 above. This consensus sequence is herein designated DNA53961. Based on the DNA53961 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO1383.

[0743] PCR primers (forward and reverse) were synthesized:

TABLE-US-00034 forward PCR primer (SEQ ID NO: 191) 5'-CATTTCCTTACCCTGGACCCAGCTCC-3' reverse PCR primer (SEQ ID NO: 192) 5'-GAAAGGCCCACAGCACATCTGGCAG-3'

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA53961 sequence which had the following nucleotide sequence

TABLE-US-00035 hybridization probe (SEQ ID NO: 193) 5'-CCACGACCCGAGCAACTTCCTCAAGACCGACTTGTTTCTCTACAG C-3'

[0744] In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PRO1383 gene using the probe oligonucleotide and one of the PCR primers. RNA for construction of the cDNA libraries was isolated from human fetal brain tissue.

[0745] DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO1383 (designated herein as DNA58743-1609 [FIG. 49, SEQ ID NO: 49]) and the derived protein sequence for PRO1383.

[0746] The entire nucleotide sequence of DNA58743-1609 is shown in FIG. 49 (SEQ ID NO:49). Clone

[0747] DNA58743-1609 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 122-124 and ending at the stop codon at nucleotide positions 1391-1393 (FIG. 49). The predicted polypeptide precursor is 423 amino acids long (FIG. 50; SEQ ID NO:50). The full-length PRO1383 protein shown in FIG. 50 has an estimated molecular weight of about 46,989 daltons and a pI of about 6.77. Analysis of the full-length PRO1383 sequence shown in FIG. 50 (SEQ ID NO:50) evidences the presence of the following: a signal peptide from about amino acid 1 to about amino acid 24, a transmembrane domain from about amino acid 339 to about amino acid 362, and potential N-glycosylation sites from about amino acid 34 to about amino acid 37, from about amino acid 58 to about amino acid 61, from about amino acid 142 to about amino acid 145, from about amino acid 197 to about amino acid 200, from about amino acid 300 to about amino acid 303 and from about amino acid 364 to about amino acid 367. Clone DNA58743-1609 has been deposited with ATCC on Aug. 25, 1998 and is assigned ATCC deposit no. 203154.

[0748] An analysis of the Dayhoff database (version 35.45 SwissProt 35), using a WU-BLAST2 sequence alignment analysis of the full-length sequence shown in FIG. 50 (SEQ ID NO:50), evidenced significant homology between the PRO1383 amino acid sequence and the following Dayhoff sequences: NMB_HUMAN, QNR_COTJA, P_W38335, P115_CHICK, P_W38164, A45993.sub.--1, MMU70209.sub.--1, D83704.sub.--1 and P_W39176.

Example 27

Isolation of cDNA Clones Encoding Human PRO1384 Polypeptides [UNQ721]

[0749] A consensus DNA sequence was assembled relative to other EST sequences using phrap as described in Example 1 above. This consensus sequence is herein designated DNA54192. Based on the DNA54192 sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO1384. PCR primers (forward and reverse) were synthesized:

TABLE-US-00036 forward PCR primer (SEQ ID NO: 194) 5'-TGCAGCCCCTGTGACACAAACTGG-3' reverse PCR primer (SEQ ID NO: 195) 5'-CTGAGATAACCGAGCCATCCTCCCAC-3'

[0750] Additionally, a synthetic oligonucleotide hybridization probe was constructed from the DNA54192 sequence which had the following nucleotide sequence:

TABLE-US-00037 hybridization probe (SEQ ID NO: 196) 5'-GGAGATAGCTGCTATGGGTTCTTCAGGCACAACTTAACATGGGAA G-3'

[0751] In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PRO1384 gene using the probe oligonucleotide and one of the PCR primers. RNA for construction of the cDNA libraries was isolated from human fetal liver.

[0752] DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO1384 (designated herein as DNA71159-1617 [FIG. 51, SEQ ID NO:51]; and the derived protein sequence for PRO1384.

[0753] The entire coding sequence of PRO1384 is shown in FIG. 51 (SEQ ID NO:51). Clone DNA71159-1617 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 182-184 and an apparent stop codon at nucleotide positions 869-871. The predicted polypeptide precursor is 229 amino acids long (FIG. 52; SEQ ID NO:52). The full-length PRO1384 protein shown in FIG. 52 has an estimated molecular weight of about 26,650 daltons and a pI of about 8.76. Additional features include a type II transmembrane domain at about amino acids 32-57, and potential N-glycosylation sites at about amino acids 68-71, 120-123, and 134-137.

[0754] An analysis of the Dayhoff database (version 35.45 SwissProt 35), using a WU-BLAST2 sequence alignment analysis of the full-length sequence shown in FIG. 52 (SEQ ID NO:52), revealed homology between the PRO1384 amino acid sequence and the following Dayhoff sequences: AF054819.sub.--1, HSAJ1687.sub.--1, AF009511.sub.--1, AB010710.sub.--1, GEN13595, HSAJ673.sub.--1, GEN13961, AB 005900.sub.--1, LECH_CHICK, AF021349.sub.--1, and NK13_RAT.

[0755] Clone DNA71159-1617 has been deposited with ATCC on Aug. 18, 1998 and is assigned ATCC deposit no. 203135.

Example 28

Isolation of cDNA Clones Encoding Human PRO1431 Polypeptides [UNQ737]

[0756] An expressed sequence tag (EST) DNA database (LIFESEQ.RTM., Incyte Pharmaceuticals, Palo Alto, Calif.) was searched and an EST (isolated from adult brain stem tissue) was identified (1370141, DNA66505) which showed homology to SH3. RNA for construction of cDNA libraries was isolated from human bone marrow. A full length cDNA corresponding to the isolated EST was isolated using an in vitro cloning technique (DNA73401-1633) in pRK5.

[0757] The cDNA libraries used to isolate the cDNA clones encoding human PRO1431 were constructed by standard methods using commercially available reagents such as those from Invitrogen, San Diego, Calif. The cDNA was primed with oligo dT containing a NotI site, linked with blunt to SalI hemikinased adaptors, cleaved with NotI, sized appropriately by gel electrophoresis, and cloned in a defined orientation into a suitable cloning vector (such as pRKB or pRKD; pRK5B is a precursor of pRK5D that does not contain the SfiI site; see, Holmes et al., Science, 253:1278-1280 (1991)) in the unique XhoI and Nod.

[0758] A cDNA clone was sequenced in entirety. The entire nucleotide sequence of DNA73401-1633 (SEQ ID NO:53) is shown in FIG. 53. Clone DNA73401-1633 contains a single open reading frame with an apparent translational initiation site at about nucleotide positions 630-632 and a stop codon at about nucleotide positions 1740-1742. The predicted polypeptide precursor encoded by DNA73401-1633 is 370 amino acids long (FIG. 54; SEQ ID NO:54). Clone DNA73401 (designated as DNA73402-1633) has been deposited with ATCC on Sep. 22, 1998 and is assigned ATCC deposit no. 203273.

[0759] Based sequence alignment analysis (using the ALIGN computer program) of the full-length sequence, PRO1431 shows significant amino acid sequence identity to SH17_HUMAN, an SH3 containing protein known as SH3P17. Additional significant identity score were found with D89164.sub.--1, AF032118.sub.--1, EXLP_TOBAC, YHR4_YEAST, S46992, RATP130CAS.sub.--2, AF043259.sub.--1, RATP130CAS.sub.--1 and MYSC_ACACA.

Example 29

Isolation of cDNA Clones Encoding Human PRO1434 Polypeptides [UNQ739]

[0760] A consensus DNA sequence was assembled relative to other EST sequences using phrap as described in Example 1 above. This consensus sequence is herein designated DNA54187. Based on the DNA54187 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO1434.

[0761] PCR primers (forward and reverse) were synthesized:

TABLE-US-00038 forward PCR primer (SEQ ID NO: 197) 5'-GAGGTGTCGCTGTGAAGCCAACGG-3' reverse PCR primer (SEQ ID NO: 198) 5'-CGCTCGATTCTCCATGTGCCTTCC-3'

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA54187 sequence which had the following nucleotide sequence

TABLE-US-00039 hybridization probe (SEQ ID NO: 199) 5'-GACGGAGTGTGTGGACCCTGTGTACGAGCCTGATCAGTGCTGTC C-3'

[0762] RNA for construction of the cDNA libraries was isolated from human retina tissue (LIB94).

[0763] DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO1434 (designated herein as DNA68818-2536 [FIG. 55, SEQ ID NO:55]; and the derived protein sequence for PRO1434.

[0764] The entire nucleotide sequence of DNA68818-2536 is shown in FIG. 55 (SEQ ID NO:55). Clone

[0765] DNA68818-2536 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 581-583 and ending at the stop codon at nucleotide positions 1556-1558 (FIG. 55). The predicted polypeptide precursor is 325 amino acids long (FIG. 56; SEQ ID NO:56). The full-length PRO1434 protein shown in FIG. 56 has an estimated molecular weight of about 35,296 daltons and a pI of about 5.37. Analysis of the full-length PRO1434 sequence shown in FIG. 56 (SEQ ID NO:56) evidences the presence of a variety of important protein domains as shown in FIG. 56. Clone DNA68818-2536 has been deposited with ATCC on Feb. 9, 1999 and is assigned ATCC deposit no. 203657.

[0766] An analysis of the Dayhoff database (version 35.45 SwissProt 35), using a WU-BLAST2 sequence alignment analysis of the full-length sequence shown in FIG. 56 (SEQ ID NO:56), evidenced significant homology between the PRO1434 amino acid sequence and the following Dayhoff sequences: NEL_MOUSE, APMU_PIG, P_W37501, NEL_RAT, TSP1_CHICK, P_W37500, NEL2_HUMAN, MMU010792.sub.--1, D86983.sub.--1 and 10 MUCS_BOVIN.

Example 30

Isolation of cDNA Clones Encoding Human PRO1475 Polypeptides [UNQ746]

[0767] A consensus DNA sequence was assembled relative to other EST sequences using phrap as described in Example 1 above. This consensus sequence is herein designated DNA45639. Based on the DNA45639 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO1475.

[0768] PCR primers (forward and reverse) were synthesized:

TABLE-US-00040 forward PCR primer (45639.11) (SEQ ID NO: 200) 5'-GATGGCAAAACGTGTGTTTGACACG-3' forward PCR primer (45639.f2) (SEQ ID NO: 201) 5'-CCTCAACCAGGCCACGGGCCAC-3' reverse PCR primer (45639.r1) (SEQ ID NO: 202) 5'-CCCAGGCAGAGATGCAGTACAGGC-3' reverse PCR primer (45639.r2) (SEQ ID NO: 203) 5'-CCTCCAGTAGGTGGATGGATTGGCTC-3'

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA45639 sequence which had the following nucleotide sequence

TABLE-US-00041 hybridization probe (45639.p1) (SEQ ID NO: 204) 5'-CTCACCTCATGAGGATGAGGCCATGGTGCTATTCCTCAACATGGTA G-3'

[0769] In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PRO1475 gene using the probe oligonucleotide and one of the PCR primers. RNA for construction of the cDNA libraries was isolated from human fetal brain tissue.

[0770] DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO1475 (designated herein as DNA61185-1646 [FIG. 57, SEQ ID NO:57]; and the derived protein sequence for PRO1475.

[0771] The entire nucleotide sequence of DNA61185-1646 is shown in FIG. 57 (SEQ ID NO:57). Clone DNA61185-1646 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 130-132 and ending at the stop codon at nucleotide positions 2110-2112 (FIG. 57). The predicted polypeptide precursor is 660 amino acids long (FIG. 58; SEQ ID NO:58). The full-length PRO1475 protein shown in FIG. 58 has an estimated molecular weight of about 75,220 daltons and a pI of about 6.76. Analysis of the full-length PRO1475 sequence shown in FIG. 58 (SEQ ID NO:58) evidences the presence of the following: a transmembrane domain from about amino acid 38 to about amino acid 55 and a homologous region to mouse GNT1 from about amino acid 229 to about amino acid 660. Clone DNA61185-1646 has been deposited with ATCC on Nov. 17, 1998 and is assigned ATCC deposit no. 203464.

[0772] An analysis of the Dayhoff database (version 35.45 SwissProt 35), using a WU-BLAST2 sequence alignment analysis of the full-length sequence shown in FIG. 58 (SEQ ID NO:58), evidenced significant homology between the PRO1475 amino acid sequence and the following Dayhoff sequences: GNT1_MOUSE, CGU65792.sub.--1, CGU65791.sub.--1, P_R24781, CELF48E3.sub.--1, G786_HUMAN, P_W06547, GNT1_CAEEL, 219_HUMAN and EF07_MOUSE.

Example 31

Isolation of cDNA Clones Encoding Human PRO1481 Polypeptides [UNQ750]

[0773] An initial DNA sequence, referred to herein as DNA53254, was identified using a yeast screen, in a human fetal kidney cDNA library that preferentially represents the 5' ends of the primary cDNA clones. Based on the DNA53254 sequence, oligonucleotides were synthesized for use as probes (or primers) to isolate a clone of the full-length coding sequence for PRO1481 from a human fetal kidney cDNA library.

[0774] The full length DNA58732-1650 clone shown in FIG. 59 contained a single open reading frame with an apparent translational initiation site at nucleotide positions 320-322 and ending at the stop codon found at nucleotide positions 1322-1324 (FIG. 59; SEQ ID NO:59). The predicted polypeptide precursor (FIG. 60, SEQ ID NO:60) is 334 amino acids long. The signal peptide is at about amino acids 1-23, and a transmembrane domain is at about amino acids 235-262 of SEQ ID NO:60. The N-glycosylation sites are indicated in FIG. 60. PRO1481 has a calculated molecular weight of approximately 36,294 daltons and an estimated pI of approximately 4.98. Clone DNA58732-1650 has been deposited with the ATCC on Sep. 29, 1998 and is assigned ATCC deposit no. 203290.

[0775] An analysis of the Dayhoff database (version 35.45 SwissProt 35), using a WU-BLAST2 sequence alignment analysis of the full-length sequence shown in FIG. 60 (SEQ ID NO:60), revealed sequence identity between the PRO1481 amino acid sequence and the following Dayhoff sequences (data incorporated herein): YN23_YEAST, 567770, H36857, YLU2_PICAN, GEN12881, CVY15035.sub.--28, YM96_YEAST, ESC1_SCHPO, CELZK783.sub.--1 and S59310.

Example 32

Isolation of cDNA Clones Encoding Human PRO1568 Polypeptides [UNQ774]

[0776] A consensus DNA sequence was assembled relative to other EST sequences using phrap to form an assembly as described in Example 1 above. The consensus sequence is designated herein "DNA54208". Based on the DNA54208 consensus sequence, the assembly and other information and discoveries provided herein, a clone including an EST in the assembly was ordered and sequenced. The EST is Incyte 3089490. Sequencing in full gave the sequence shown in FIG. 61.

[0777] The entire coding sequence of PRO1568 is included in FIG. 61 (SEQ ID NO:61). Clone

[0778] DNA68880-1676 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 208-210 and an apparent stop codon at nucleotide positions 1123-1125 of SEQ ID NO:61. The predicted polypeptide precursor is 305 amino acids long (FIG. 62; SEQ ID NO:62). The signal peptide, transmembrane regions, N-myristoylation and amidation sites are also indicated in FIG. 62. Clone DNA68880-1676 has been deposited with the ATCC on Oct. 6, 1998 and is assigned ATCC deposit no. 203319. The full-length PRO1568 protein shown in FIG. 62 has an estimated molecular weight of about 35,383 daltons and a pI of about 5.99.

[0779] An analysis of the Dayhoff database (version 35.45 SwissProt 35), using a WU-BLAST2 sequence alignment analysis of the full-length sequence shown in FIG. 62 (SEQ ID NO:62), revealed sequence identity between the PRO1568 amino acid sequence and the following Dayhoff sequences (incorporated herein): AF089749.sub.--1, AF054841.sub.--1, NAG2_HUMAN, CD63_HUMAN, CD82_HUMAN, P_W05732, P_R86834, A15_HUMAN, P_W27333 and CD37_HUMAN.

Example 33

Isolation of cDNA Clones Encoding Human PRO1573 Polypeptides [UNQ779]

[0780] EST 3628990 was identified in an Incyte Database, (LIFESEQ.RTM., Incyte Pharmaceuticals, Palo Alto, Calif.) and extended in a comparison to other sequences in databases to form an assembly. The alignment search was performed using the computer program BLAST or BLAST2 [Altschul et al., Methods in Enzymology, 266:460-480 (1996)] as a comparison of the ECD protein sequences to a 6 frame translation of the EST sequences. Those comparisons resulting in a BLAST score of 70 (or in some cases, 90) or greater that did not encode known proteins were clustered and assembled into consensus DNA sequences with the program "phrap" (Phil Green, University of Washington, Seattle, Wash.). The consensus sequence is designated herein "DNA69561".

[0781] Based on the DNA69561 consensus sequence and other information provided herein, a clone including another EST (Incyte DNA3752657) from the assembly was purchased and sequenced. This clone came from a breast tumor tissue library.

[0782] The entire coding sequence of PRO1573 is included in FIG. 63 (SEQ ID NO:63). Clone DNA73735-1681 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 97-99 and an apparent stop codon at nucleotide positions 772-774. The predicted polypeptide precursor is 225 amino acids long (FIG. 64; SEQ ID NO:64). The signal peptide is at about amino acids 1-17 and the transmembrane domains are at about amino acids 82-101, 118-145, and 164-188 of SEQ ID NO:64. One or more of the transmembrane domains can be deleted or inactivated. A phosphorylation site, amidation site, and N-myristoylation sites are shown in FIG. 64. Clone DNA73735-1681 has been deposited with ATCC on Oct. 20, 1998 and is assigned ATCC deposit no. 203356. The full-length PRO1573 protein shown in FIG. 64 has an estimated molecular weight of about 24,845 daltons and a pI of about 9.07.

[0783] An analysis of the Dayhoff database (version 35.45 SwissProt 35), using a WU-BLAST2 sequence alignment analysis of the full-length sequence shown in FIG. 64 (SEQ ID NO:64), revealed sequence identity between the PRO1573 amino acid sequence and the following Dayhoff sequences (incorporated herein): AF007189.sub.--1, AB000714.sub.--1, AB000713.sub.--1, AB000712.sub.--1, A39484, AF000959.sub.--1, AF072127_, AF072128.sub.--1, AF068863.sub.--1 and AF077739.sub.--1.

Example 34

Isolation of cDNA Clones Encoding Human PRO1599 Polypeptides [UNQ782]

[0784] Incyte EST no. 1491360 was identified as a sequence of interest using the techniques described in Example 1 above having a BLAST score of 70 or greater that does not encode a known protein. The nucleotide sequence of EST no. 1491360 and its complementary sequence is designated herein "DNA37192". Based on the DNA37192 sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO1599.

[0785] PCR primers (forward and reverse) were synthesized:

TABLE-US-00042 forward PCR primer: (37192.f1; SEQ ID NO: 205) GACGTCTGCAACAGCTCCTGGAAG reverse PCR primer: (37192.r1; SEQ ID NO: 206) CGAGAAGGAAACGAGGCCGTGAG

[0786] Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus

[0787] DNA37192 sequence which had the following nucleotide sequence:

TABLE-US-00043 hybridization probe: (SEQ ID NO: 207) TGACACTTACCATGCTCTGCACCCGCAGTGGGGACAGCCACAGA.

[0788] In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PRO1599 gene using the probe oligonucleotide and one of the PCR primers. RNA for construction of the cDNA libraries was isolated from human fetal liver tissue.

[0789] DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO1599 (designated herein as DNA62845-1684 [FIG. 65, SEQ ID NO:65]; and the derived protein sequence for PRO1599.

[0790] The entire coding sequence of PRO1599 is shown in FIG. 65 (SEQ ID NO:65). Clone DNA62845-1684 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 69-71 and an apparent stop codon at nucleotide positions 918-920. The predicted polypeptide precursor is 283 amino acids long (FIG. 66; SEQ ID NO:66). The full-length PRO1599 protein shown in FIG. 66 has an estimated molecular weight of about 30,350 daltons and a pI of about 9.66. Additional features of PRO1599 include: a signal peptide at about amino acids 1-30; potential N-glycosylation sites at about amino acids 129-132 and 189-192; a potential cAMP and cGMP-dependent protein kinase phosphorylation site at about amino acids 263-266; potential N-myristoylation sites at about amino acids 28-33, 55-60, 174-179, and 236-241; a potential amidation site at about amino acids 144-147; and a serine protease, trypsin family, histidine active site at about amino acids 70-75.

[0791] An analysis of the Dayhoff database (version 35.45 SwissProt 35), using a WU-BLAST2 sequence alignment analysis of the full-length sequence shown in FIG. 66 (SEQ ID NO:66), revealed significant homology between the PRO1599 amino acid sequence and the following Dayhoff sequence: CFAD_PIG. Homology was also found between the PRO1599 amino acids sequence and the following additional Dayhoff sequences. CFAD_HUMAN; P_R05421; P_R55757; P_R05772; GRAM_HUMAN; MUSLMET.sub.--1; P_P80335; P_R55758; A42048.sub.--1; and P_W05383.

[0792] Clone DNA62845-1684 was deposited with the ATCC on Oct. 20, 1998 and is assigned ATCC deposit no. 203361.

Example 35

Isolation of cDNA Clones Encoding Human PRO1604 Polypeptides [UNQ785]

[0793] An expressed sequence tag (EST) DNA database (LIFESEQ.RTM., Incyte Pharmaceuticals, Palo Alto, Calif.) was searched. Incyte EST No. 3550440 was identified as having homology to HDGF. EST No. 3550440 was then compared to various EST databases including public EST databases (e.g. GenBank), and the LIFESEQ.RTM. database, to identify homologous EST sequences. The search was performed using the computer program BLAST or BLAST2 [Altschul et al., Methods in Enzymology, 266:460-480 (1996)]. Those comparisons resulting in a BLAST score of 70 (or in some cases, 90) or greater that did not encode known proteins were clustered and assembled into consensus DNA sequences with the program "phrap" (Phil Green, University of Washington, Seattle, Wash.). This consensus sequence is designated herein "DNA67237".

[0794] In light of the sequence homology between the DNA67237 sequence and EST no. 3367060 from the LIFESEQ.RTM. database, the clone containing Incyte EST No. 3367060 was purchased and the cDNA insert was obtained and sequenced to obtain the entire coding sequence of PRO1604 which is shown in FIG. 67 (SEQ ID NO:67).

[0795] Clone DNA71286-1687 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 65-67 and an apparent stop codon at nucleotide positions 2078-2080. The predicted polypeptide precursor is 671 amino acids long (FIG. 68; SEQ ID NO:68). The full-length PRO1604 protein shown in FIG. 68 has an estimated molecular weight of about 74,317 daltons and a pI of about 7.62. Additional features include a signal peptide at about amino acids 1-13; potential cAMP- and cGMP-dependent protein kinase phosphorylation sites at about amino acids 156-159, 171-174, and 451-454; potential N-myristoylation sites at about amino acids 46-51, 365-370, and 367-372; and a cell attachment sequence at about amino acids 661-663.

[0796] An analysis of the Dayhoff database (version 35.45 SwissProt 35), using a WU-BLAST2 sequence alignment analysis of the full-length sequence shown in FIG. 68 (SEQ ID NO:68), revealed significant homology between the PRO1604 amino acid sequence and Dayhoff sequence no. P_W37483. Homology was also shown between the PRO1604 amino acid sequence and the following additional Dayhoff sequences: AF063020.sub.--1, P_R66727, P_W37482, JC5661, CEC25A1.sub.--11, CEU33058.sub.--1, I38073, MST2_DROHY, and HSATRX36.sub.--1.

[0797] Clone DNA71286-1687 was deposited with the ATCC on Oct. 20, 1998, and is assigned ATCC deposit no. 203357.

Example 36

Isolation of cDNA Clones Encoding Human PRO1605 Polypeptides [UNQ786]

[0798] A cDNA clone (DNA77648-1688) encoding a native human PRO1605 polypeptide was identified by a yeast screen, in a human fetal kidney cDNA library that preferentially represents the 5' ends of the primary cDNA clones.

[0799] The full-length DNA77648-1688 clone shown in FIG. 69 (SEQ ID NO:69) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 425-427 and ending at the stop codon at nucleotide positions 845-847 (FIG. 69). The predicted polypeptide precursor is 140 amino acids long (FIG. 70; SEQ ID NO:70). The full-length PRO1605 protein shown in FIG. 70 has an estimated molecular weight of about 15,668 daltons and a pI of about 10.14. Analysis of the full-length PRO1605 sequence shown in FIG. 70 (SEQ ID NO:70) evidences the presence of the following: a signal peptide from about amino acid 1 to about amino acid 26. Clone DNA77648-1688 has been deposited with ATCC on Oct. 27, 1998 and is assigned

[0800] ATCC deposit no. 203408.

[0801] An analysis of the Dayhoff database (version 35.45 SwissProt 35), using a WU-BLAST2 sequence alignment analysis of the full-length sequence shown in FIG. 70 (SEQ ID NO:70), evidenced significant homology between the PRO1605 amino acid sequence and the following Dayhoff sequences: GNT5_HUMAN, P_R48975, P_W22519, MM26SPROT.sub.--1, HSU86782.sub.--1, CH60_LEPIN, HMCT_HELPY, F65126, HIU08875.sub.--1 and P_R41724.

Example 37

Isolation of cDNA Clones Encoding Human PRO1693 Polypeptides [UNQ803]

[0802] A consensus DNA sequence was assembled relative to other EST sequences using phrap as described in Example 1 above. This consensus sequence is herein designated DNA38251. Based on the DNA38251 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO1693.

[0803] PCR primers (forward and reverse) were synthesized:

TABLE-US-00044 forward PCR primer (38251.f1) (SEQ ID NO: 208) 5'-CTGGGATCTGAACAGTTTCGGGGC-3' reverse PCR primer (38251.r1) (SEQ ID NO: 209) 5'-GGTCCCCAGGACATGGTCTGTCCC-3'

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA38251 sequence which had the following nucleotide sequence

TABLE-US-00045 hybridization probe (38251.p1) (SEQ ID NO: 210) 5'-GCTGAGTTTACATTTACGGTCTAACTCCCTGAGAACCATCCCTGTG CG-3'

[0804] In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PRO1693 gene using the probe oligonucleotide and one of the PCR primers. RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue.

[0805] DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO1693 (designated herein as DNA77301-1708 [FIG. 71, SEQ ID NO:71]; and the derived protein sequence for PRO1693.

[0806] The entire nucleotide sequence of DNA77301-1708 is shown in FIG. 71 (SEQ ID NO:71). Clone DNA77301-1708 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 508-510 and ending at the stop codon at nucleotide positions 2047-2049 (FIG. 71). The predicted polypeptide precursor is 513 amino acids long (FIG. 72; SEQ ID NO:72). The full-length PRO1693 protein shown in FIG. 72 has an estimated molecular weight of about 58,266 daltons and a pI of about 9.84. Analysis of the full-length PRO1693 sequence shown in FIG. 72 (SEQ ID NO:72) evidences the presence of the following: a signal peptide from about amino acid 1 to about amino acid 33, a transmembrane domain from about amino acid 420 to about amino acid 442, potential N-glycosylation sites from about amino acid 126 to about amino acid 129, from about amino acid 357 to about amino acid 360, from about amino acid 496 to about amino acid 499 and from about amino acid 504 to about amino acid 507, a cAMP- and cGMP-dependent protein kinase phosphorylation site from about amino acid 465 to about amino acid 468, a tyrosine kinase phosphorylation site from about amino acid 136 to about amino acid 142 and potential N-myristolation sites from about amino acid 11 to about amino acid 16, from about amino acid 33 to about amino acid 38, from about amino acid 245 to about amino acid 250, from about amino acid 332 to about amino acid 337, from about amino acid 497 to about amino acid 502 and from about amino acid 507 to about amino acid 512. Clone DNA77301-1708 has been deposited with ATCC on Oct. 27, 1998 and is assigned ATCC deposit no. 203407.

[0807] An analysis of the Dayhoff database (version 35.45 SwissProt 35), using a WU-BLAST2 sequence alignment analysis of the full-length sequence shown in FIG. 72 (SEQ ID NO:72), evidenced significant homology between the PRO1693 amino acid sequence and the following Dayhoff sequences: AB007876.sub.--1, ALS_MOUSE, HSCHON03.sub.--1, P_R85889, AF062006.sub.--1, AB 014462.sub.--1, A58532, MUSLRRPA.sub.--1, AB007865.sub.--1 and AF030435.sub.--1.

Example 38

Isolation of cDNA Clones Encoding Human PRO1753 Polypeptides [UNQ826]

[0808] DNA68883 was identified by applying a proprietary signal sequence finding algorithm developed by Genentech, Inc. (South San Francisco, Calif.) upon ESTs as well as clustered and assembled EST fragments from public (e.g., GenBank) and/or private (LIFESEQ.RTM., Incyte Pharmaceuticals, Inc., Palo Alto, Calif.) databases. The signal sequence algorithm computes a secretion signal score based on the character of the DNA nucleotides surrounding the first and optionally the second methionine codon(s) (ATG) at the 5'-end of the sequence or sequence fragment under consideration. The nucleotides following the first ATG must code for at least 35 unambiguous amino acids without any stop codons. If the first ATG has the required amino acids, the second is not examined. If neither meets the requirement, the candidate sequence is not scored. In order to determine whether the EST sequence contains an authentic signal sequence, the DNA and corresponding amino acid sequences surrounding the ATG codon are scored using a set of seven sensors (evaluation parameters) known to be associated with secretion signals.

[0809] Use of the above described signal sequence algorithm allowed identification of an EST cluster sequence from the LIFESEQ.RTM. database, designated Incyte Cluster No. 54463. This EST cluster sequence was then compared to a variety of expressed sequence tag (EST) databases which included public EST databases (e.g., GenBank) and a proprietary EST DNA database (LIFESEQ.RTM., Incyte Pharmaceuticals, Palo Alto, Calif.) to identify existing homologies. The homology search was performed using the computer program BLAST or BLAST2 (Altshul et al., Methods in Enzymology 266:460-480 (1996)). Those comparisons resulting in a BLAST score of 70 (or in some cases 90) or greater that did not encode known proteins were clustered and assembled into a consensus DNA sequence with the program "phrap" (Phil Green, University of Washington, Seattle, Wash.). The consensus sequence is herein designated "DNA54233". In light of the sequence homology between the DNA54233 sequence and EST no. 2597444, the EST clone 2597444 was purchased and the cDNA insert was obtained and sequenced in its entirety. EST clone 2597444 was derived from RNA isolated from ovarian tumor tissue. The sequence of this cDNA insert is shown in FIG. 73 and is herein designated as "DNA68883-1691".

[0810] The full length clone shown in FIG. 73 contained a single open reading frame with an apparent translational initiation site at nucleotide positions 197 to 199 and ending at the stop codon found at nucleotide positions 1832 to 1834 (FIG. 73; SEQ ID NO:73). The predicted polypeptide precursor (FIG. 74, SEQ ID NO:74) is 545 amino acids long. PRO1753 has a calculated molecular weight of approximately 60022 daltons and an estimated pI of approximately 5.50. Additional features of PRO1753 include: a signal peptide at about amino acids 1-16; potential N-glycosylation sites at about amino acids 89-92, 116-119, 259-262, 291-294, and 299-302; potential tyrosine kinase phosphorylation sites at about amino acids 411-417 and 443-450; potential N-myristoylation sites at about amino acids 226-231, 233-238, 240-245, 252-257, 296-301, 300-305, 522-527, and 531-536; and an aspartic acid and asparagine hydroxylation site at about amino acids 197-208.

[0811] An analysis of the Dayhoff database (version 35.45 SwissProt 35), using a WU-BLAST2 sequence alignment analysis of the full-length sequence shown in FIG. 74 (SEQ ID NO:74), revealed significant homology between the PRO1753 amino acid sequence and Dayhoff sequence MMU72678.sub.--1. Homology was also revealed between the PRO1753 amino acid sequence and the following additional the following Dayhoff sequences: GP2_HUMAN; UROM_HUMAN; MMU69262.sub.--1; P_W52840; EGF_HUMAN; P_P50296; P_W31705; CET05A1.sub.--8; and HSAJ474.sub.--1.

[0812] Clone DNA68883 (UNQ826), designated as DNA68883-1691 was deposited with the ATCC on Dec. 15, 1998 and is assigned ATCC deposit no. 203535.

Example 39

Isolation of cDNA Clones Encoding Human PRO1755 Polypeptides [UNQ828]

[0813] Use of the signal sequence algorithm described in Example 3 above allowed identification of an EST cluster sequence from the LIFESEQ.RTM. database, designated EST Cluster No. 141872. This EST cluster sequence was then compared to a variety of ESTs from the databases listed above to identify existing homologies. The homology search was performed using the computer program BLAST or BLAST2 (Altshul et al., Methods in Enzymology 266:460-480 (1996)). Those comparisons resulting in a BLAST score of 70 (or in some cases 90) or greater that did not encode known proteins were clustered and assembled into a consensus DNA sequence with the program "pinup" (Phil Green, University of Washington, Seattle, Wash.). The consensus sequence obtained therefrom is herein designated "DNA55731".

[0814] In light of the sequence homology between the DNA55731 sequence and a sequence contained within Incyte EST no. 257323, the EST clone was purchased and the cDNA insert was obtained and sequenced. Incyte clone 257323 was derived from a library constructed using RNA isolated from the hNT2 cell line (Stratagene library no. STR9372310), which was derived from a human teratocarcinoma that exhibited properties characteristic of a committed neuronal precursor at an early stage of development. The sequence of this cDNA insert is shown in FIG. 75 and is herein designated "DNA76396-1698". Alternatively, the DNA76396-1698 sequence can be obtained by preparing oligonucleotide probes and primers and isolating the sequence from an appropriate library (e.g. STR9372310).

[0815] The full length clone shown in FIG. 75 contained a single open reading frame with an apparent translational initiation site at nucleotide positions 58 to 60 and ending at the stop codon found at nucleotide positions 886 to 888 (FIG. 75; SEQ ID NO:75). The predicted polypeptide precursor (FIG. 76, SEQ ID NO:76) is 276 amino acids long. PRO1755 has a calculated molecular weight of approximately 29,426 daltons and an estimated pI of approximately 9.40. Additional features include: a signal peptide sequence at about amino acids 1-31; a transmembrane domain at about amino acids 178-198; a cAMP and cGMP-dependent protein kinase phosphorylation site at about amino acids 210-213; potential N-myristoylation sites at about amino acids 117-122, 154-149, and 214-219; and a cell attachment sequence at about amino acids 149-151.

[0816] An analysis of the Dayhoff database (version 35.45 SwissProt 35), using a WU-BLAST2 sequence alignment analysis of the full-length sequence shown in FIG. 76 (SEQ ID NO:76), revealed some homology between the PRO1755 amino acid sequence and the following Dayhoff sequences: APG-BRANA, P_R37743, NAU88587.sub.--1, YHL1_EBV, P_W31855, CET10B10.sub.--4, AF039404.sub.--1, PRP1_HUMAN, AF038575.sub.--1, and AF053091.sub.--1.

[0817] Clone DNA76396-1698 was deposited with the ATCC on Nov. 17, 1998, and is assigned ATCC deposit no. 203471.

Example 40

Isolation of cDNA Clones Encoding Human PRO1777 Polypeptides [UNQ839]

[0818] The extracellular domain (ECD) sequences (including the secretion signal sequence, if any) from about 950 known secreted proteins from the Swiss-Prot public database were used to search EST databases. The EST databases included public EST databases (e.g., GenBank), and a proprietary EST database (LLFESEQ.RTM., Incyte Pharmaceuticals, Palo Alto, Calif.). The search was performed using the computer program BLAST or BLAST2 [Altschul et al., Methods in Enzymology, 266:460-480 (1996)] as a comparison of the ECD protein sequences to a 6 frame translation of the EST sequences. Those comparisons resulting in a BLAST score of 70 (or in some cases, 90) or greater that did not encode known proteins were clustered and assembled into consensus DNA sequences with the program "phrap" (Phil Green, University of Washington, Seattle, Wash.).

[0819] A consensus DNA sequence was assembled relative to other EST sequences using phrap. This consensus sequence is herein designated DNA47435.

[0820] Based on the DNA47435 consensus sequence oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO1777. Forward and reverse PCR primers generally range from 20 to 30 nucleotides and are often designed to give a PCR product of about 100-1000 bp in length. The probe sequences are typically 40-55 bp in length. In some cases, additional oligonucleotides are synthesized when the consensus sequence is greater than about 1-1.5 kbp. In order to screen several libraries for a full-length clone, DNA from the libraries was screened by PCR amplification, as per Ausubel et al., Current Protocols in Molecular Biology, supra, with the PCR primer pair. A positive library was then used to isolate clones encoding the gene of interest using the probe oligonucleotide and one of the primer pairs.

[0821] PCR primers (forward and reverse) were synthesized:

TABLE-US-00046 forward PCR primer (47434.f1) (SEQ ID NO: 211) 5'-CTGTTACACTGACGTGGCCCTCCC-3' reverse PCR primer (47434.r1) (SEQ ID NO: 212) 5'-CATTCTGACCCACGGGCCATTGTC-3'

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA47435 sequence which had the following nucleotide sequence

TABLE-US-00047 hybridization probe (47434.p1) (SEQ ID NO: 213) 5'-GTGGAGCAGCCGGTGAACTTGAGCAGCCTTGCCCAGAAGTATGC-3'

[0822] RNA for construction of the cDNA libraries was isolated from human hippocampus tissue. The cDNA libraries used to isolate the cDNA clones were constructed by standard methods using commercially available reagents such as those from Invitrogen, San Diego, Calif. The cDNA was primed with oligo dT containing a Nod site, linked with blunt to Sail hemikinased adaptors, cleaved with NotI, sized appropriately by gel electrophoresis, and cloned in a defined orientation into a suitable cloning vector (such as pRKB or pRKD; pRK5B is a precursor of pRK5D that does not contain the SfiI site; see, Holmes et al., Science, 253:1278-1280 (1991)) in the unique XhoI and NotI sites.

[0823] DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO1777 (designated herein as DNA71235-1706 [FIG. 77, SEQ ID NO: 77]; (UNQ839) and the derived protein sequence for PRO1777.

[0824] The entire nucleotide sequence of UNQ839 (DNA71235-1706) is shown in FIG. 77 (SEQ ID NO:77). Clone UNQ839 (DNA71235-1706) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 797-799 and ending at the stop codon at nucleotide positions 2372-2374 (FIG. 77). The predicted polypeptide precursor is 525 amino acids long (FIG. 78; SEQ ID NO:78). The full-length PRO1777 protein shown in FIG. 78 has an estimated molecular weight of about 57,133 daltons and a pI of about 6.55. Analysis of the full-length PRO1777 sequence shown in FIG. 78 (SEQ ID NO:78) evidences the presence of the following: a signal peptide from about amino acid 1 to about amino acid 16, a transmembrane domain from about amino acid 353 to about amino acid 373, potential N-glycosylation sites from about amino acid 117 to about amino acid 120, from about amino acid 215 to about amino acid 218, from about amino acid 356 to about amino acid 359 and from about amino acid 497 to about amino acid 500, potential N-myristolation sites from about amino acid 12 to about amino acid 17, from about amino acid 33 to about amino acid 38, from about amino acid 52 to about amino acid 57, from about amino acid 97 to about amino acid 102, from about amino acid 101 to about amino acid 106, from about amino acid 113 to about amino acid 118, from about amino acid 158 to about amino acid 163, from about amino acid 328 to about amino acid 333, from about amino acid 388 to about amino acid 393, from about amino acid 418 to about amino acid 423, from about amino acid 435 to about amino acid 440 and from about amino acid 436 to about amino acid 441, an amidation site from about amino acid 382 to about amino acid

385 and a sulfatase signature 2 sequence from about amino acid 129 to about amino acid 138. Clone UNQ839 (DNA71235-1706) has been deposited with ATCC on Jan. 12, 1999 and is assigned ATCC deposit no. 203584.

[0825] An analysis of the Dayhoff database (version 35.45 SwissProt 35), using a WU-BLAST2 sequence alignment analysis of the full-length sequence shown in FIG. 78 (SEQ ID NO:78), evidenced significant homology between the PRO1777 amino acid sequence and the following Dayhoff sequences: G02857, GA6S_HUMAN, HGS_A139, GEN12647, STS_HUMAN, GEN12648, SPHM_HUMAN, P_W47298, GEN13892 and AF050145.sub.--1.

Example 41

Isolation of cDNA Clones Encoding Human PRO1788 Polypeptides [UNQ850]

[0826] The extracellular domain (ECD) sequences (including the secretion signal sequence, if any) from about 950 known secreted proteins from the Swiss-Prot public database were used to search EST databases. The EST databases included public EST databases (e.g., GenBank), and a proprietary EST database (LIFESEQ.RTM., Incyte Pharmaceuticals, Palo Alto, Calif.). The search was performed using the computer program BLAST or BLAST2 [Altschul et al., Methods in Enzymology, 266:460-480 (1996)] as a comparison of the ECD protein sequences to a 6 frame translation of the EST sequences. Incyte Clone No. 2968304 was identified as a sequence of interest having a BLAST score of 70 or greater that did not encode known proteins. The nucleotide sequence of Incyte Clone No. 2968304 is designated herein as "DNA6612".

[0827] In addition, the DNA6612 sequence was extended using repeated cycles of BLAST and phrap (Phil Green, University of Washington, Seattle, Wash.) to extend the sequence as far as possible using the sources of EST sequences discussed above. The extended consensus sequence is designated herein as "DNA49648". Based on the DNA49648 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO1788.

[0828] PCR primers (forward and reverse) were synthesized:

TABLE-US-00048 forward PCR primer: (49648.f1; SEQ ID NO: 214) CCCTGCCAGCCGAGAGCTTCACC reverse PCR primer: (49648.r1; SEQ ID NO: 215) GGTTGGTGCCCGAAAGGTCCAGC

[0829] Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus

[0830] DNA49648 sequence which had the following nucleotide sequence:

TABLE-US-00049 hybridization probe: (49648.p1; SEQ ID NO: 216) CAACCCCAAGCTTAACTGGGCAGGAGCTGAGGTGTTTTCAGGCC

[0831] In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PRO1788 gene using the probe oligonucleotide and one of the PCR primers. RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue.

[0832] DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO1788 (designated herein as DNA77652-2505 [FIG. 79, SEQ ID NO:79]; and the derived protein sequence for PRO1788.

[0833] The entire coding sequence of DNA77652-2505 is shown in FIG. 79 (SEQ ID NO:79). Clone DNA77652-2505 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 64-66 and an apparent stop codon at nucleotide positions 1123-1125. The predicted polypeptide precursor is 353 amino acids long (FIG. 80; SEQ ID NO:80). The full-length PRO1788 protein shown in FIG. 80 has an estimated molecular weight of about 37,847 daltons and a pI of about 6.80. Additional features of PRO1788 include: a signal peptide at about amino acids 1-16; transmembrane domains at about amino acids 215-232 and 287-304; potential N-glycosylation sites at about amino acids 74-77 and 137-140; a glycosaminoglycan attachment site at about amino acids 45-48; a tyrosine kinase phosphorylation site at about amino acids 318-325; N-myristoylation sites at about amino acids 13-18, 32-37, 88-93, 214-219, and 223-228; and a leucine zipper pattern at about amino acids 284-305.

[0834] An analysis of the Dayhoff database (version 35.45 SwissProt 35), using a WU-BLAST2 sequence alignment analysis of the full-length sequence shown in FIG. 80 (SEQ ID NO:80), revealed significant homology between the PRO1788 amino acid sequence and the following Dayhoff sequences: AF030435.sub.--1; AF062006.sub.--1; DMTARTAN.sub.--1; GARP_HUMAN; S42799; P_R71294; HSU88879.sub.--1; DROWHEELER.sub.--1; A58532; and AF068920.sub.--1.

[0835] Clone DNA77652-2505 was deposited with the ATCC on Nov. 17, 1998, and is assigned ATCC deposit no. 203480.

Example 42

Isolation of cDNA Clones Encoding Human PRO1864 Polypeptides [UNQ855]

[0836] The extracellular domain (ECD) sequences (including the secretion signal sequence, if any) from about 950 known secreted proteins from the Swiss-Prot public database were used to search EST databases. The EST databases included public EST databases (e.g., GenBank), a proprietary EST database (LIFESEQ.RTM., Incyte Pharmaceuticals, Palo Alto, Calif.), and proprietary ESTs from Genentech. The search was performed using the computer program BLAST or BLAST2 [Altschul et al., Methods in Enzymology, 266:460-480 (1996)] as a comparison of the ECD protein sequences to a 6 frame translation of the EST sequences. Those comparisons resulting in a BLAST score of 70 (or in some cases, 90) or greater that did not encode known proteins were clustered and assembled into consensus DNA sequences with the program "phrap" (Phil Green, University of Washington, Seattle, Wash.).

[0837] A consensus DNA sequence was assembled relative to other EST sequences using phrap. This consensus sequence is herein designated Concen1424. In addition, the Consen1424 consensus DNA sequence was extended using repeated cycles of BLAST and phrap to extend the consensus sequence as far as possible using the sources of EST sequences discussed above. The extended consensus sequence is herein designated DNA40649.

[0838] Based on the DNA40649 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO1864. Forward and reverse PCR primers generally range from 20 to 30 nucleotides and are often designed to give a PCR product of about 100-1000 bp in length. The probe sequences are typically 40-55 bp in length. In some cases, additional oligonucleotides are synthesized when the consensus sequence is greater than about 1-1.5 kbp. In order to screen several libraries for a full-length clone, DNA from the libraries was screened by PCR amplification, as per Ausubel et al., Current Protocols in Molecular Biology, supra, with the PCR primer pair. A positive library was then used to isolate clones encoding the gene of interest using the probe oligonucleotide and one of the primer pairs.

[0839] PCR primers (forward and reverse) were synthesized:

TABLE-US-00050 forward PCR primer (40649.f1) (SEQ ID NO: 217) 5'-CTCCTCCAGGATGAACCACCTGCC-3' forward PCR primer (40649.f2) (SEQ ID NO: 218) 5'-CAGGATGCTTCAGAGAGG-3' reverse PCR primer (40649.r1) (SEQ ID NO: 219) 5'-CCTGCCTTCGGATTCCAGGAGGGG-3'

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA40649 sequence which had the following nucleotide sequence

TABLE-US-00051 hybridization probe (40649.p1) (SEQ ID NO: 220) 5'-CCATCAACCCCACACAACTCATGGCCAGGATTGAGTCCTATG-3'

[0840] RNA for construction of the cDNA libraries was isolated from human fetal liver tissue. The cDNA libraries used to isolate the cDNA clones were constructed by standard methods using commercially available reagents such as those from Invitrogen, San Diego, Calif. The cDNA was primed with oligo dT containing a Nod site, linked with blunt to SalI hemikinased adaptors, cleaved with NotI, sized appropriately by gel electrophoresis, and cloned in a defined orientation into a suitable cloning vector (such as pRKB or pRKD; pRK5B is a precursor of pRK5D that does not contain the SfiI site; see, Holmes et al., Science, 253:1278-1280 (1991)) in the unique XhoI and NotI sites.

[0841] DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for PRO1864 (designated herein as DNA45409-2511 [FIG. 81, SEQ ID NO: 81]; (UNQ855) and the derived protein sequence for PRO1864.

[0842] The entire nucleotide sequence of UNQ855 (DNA45409-2511) is shown in FIG. 81 (SEQ ID NO:81). Clone UNQ855 (DNA45409-2511) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 100-102 and ending at the stop codon at nucleotide positions 802-804 (FIG. 81). The predicted polypeptide precursor is 234 amino acids long (FIG. 82; SEQ ID NO:82). The full-length PRO1864 protein shown in FIG. 82 has an estimated molecular weight of about 26,655 daltons and a pI of about 4.79. Analysis of the full-length PRO1864 sequence shown in FIG. 82 (SEQ ID NO:82) evidences the presence of the following: a signal peptide from about amino acid 1 to about amino acid 20 and transmembrane domains from about amino acid 54 to about amino acid 72, from about amino acid 100 to about amino acid 118, from about amino acid 130 to about amino acid 144 and from about amino acid 146 to about amino acid 166. Clone UNQ855 (DNA45409-2511) has been deposited with ATCC on Jan. 12, 1999 and is assigned ATCC deposit no. 203579.

[0843] An analysis of the Dayhoff database (version 35.45 SwissProt 35), using a WU-BLAST2 sequence alignment analysis of the full-length sequence shown in FIG. 82 (SEQ ID NO:82), evidenced significant homology between the PRO1864 amino acid sequence and the following Dayhoff sequences: P_W25768, I38027, D38255.sub.--1, MMES64.sub.--1, OCU92812.sub.--1, DRPATCH.sub.--1, DPOD_PLAFK, RTM1_YEAST, P_R77844 and P_R90765.

Example 43

Isolation of cDNA Clones Encoding Human PRO1925 Polypeptides [UNQ904]

[0844] DNA82302 was identified by applying a proprietary signal sequence finding algorithm developed by Genentech, Inc. (South San Francisco, Calif.) upon expressed sequence tags (ESTs) as well as clustered and assembled EST fragments from public (e.g., GenBank) and/or private (LIFESEQ.RTM., Incyte Pharmaceuticals, Inc., Palo Alto, Calif.) databases. The signal sequence algorithm computes a secretion signal score based on the character of the DNA nucleotides surrounding the first and optionally the second methionine codon(s) (ATG) at the 5'-end of the sequence or sequence fragment under consideration. The nucleotides following the first ATG must code for at least 35 unambiguous amino acids without any stop codons. If the first ATG has the required amino acids, the second is not examined. If neither meets the requirement, the candidate sequence is not scored. In order to determine whether the EST sequence contains an authentic signal sequence, the DNA and corresponding amino acid sequences surrounding the ATG codon are scored using a set of seven sensors (evaluation parameters) known to be associated with secretion signals.

[0845] Use of the above described signal sequence algorithm allowed identification of an EST cluster sequence from the LIFESEQ.RTM. database, designated cluster sequence no. 31113.sub.--2. This EST cluster sequence was then compared to the EST databases listed above to identify existing homologies. The homology search was performed using the computer program BLAST or BLAST2 (Altshul et al., Methods in Enzymology 266:460-480 (1996)). Those comparisons resulting in a BLAST score of 70 (or in some cases 90) or greater that did not encode known proteins were clustered and assembled into a consensus DNA sequence with the program "phrap" (Phil Green, University of Washington, Seattle, Wash.). The consensus sequence obtained therefrom is herein designated "DNA73884". In light of the sequence homology between the DNA73884 sequence and EST no. 3271608111 from the LIFESEQ.RTM. database, EST clone no. 3271608HI was purchased and the cDNA insert was obtained and sequenced. The clone originated from a library constructed using diseased human brain tissue. The sequence of this cDNA insert is shown in FIG. 83 and is herein designated as DNA82302.

[0846] The full length clone shown in FIG. 83 contained a single open reading frame with an apparent translational initiation site at nucleotide positions 89 to 91 and ending at the stop codon found at nucleotide positions 1409 to 1411 (FIG. 83; SEQ ID NO:83). The predicted polypeptide precursor (FIG. 84, SEQ ID NO:84) is 440 amino acids long. PRO1925 has a calculated molecular weight of approximately 49,403 daltons and an estimated pI of approximately 7.16. Additional features include a type II transmembrane domain at about amino acids 39-56; tyrosine kinase phosphorylation sites at about amino acids 149-155 and 274-281; N-myristoylation sites at about amino acids 10-15, 20-25, 63-68, and 208-213; an amidation site at about amino acids 10-13; and a glycoprotein hormones beta chain signature 1 at about amino acids 230-236.

[0847] An analysis of the Dayhoff database (version 35.45 SwissProt 35), using a WU-BLAST2 sequence alignment analysis of the full-length sequence shown in FIG. 84 (SEQ ID NO:84), revealed some homology between the PRO1925 amino acid sequence and the following Dayhoff sequences: P_R95913, AF010144.sub.--1, HSAF000996.sub.--1, HUMTRRP.sub.--1, P_W00838, I54374, PVPVA1.sub.--1, REL_HUMAN, HSU94362.sub.--1, and P_W19943.

[0848] Clone DNA82302 (UNQ904), designated as DNA82302-2529 was deposited with the ATCC on Dec. 15, 1998 and is assigned ATCC deposit no. 203534.

Example 44

Isolation of cDNA Clones Encoding Human PRO1926 Polypeptides [UNQ905]

[0849] DNA82340 was identified by applying a proprietary signal sequence finding algorithm developed by Genentech, Inc. (South San Francisco, Calif.) upon ESTs as well as clustered and assembled EST fragments from public (e.g., GenBank) and/or private (LIFESEQ.RTM., Incyte Pharmaceuticals, Inc., Palo Alto, Calif.) databases. The signal sequence algorithm computes a secretion signal score based on the character of the DNA nucleotides surrounding the first and optionally the second methionine codon(s) (ATG) at the 5'-end of the sequence or sequence fragment under consideration. The nucleotides following the first ATG must code for at least 35 unambiguous amino acids without any stop codons. If the first ATG has the required amino acids, the second is not examined. If neither meets the requirement, the candidate sequence is not scored. In order to determine whether the EST sequence contains an authentic signal sequence, the DNA and corresponding amino acid sequences surrounding the ATG codon are scored using a set of seven sensors (evaluation parameters) known to be associated with secretion signals.

[0850] An EST sequence which was identified was then compared to a variety of ESTs from the databases mentioned above to identify existing homologies. The homology search was performed using the computer program BLAST or BLAST2 (Altshul et al., Methods in Enzymology 266:460-480 (1996)). Those comparisons resulting in a BLAST score of 70 (or in some cases 90) or greater that did not encode known proteins were clustered and assembled into a consensus DNA sequence with the program "phrap" (Phil Green, University of Washington, Seattle, Wash.). The consensus sequence obtained therefrom is here in designated DNA73887. In light of the sequence homology between the DNA73887 sequence and EST no. 3577105 from the LIFESEQ.RTM., the EST clone, which was obtained from a cDNA library constructed from human bronchial tissue, was purchased and the cDNA insert was obtained and sequenced. The sequence of this cDNA insert is shown in FIG. 85 and is herein designated "DNA82340-2530".

[0851] The full length clone shown in FIG. 85 contained a single open reading frame with an apparent translational initiation site at nucleotide positions 74 to 76 and ending at the stop codon found at nucleotide positions 800 to 802 (FIG. 85; SEQ ID NO:85). The predicted polypeptide precursor (FIG. 86, SEQ ID NO:86) is 242 amino acids long. PRO1926 has a calculated molecular weight of approximately 26,471 daltons and an estimated pI of approximately 9.50. Additional features include: a signal peptide at about amino acids 1-23; a transmembrane domain at about amino acids 136-180; a potential N-glycosylation site at about amino acids 184-187; glycosaminoglycan attachment sites at about amino acids 37-40 and 236-239; a cAMP- and cGMP-dependent protein kinase phosphorylation site at about amino acids 151-154; potential N-myristoylation sites at about amino acids 33-38, 36-41, 38-43, and 229-234; an amidation site at about amino acids 238-241; and an ATP/GTP binding site motif A (P-loop) at about amino acids 229-236.

[0852] An analysis of the Dayhoff database (version 35.45 SwissProt 35), using a WU-BLAST2 sequence alignment analysis of the full-length sequence shown in FIG. 86 (SEQ ID NO:86), revealed 100 percent sequence identity between the last 81 carboxy terminus amino acids of the PRO1926 sequence and Dayhoff sequences P_W57893. Some homology was also found between the PRO1926 amino acid sequence and the following Dayhoff sequences: S72578, AR20_CAEEL, HGS_A198, HGS_A273, AF007570.sub.--1, GEN12401, DMSTKIN.sub.--1, FAT_DROME, MNB_DROME.

[0853] Clone DNA82340 (UNQ905), designated as DNA82340-2530 was deposited with the ATCC on Dec. 22, 1998, and is assigned ATCC deposit no. 203547.

Example 45

Isolation of cDNA Clones Encoding Human PRO3566 Polypeptides [UNQ1840]

[0854] DNA59844-2542 was identified by applying a proprietary signal sequence finding algorithm developed by Genentech, Inc. (South San Francisco, Calif.) upon ESTs as well as clustered and assembled EST fragments from public (e.g., GenBank) and/or private (LIFESEQ.RTM., Incyte Pharmaceuticals, Inc., Palo Alto, Calif.) databases. The signal sequence algorithm computes a secretion signal score based on the character of the DNA nucleotides surrounding the first and optionally the second methionine codon(s) (ATG) at the 5'-end of the sequence or sequence fragment under consideration. The nucleotides following the first ATG must code for at least 35 unambiguous amino acids without any stop codons. If the first ATG has the required amino acids, the second is not examined. If neither meets the requirement, the candidate sequence is not scored. In order to determine whether the EST sequence contains an authentic signal sequence, the DNA and corresponding amino acid sequences surrounding the ATG codon are scored using a set of seven sensors (evaluation parameters) known to be associated with secretion signals.

[0855] Use of the above described signal sequence algorithm allowed identification of an EST cluster sequence from the Incyte database. This EST cluster sequence was then compared to a variety of expressed sequence tag (EST) databases which included public EST databases (e.g., GenBank) and a proprietary EST DNA database (Lifeseq.RTM., Incyte Pharmaceuticals, Palo Alto, Calif.) to identify existing homologies. The homology search was performed using the computer program BLAST or BLAST2 (Altshul et al., Methods in Enzymology 266:460-480 (1996)). Those comparisons resulting in a BLAST score of 70 (or in some cases 90) or greater that did not encode known proteins were clustered and assembled into a consensus DNA sequence with the program "phrap" (Phil Green, University of Washington, Seattle, Wash.). The consensus sequence obtained therefrom is herein designated DNA56016. In light of the sequence homology between the DNA56016 sequence and the Incyte EST clone no. 2603392, the Incyte EST clone no. 2603392 was purchased and the cDNA insert was obtained and sequenced. The sequence of this cDNA insert is shown in FIG. 87 and is herein designated as DNA59844-2542.

[0856] Clone UNQ1840 (DNA59844-2542) contains a single open reading frame with an apparent translational initiation site at nucleotide positions 5-7 and ending at the stop codon at nucleotide positions 980-982 (FIG. 87; SEQ ID NO:87). The predicted polypeptide precursor is 325 amino acids long (FIG. 88; SEQ ID NO:88). The full-length PRO3566 protein shown in FIG. 88 has an estimated molecular weight of about 34,256 daltons and a pI of about 7.14. Analysis of the full-length PRO3566 sequence shown in FIG. 88 (SEQ ID NO:88) evidences the presence of the following: a signal peptide from about amino acid 1 to about amino acid 26, and various other regions shown in FIG. 88. Clone UNQ1840 (DNA59844-2542) has been deposited with ATCC on Feb. 9, 1999 and is assigned ATCC deposit no. 203650.

[0857] An analysis of the Dayhoff database (version 35.45 SwissProt 35), using a WU-BLAST2 sequence alignment analysis of the full-length sequence shown in FIG. 88 (SEQ ID NO:88), evidenced significant homology between the PRO3566 amino acid sequence and the following Dayhoff sequences: HELWAMIDE.sub.--1, CA21_MOUSE, SP62_HUMAN, AP095464.sub.--1, HMU92813.sub.--1, PRIO_BOVIN, SN24_HUMAN, TPM4_DROME, SYN1_RAT and CELT28F2.sub.--7.

Example 46

Isolation of cDNA Clones Encoding Human PRO4330 Polypeptides [UNQ1886]

[0858] An expressed sequence tag (EST) DNA database (LIFESEQ.RTM., Incyte Pharmaceuticals, Palo Alto, Calif.) was searched and an EST, 4287529H1, (SEQ ID NO:3, also referred to herein as DNA85538 or from DNA) was identified which showed homology to thrombospondin.

[0859] RNA for construction of cDNA libraries was isolated from human aortic endothelial cells. The cDNA libraries used to isolate the cDNA clones encoding human PRO4330 were constructed by standard methods using commercially available reagents such as those from Invitrogen, San Diego, Calif. The cDNA was primed with oligo dT containing a NotI site, linked with blunt to Sad hemikinased adaptors, cleaved with NotI, sized appropriately by gel electrophoresis, and cloned in a defined orientation into a suitable cloning vector (such as pRKB or pRKD; pRK5B is a precursor of pRK5D that does not contain the SfiI site; see, Holmes et al., Science, 253:1278-1280 (1991)) in the unique XhoI and Nod.

[0860] The human cDNA libraries (prepared as described above), were screened by hybridization with a synthetic oligonucleotide probe:

TABLE-US-00052 (forward, SEQ ID NO: 221) 5'GGAGACATGTTTCGAATGGACAACTGTC3'; (reverse, SEQ ID NO: 222) 5'CTGGATCTTCACACACTGGGCAGC3'; and (plasmid, SEQ ID NO: 223) 5'CCCAGTGTGGTGAGATAAACTGCGAGAGGTACTACGTGCCCGAAG G3'.

[0861] A cDNA clone was sequenced in entirety. The entire nucleotide sequence including that coding PRO4330 is shown in FIG. 89 (SEQ ID NO:89). Clone DNA90842-2574 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 368-370, and a stop codon at nucleotide positions 3476-3478 (FIG. 89; SEQ ID NO:89). The predicted polypeptide precursor is 1036 amino acids long (FIG. 90; SEQ ID NO:90).

[0862] The full-length PRO4330 protein shown in FIG. 90 has an estimated molecular weight of about 113738 daltons and a pI of about 5.14.

[0863] An analysis of the Dayhoff database (version 35.45 SwissProt 35), using a WU-BLAST2 sequence alignment analysis of the full-length sequence shown in FIG. 90 (SEQ ID NO:90), revealed homology between the PRO4330 amino acid sequence and the following Dayhoff sequences (incorporated herein): D83017.sub.--1, P_W37500, NEL_RAT, P_W37501, NEL2_HUMAN, AF034606.sub.--1, P_W40288, CHRD_XENLA, TSP1_CHICK, and SOG_DROME.

Example 47

Isolation of cDNA Clones Encoding Human PRO4423 Polypeptides [UNQ1940]

[0864] DNA96893-2621 was identified by applying a proprietary signal sequence finding algorithm developed by Genentech, Inc. (South San Francisco, Calif.) upon ESTs as well as clustered and assembled EST fragments from public (e.g., GenBank) and/or private (LIFESEQ.RTM., Incyte Pharmaceuticals, Inc., Palo Alto, Calif.) databases. The signal sequence algorithm computes a secretion signal score based on the character of the DNA nucleotides surrounding the first and optionally the second methionine codon(s) (ATG) at the 5'-end of the sequence or sequence fragment under consideration. The nucleotides following the first ATG must code for at least 35 unambiguous amino acids without any stop codons. If the first ATG has the required amino acids, the second is not examined. If neither meets the requirement, the candidate sequence is not scored. In order to determine whether the EST sequence contains an authentic signal sequence, the DNA and corresponding amino acid sequences surrounding the ATG codon are scored using a set of seven sensors (evaluation parameters) known to be associated with secretion signals.

[0865] Use of the above described signal sequence algorithm allowed identification of an EST sequence from the Incyte database, a proprietary EST DNA database (LIFESEQ.RTM., Incyte Pharmaceuticals, Palo Alto, Calif.). Based on DNA80594, DNA96893-2621 was identified and sequenced.

[0866] The full length clone shown in FIG. 91 contained a single open reading frame with an apparent translational initiation site at nucleotide positions 110-112 and ending at the stop codon found at nucleotide positions 639-641 (FIG. 91; SEQ ID NO:91). The predicted polypeptide precursor (FIG. 92, SEQ ID NO:92) is 173 amino acids long. PRO4423 has a calculated molecular weight of approximately 19733 daltons and an estimated pI of approximately 8.78.

[0867] An analysis of the Dayhoff database (version 35.45 SwissProt 35), using a WU-BLAST2 sequence alignment analysis of the full-length sequence shown in FIG. 92 (SEQ ID NO:92), revealed homology between the PRO4423 amino acid sequence and the following Dayhoff sequences: S09646 and YHY4_YEAST.

[0868] Clone DNA96893-2621 (UNQ1940), designated as DNA96893-2621 was deposited with the ATCC on May 4, 1999 and is assigned ATCC deposit no. PTA-12.

Example 48

Isolation of cDNA Clones Encoding Human PRO4977 Polypeptides [UNQ2420]

[0869] A consensus DNA sequence was assembled relative to other EST sequences using phrap as described in Example 1 above. Based on this consensus sequence, oligonucleotides were synthesized to identify by PCR a cDNA library that contained the sequence of interest and for use as probes to isolate a clone of the full-length coding sequence for PRO4977.

[0870] A pair of PCR primers (forward and reverse) were synthesized:

TABLE-US-00053 forward PCR primer (SEQ ID NO: 224) 5'-ATGCCAATAACTTTGCCTCGGAGC-3' reverse PCR primer (SEQ ID NO: 225) 5'-CCAGAAGGCCAGGGCTTTCTCTG-3'

A hybridization probe was also synthesized:

TABLE-US-00054 (SEQ ID NO: 226) 5'-GAGTGCATGAGCAGCTGCCAGGGATCTCTCCATGGGCCCC-3'

[0871] In order to screen several libraries for a source of a full-length clone, DNA from the libraries was screened by PCR amplification with the PCR primer pair identified above. A positive library was then used to isolate clones encoding the PRO4977 gene using the probe oligonucleotide and one of the PCR primers.

[0872] RNA for construction of the cDNA libraries was isolated from a human fetal kidney library. DNA sequencing of the clones isolated as described above gave the full-length DNA sequence and the derived protein sequence for PR4977.

[0873] The entire nucleotide sequence of DNA62849-2647 is shown in FIG. 95 (SEQ ID NO:95). Clone DNA62849-2647 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 330-332, and an apparent stop codon at nucleotide positions 1761-1763. The predicted polypeptide precursor is 477 amino acids long (FIG. 96; SEQ ID NO:96). Clone DNA62849-2647 has been deposited with ATCC on Jun. 8, 1999 (designated as DNA62849-2647) and is assigned ATCC deposit no. PTA-205. The full-length PRO4977 protein has An estimated molecular weight of about 51112 daltons and a pI of about 6.66.

[0874] An analysis of the Dayhoff database (version 35.45 SwissProt 35), using a WU-BLAST2 sequence alignment analysis of the full-length sequence shown in FIG. 96 (SEQ ID NO:96), revealed homology between PTO4977 amino acid sequence and the following Dayhoff sequences: DJ534K4.sub.--3, AF41053.sub.--1, CELZK3777.sub.--2. AF060570.sub.--1, AF026465.sub.--1; I50600, HSU61262.sub.--1, DMU88578.sub.--1, P_W08747, and DMNRG2.sub.--2.

Example 49

Isolation of cDNA Clones Encoding Human PRO4980 Polypeptides [UNQ2422]

[0875] An initial DNA sequence, referred to herein as DNA81573 was identified by a yeast screen, in a human cDNA library that preferentially represents the 5' ends of the primary cDNA clones. This cDNA was then compared to ESTs from public databases (e.g., GenBank), and a proprietary EST database (LIFESEQ.RTM., Incyte Pharmaceuticals, Palo Alto, Calif.), using the computer program BLAST or BLAST2 [Altschul et al., Methods in Enzymology, 266:460-480 (1996)]. The ESTs were clustered and assembled into a consensus DNA sequence with the program "phrap" (Phil Green, University of Washington, Seattle, Wash.). The consensus sequence is herein designated DNA90613.

[0876] PCR primers (forward and reverse) were synthesized based upon the DNA90613 sequence for use as probes to isolate a clone of the full-length coding sequence for PRO4980 from a human aortic endothelial cell cDNA library:

TABLE-US-00055 forward PCR primer: (SEQ ID NO: 227) 5'-CAACCGTATGGGACCGATACTCG-3' reverse PCR primer: (SEQ ID NO: 228) 5'-CACGCTCAACGAGTCTTCATG-3' hybridization probe: (SEQ ID NO: 229) 5'-GTGGCCCTCGCAGTGCAGGCCTTCTACGTCCAATACAAGTG-3'

[0877] RNA for construction of the cDNA libraries was isolated from human aortic endothelial cell tissue. The cDNA libraries used to isolate the cDNA clones were constructed by standard methods using commercially available reagents such as those from Invitrogen, San Diego, Calif. The cDNA was primed with oligo dT containing a Not site, linked with blunt to Sal hemikinased adaptors, cleaved with Not, sized appropriately by gel electrophoresis, and cloned in a defined orientation into a suitable cloning vector (such as pRKB or pRKD; pRK5B is a precursor of pRK5D that does not contain the Sfi site; see, Holmes et al., Science, 253:1278-1280 (1991)) in the unique Xho and Not sites.

[0878] The full-length DNA97003-2649 clone obtained from this screen is shown in FIG. 99 [SEQ ID NO:99] and contains a single open reading frame with an apparent translational initiation site at nucleotide positions 286-288, and an apparent stop codon at nucleotide positions 1900-1902. The predicted polypeptide precursor is 538 amino acids long (FIG. 100; SEQ ID NO:100). The full-length PRO4980 protein shown in FIG. 100 has an estimated molecular weight of about 59,268 daltons and a pI of about 8.94. Analysis of the full-length PRO4980 sequence shown in FIG. 100 (SEQ ID NO:100) evidences the presence of a variety of important polypeptide domains, wherein the locations given for those important polypeptide domains are approximate as described above. Analysis of the full-length PRO4980 polypeptide shown in FIG. 100 evidences the presence of the following: a signal peptide from about amino acid 1 to about amino acid 36; transmembrane domains from about amino acid 77 to about amino acid 95, from about amino acid 111 to about amino acid 133, from about amino acid 161 to about amino acid 184, from about amino acid 225 to about amino acid 248, from about amino acid 255 to about amino acid 273, from about amino acid 299 to about amino acid 314, from about amino acid 348 to about amino acid 373, from about amino acid 406 to about amino acid 421, from about amino acid 435 to about amino acid 456, and from about amino acid 480 to about amino acid 497; an N-glycosylation site from about amino acid 500 to about amino acid 504; a cAMP- and cGMP-dependent protein kinase phosphorylation site from about amino acid 321 to about amino acid 325; N-myristoylation sites from about amino acid 13 to about amino acid 19, from about amino acid 18 to about amino acid 24, from about amino acid 80 to about amino acid 86, from about amino acid 111 to about amino acid 117, from about amino acid 118 to about amino acid 124, from about amino acid 145 to about amino acid 151, from about amino acid 238 to about amino acid 244, from about amino acid 251 to about amino acid 257, from about amino acid 430 to about amino acid 436, from about amino acid 433 to about amino acid 439, from about amino acid 448 to about amino acid 454, from about amino acid 458 to about amino acid 464, from about amino acid 468 to about amino acid 474, from about amino acid 475 to about amino acid 481, from about amino acid 496 to about amino acid 502, and from about amino acid 508 to about amino acid

514; and a prokaryotic membrane lipoprotein lipid attachment site from about amino acid 302 to about amino acid 313. Clone DNA97003-2649 has been deposited with the ATCC on May 11, 1999 and is assigned ATCC deposit no. PTA-43.

[0879] An analysis of the Dayhoff database (version 35.45 SwissProt 35), using a WU-BLAST2 sequence alignment analysis of the full-length sequence shown in FIG. 100 (SEQ ID NO:100), evidenced significant homology between the PRO4980 amino acid sequence and the following Dayhoff sequences: SC59_YEAST, S76857, CELF31F4.sub.--12, AC002464.sub.--1, NU5M_CHOCR, S59109, SAY10108.sub.--2, AF055482.sub.--2, F69049, and G70433.

Example 50

Isolation of cDNA Clones Encoding Human PRO4981 Polypeptides [UNQ2423]

[0880] A cDNA clone (DNA94849-2960) encoding a native human PRO4981 polypeptide was identified using a yeast screen, in a human Human testis cDNA library that preferentially represents the 5' ends of the primary cDNA clones.

[0881] Clone DNA94849-2960 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 145-147 and ending at the stop codon at nucleotide positions 1690-1692 (FIG. 101; SEQ ID NO:101). The predicted polypeptide precursor is 515 amino acids long (FIG. 102; SEQ ID NO:102). The full-length PRO4981 protein shown in FIG. 102 has an estimated molecular weight of about 59357 daltons and a pI of about 9.40. Analysis of the full-length PRO4981 sequence shown in FIG. 102 (SEQ ID NO:102) evidences the presence of a variety of important polypeptide domains as shown in FIG. 102, wherein the locations given for those important polypeptide domains are approximate as described above. Clone DNA94849-2960 has been deposited with ATCC on Jul. 25, 2000 and is assigned ATCC deposit no. PTA-2306.

[0882] An analysis of the Dayhoff database (version 35.45 SwissProt 35), using the ALIGN-2 sequence alignment analysis of the full-length sequence shown in FIG. 102 (SEQ ID NO:102), evidenced sequence identity between the PRO4981 amino acid sequence and the following Dayhoff sequences: TMA272073.sub.--1, AK001324.sub.--1, AE003806.sub.--12, AE003745.sub.--18, MS2_ARATH, AF149917.sub.--1, ATMS2LIPR.sub.--1, HETM_ANASP, T18552, LYS2_YEAST.

Example 51

Isolation of cDNA Clones Encoding Human PRO5801 Polypeptides [UNQ2501]

[0883] The extracellular domain (ECD) sequences (including the secretion signal sequence, if any) from about 950 known secreted proteins from the Swiss-Prot public database were used to search EST databases. The EST databases included (1) public EST databases (e.g., GenBank) and (2) a proprietary EST database (LIFESEQ.RTM., Incyte Pharmaceuticals, Palo Alto, Calif.). The search was performed using the computer program BLAST or BLAST2 [Altschul et al., Methods in Enzymology, 266:460-480 (1996)] as a comparison of the ECD protein sequences to a 6 frame translation of the EST sequences. Those comparisons resulting in a BLAST score of 70 (or in some cases, 90) or greater that did not encode known proteins were clustered and assembled into consensus DNA sequences with the program "phrap" (Phil Green, University of Washington, Seattle, Wash.).

[0884] A consensus DNA sequence was assembled relative to other EST sequences using phrap as described above. This consensus sequence is herein designated DNA105850. In some cases, the consensus sequence derives from an intermediate consensus DNA sequence which was extended using repeated cycles of BLAST and phrap to extend that intermediate consensus sequence as far as possible using the sources of EST sequences discussed above.

[0885] Based on the DNA105850 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO5801. Forward and reverse PCR primers generally range from 20 to 30 nucleotides and are often designed to give a PCR product of about 100-1000 bp in length. The probe sequences are typically 40-55 by in length. In some cases, additional oligonucleotides are synthesized when the consensus sequence is greater than about 1-1.5 kbp. In order to screen several libraries for a full-length clone, DNA from the libraries was screened by PCR amplification, as per Ausubel et al., Current Protocols in Molecular Biology, supra, with the PCR primer pair. A positive library was then used to isolate clones encoding the gene of interest using the probe oligonucleotide and one of the primer pairs.

[0886] PCR primers (forward and reverse) were synthesized:

TABLE-US-00056 forward PCR primer 1 5'-ACTCCATATTTTCCTACTTGTGGCA-3' (SEQ ID NO: 230) forward PCR primer 2 5'-CCCAAAGTGACCTAAGAAC-3' (SEQ ID NO: 231) reverse PCR primer 5'-TCACTGAATTTCTTCAAAACCATTGCA-3' (SEQ ID NO: 232)

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA105850 sequence which had the following nucleotide sequence

TABLE-US-00057 hybridization probe (SEQ ID NO: 233) 5'-TGTGGCAGCGACTGCATCCGACATAAAGGAACAGTTGTGCTCTGC CCACA-3'

[0887] RNA for construction of the cDNA libraries was isolated from human fetal liver tissue. The cDNA libraries used to isolate the cDNA clones were constructed by standard methods using commercially available reagents such as those from Invitrogen, San Diego, Calif. The cDNA was primed with oligo dT containing a Nod site, linked with blunt to SalI hemikinased adaptors, cleaved with Not', sized appropriately by gel electrophoresis, and cloned in a defined orientation into a suitable cloning vector (such as pRKB or pRKD; pRK5B is a precursor of pRK5D that does not contain the SfiI site; see, Holmes et al., Science, 253:1278-1280 (1991)) in the unique XhoI and NotI sites.

[0888] DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for a full-length PRO5801 polypeptide (designated herein as DNA115291-2681 [FIG. 103, SEQ ID NO: 103]) and the derived protein sequence for that PRO5801 polypeptide.

[0889] The full length clone identified above contained a single open reading frame with an apparent translational initiation site at nucleotide positions 7-9 and a stop signal at nucleotide positions 1513-1515 (FIG. 103, SEQ ID NO:103). The predicted polypeptide precursor is 502 amino acids long, has a calculated molecular weight of approximately 55,884 daltons and an estimated pI of approximately 8.52. Analysis of the full-length PRO5801 sequence shown in FIG. 104 (SEQ ID NO:104) evidences the presence of a variety of important polypeptide domains as shown in FIG. 104, wherein the locations given for those important polypeptide domains are approximate as described above. Clone DNA115291-2681 has been deposited with ATCC on Jun. 8, 1999 and is assigned ATCC deposit no. PTA-202.

[0890] An analysis of the Dayhoff database shows that PRO5801 has sequence similarity to an IL-17 receptor protein and PRO5801 is also designated herein as IL-17RH1. Specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35), using the ALIGN-2 sequence alignment analysis of the full-length sequence shown in FIG. 104 (SEQ ID NO:104), evidenced sequence identity between the PRO5801 amino acid sequence and the following Dayhoff sequences: HSU58917.sub.--1, P_W92409, P_W61272, P_W04185, P_W61271, P_W04184, P_W92408, GEN13979, MMU31993.sub.--1 and YSO2_CAEEL.

Example 52

Isolation of cDNA Clones Encoding Human PRO5995 Polypeptides [UNQ2507]

[0891] The extracellular domain (ECD) sequences (including the secretion signal sequence, if any) from about 950 known secreted proteins from the Swiss-Prot public database were used to search EST databases. The EST databases included (1) public EST databases (e.g., Merck/Washington University) and (2) a proprietary EST database (LIFESEQ.RTM., Incyte Pharmaceuticals, Palo Alto, Calif.). The search was performed using the computer program BLAST or BLAST2 [Altschul et al., Methods in Enzymology, 266:460-480 (1996)] as a comparison of the ECD protein sequences to a 6 frame translation, of the EST sequences. Those comparisons resulting in a BLAST score of 70 (or in some cases, 90) or greater that did not encode known proteins were clustered and assembled into consensus DNA sequences with the program "phrap" (Phil Green, University of Washington, Seattle, Wash.).

[0892] A consensus DNA sequence was assembled relative to other EST sequences using phrap as described above. This consensus sequence is herein designated DNA92934. In some cases, the DNA92934 consensus sequence derives from an intermediate consensus DNA sequence which was extended using repeated cycles of BLAST and phrap to extend that intermediate consensus sequence as far as possible using the sources of EST sequences discussed above.

[0893] Based on the DNA92934 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO5995. Forward and reverse PCR primers generally range from 20 to 30 nucleotides and are often designed to give a PCR product of about 100-1000 bp in length. The probe sequences are typically 40-55 bp in length. In some cases, additional oligonucleotides are synthesized when the consensus sequence is greater than about 1-1.5 kbp. In order to screen several libraries for a full-length clone, DNA from the libraries was screened by PCR amplification, as per Ausubel et al., Current Protocols in Molecular Biology, supra, with the PCR primer pair. A positive library was then used to isolate clones encoding the gene of interest using the probe oligonucleotide and one of the primer pairs.

[0894] PCR primers (forward and reverse) were synthesized:

TABLE-US-00058 forward PCR primer 5'GGATCTCTTGTTCAAGCATCCTACCAAC 3' (SEQ ID NO: 234) reverse PCR primer 5'TGTCATCACTGCAAGTTAAGGCTTCCC 3' (SEQ ID NO: 235)

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA92934 sequence which had the following nucleotide sequence

TABLE-US-00059 hybridization probe (SEQ ID NO: 236) 5'CGTAGAGAAGTTATAATGCTGGCCTGCAGTTTTGGCAACAAGCAC TG 3'

[0895] RNA for construction of the cDNA libraries was isolated from human fetal kidney tissue. The cDNA libraries used to isolate the cDNA clones were constructed by standard methods using commercially available reagents such as those from Invitrogen, San Diego, Calif. The cDNA was primed with oligo dT containing a Nod site, linked with blunt to Sail hemikinased adaptors, cleaved with Nod, sized appropriately by gel electrophoresis, and cloned in a defined orientation into a suitable cloning vector (such as pRKB or pRKD; pRK5B is a precursor of pRK5D that does not contain the SfiI site; see, Holmes et al., Science, 253:1278-1280 (1991)) in the unique XhoI and NotI sites.

[0896] DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for a full-length PRO5995 polypeptide (designated herein as DNA96988-2685 [FIG. 105, SEQ ID NO: 105]) and the derived protein sequence for that PRO5995 polypeptide.

[0897] The full length clone identified above contained a single open reading frame with an apparent translational initiation site at nucleotide positions 24-26 and a stop signal at nucleotide positions 3096-3098 (FIG. 105, SEQ ID NO: 105). The predicted polypeptide precursor is 1024 amino acids long, has a calculated molecular weight of approximately 117049 daltons and an estimated pI of approximately 6.90. Analysis of the full-length PRO5995 sequence shown in FIG. 106 (SEQ ID NO: 106) evidences the presence of a variety of important polypeptide domains as shown in FIG. 106, wherein the locations given for those important polypeptide domains are approximate as described above. Clone DNA96988-2685 has been deposited with ATCC on Jul. 20, 1999 and is assigned ATCC Deposit No. PTA-384.

[0898] An analysis of the Dayhoff database (version 35.45 SwissProt 35), using the ALIGN-2 sequence alignment analysis of the full-length sequence shown in FIG. 106 (SEQ ID NO: 106), evidenced sequence identity between the PRO5995 amino acid sequence and the following Dayhoff sequences: 159331; AMPN_RAT; AMPN_HUMAN; AMPN_HUMAN; P_R94512; HUMPLAA.sub.--1; A65888.sub.--1; AAP1_YEAST; P_W33661; AF049234.sub.--1.

Example 53

Isolation of cDNA Clones Encoding Human PRO6095 Polypeptides [UNQ2543]

[0899] A cDNA clone (DNA105680-2710) encoding a native human PRO6095 polypeptide was identified using a yeast screen, in a human bone marrow cDNA library that preferentially represents the 5' ends of the primary cDNA clones.

[0900] Clone DNA105680-2710 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 372-374 and ending at the stop codon at nucleotide positions 458-460 (FIG. 109; SEQ ID NO:109). The predicted polypeptide precursor is 457 amino acids long (FIG. 110; SEQ ID NO:110). The full-length PRO6095 protein shown in FIG. 110 has an estimated molecular weight of about 52,015 daltons and a pI of about 9.22. Analysis of the full-length PRO6095 sequence shown in FIG. 110 (SEQ ID NO: 110) evidences the presence of a variety of important polypeptide domains as shown in FIG. 110, wherein the locations given for those important polypeptide domains are approximate as described above. Clone DNA105680-2710 has been deposited with ATCC on Aug. 3, 1999 and is assigned ATCC Deposit No. PTA-483.

[0901] An analysis of the Dayhoff database (version 35.45 SwissProt 35), using the ALIGN-2 sequence alignment analysis of the full-length sequence shown in FIG. 110 (SEQ ID NO: 110), evidenced sequence identity between the PRO6095 amino acid sequence and the following Dayhoff sequences: CELZC328.sub.--5, F15K.sub.--2, S59792, S78570, S53021, F1003.sub.--10, A57514, GAR2_SCHPO, A70387, and CELW09C3.sub.--4.

Example 54

Isolation of cDNA Clones Encoding Human PRO6182 Polypeptides [UNQ2553]

[0902] A cDNA clone (DNA110700-2716) encoding a native human PRO6182 polypeptide was identified using a yeast screen, in a human breast carcinoma cDNA library that preferentially represents the 5' ends of the primary cDNA clones.

[0903] Clone DNA110700-2716 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 18-20 and ending at the stop codon at nucleotide positions 1236-1238 (FIG. 111; SEQ ID NO:111). The predicted polypeptide precursor is 406 amino acids long (FIG. 112). The full-length PRO6182 protein shown in FIG. 112 has an estimated molecular weight of about 43,878 daltons and a pI of about 6.50. Analysis of the full-length PRO6182 sequence shown in FIG. 112 (SEQ ID NO: 112) evidences the presence of a variety of important polypeptide domains as shown in FIG. 112, wherein the locations given for those important polypeptide domains are approximate as described above. Clone DNA110700-2716 has been deposited with ATCC on Aug. 10, 1999 and is assigned ATCC Deposit No. PTA-512.

[0904] An analysis of the Dayhoff database (version 35.45 SwissProt 35), using the ALIGN-2 sequence alignment analysis of the full-length sequence shown in FIG. 112 (SEQ ID NO: 112), evidenced sequence identity between the PRO6182 amino acid sequence and the following Dayhoff sequences: AB011161.sub.--1; AC005542.sub.--2; EMU41602.sub.--1; HUMIGCH06.sub.--1; PTN8_MOUSE; HUMIGCH08.sub.--1; AF012848.sub.--1; S17597; P_P40254; DTC_HUMAN.

Example 55

Isolation of cDNA Clones Encoding Human PRO7170 Polypeptides [UNQ2782]

[0905] DNA108722-2743 was identified by applying a proprietary signal sequence finding algorithm developed by Genentech, Inc. (South San Francisco, Calif.) upon ESTs as well as clustered and assembled EST fragments from public (e.g., Genbank) and/or private (LIFESEQ.RTM., Incyte Pharmaceuticals, Inc., Palo Alto, Calif.) databases. The signal sequence algorithm computes a secretion signal score based on the character of the DNA nucleotides surrounding the first and optionally the second methionine codon(s) (ATG) at the 5'-end of the sequence or sequence fragment under consideration. The nucleotides following the first ATG must code for at least 35 unambiguous amino acids without any stop codons. If the first ATG has the required amino acids, the second is not examined. If neither meets the requirement, the candidate sequence is not scored. In order to determine whether the EST sequence contains an authentic signal sequence, the DNA and corresponding amino acid sequences surrounding the ATG codon are scored using a set of seven sensors (evaluation parameters) known to be associated with secretion signals.

[0906] Use of the above described signal sequence algorithm allowed identification of an EST cluster sequence from the LIFESEQ.RTM. database, Incyte Pharmaceuticals, Palo Alto, designated herein as CLU57836. This EST cluster sequence was then compared to a variety of expressed sequence tag (EST) databases which included public EST databases (e.g., Genbank) and a proprietary EST DNA database (LIFESEQ.RTM., Incyte Pharmaceuticals, Palo Alto, Calif.) to identify existing homologies. The homology search was performed using the computer program BLAST or BLAST2 (Altshul et al., Methods in Enzymology 266:460-480 (1996)). Those comparisons resulting in a BLAST score of 70 (or in some cases 90) or greater that did not encode known proteins were clustered and assembled into a consensus DNA sequence with the program "phrap" (Phil Green, University of Washington, Seattle, Wash.). The consensus sequence obtained therefrom is herein designated DNA58756.

[0907] In light of an observed sequence homology between the DNA58756 sequence and an EST sequence encompassed within clone no. 2251462 from the LIFESEQ.RTM. database, Incyte Pharmaceuticals, Palo Alto, Calif., clone no. 2251462 was purchased and the cDNA insert was obtained and sequenced. It was found herein that that cDNA insert encoded a full-length protein. The sequence of this cDNA insert is shown in FIG. 113 and is herein designated as DNA108722-2743.

[0908] Clone DNA108722-2743 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 60-62 and ending at the stop codon at nucleotide positions 1506-1508 (FIG. 113; SEQ ID NO:113). The predicted polypeptide precursor is 482 amino acids long (FIG. 114; SEQ ID NO:114). The full-length PRO7170 protein shown in FIG. 114 has an estimated molecular weight of about 49,060 daltons and a pI of about 4.74. Analysis of the full-length PRO7170 sequence shown in FIG. 114 (SEQ ID NO: 114) evidences the presence of a variety of important polypeptide domains as shown in FIG. 114, wherein the locations given for those important polypeptide domains are approximate as described above. Clone DNA108722-2743 has been deposited with ATCC on Aug. 17, 1999 and is assigned ATCC Deposit No. PTA-552.

[0909] An analysis of the Dayhoff database (version 35.45 SwissProt 35), using the ALIGN-2 sequence alignment analysis of the full-length sequence shown in FIG. 114 (SEQ ID NO: 114), evidenced sequence identity between the PRO7170 amino acid sequence and the following Dayhoff sequences: P_Y12291, I47141, D88733.sub.--1, DMC56G7.sub.--1, P_Y11606, HWP1_CANAL, HSMUC5BEX.sub.--1, HSU78550.sub.--1, HSU70136.sub.--1, and SGS3_DROME

Example 56

Isolation of cDNA Clones Encoding Human PRO7171 Polypeptides [UNQ2783]

[0910] DNA108670-2744 was identified by applying a proprietary signal sequence finding algorithm developed by Genentech, Inc. (South San Francisco, Calif.) upon ESTs as well as clustered and assembled EST fragments from public (e.g., Genbank) and/or private (LIFESEQ.RTM., Incyte Pharmaceuticals, Inc., Palo Alto, Calif.) databases. The signal sequence algorithm computes a secretion signal score based on the character of the DNA nucleotides surrounding the first and optionally the second methionine codon(s) (ATG) at the 5'-end of the sequence or sequence fragment under consideration. The nucleotides following the first ATG must code for at least 35 unambiguous amino acids without any stop codons. If the first ATG has the required amino acids, the second is not examined. If neither meets the requirement, the candidate sequence is not scored. In order to determine whether the EST sequence contains an authentic signal sequence, the DNA and corresponding amino acid sequences surrounding the ATG codon are scored using a set of seven sensors (evaluation parameters) known to be associated with secretion signals.

[0911] Use of the above described signal sequence algorithm allowed identification of an EST sequence from the LIFESEQ.RTM. database, Incyte Pharmaceuticals, Palo Alto, Calif., designated herein as 212369. This EST sequence was then compared to a variety of expressed sequence tag (EST) databases which included public EST databases (e.g., Genbank) and a proprietary EST DNA database (LLFESEQ.RTM., Incyte Pharmaceuticals, Palo Alto, Calif.) to identify existing homologies. The homology search was performed using the computer program BLAST or BLAST2 (Altshul et al., Methods in Enzymology 266:460-480 (1996)). Those comparisons resulting in a BLAST score of 70 (or in some cases 90) or greater that did not encode known proteins were clustered and assembled into a consensus DNA sequence with the program "phrap" (Phil Green, University of Washington, Seattle, Wash.). The consensus sequence obtained therefrom is herein designated DNA79089.

[0912] In light of an observed sequence homology between the DNA79089 sequence and an EST sequence encompassed within clone no. 212369 from the LIFESEQ.RTM. database, Incyte Pharmaceuticals, Palo Alto, Calif., clone no. 212369 was purchased and the cDNA insert was obtained and sequenced. It was found herein that that cDNA insert encoded a full-length protein. The sequence of this cDNA insert is shown in FIG. 115 and is herein designated as DNA108670-2744.

[0913] Clone DNA108670-2744 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 93-95 and ending at the stop codon at nucleotide positions 495-497 (FIG. 115; SEQ ID NO:115). The predicted polypeptide precursor is 134 amino acids long (FIG. 116; SEQ ID NO:116). The full-length PRO7171 protein shown in FIG. 116 has an estimated molecular weight of about 14,120 daltons and a pI of about 4.77. Analysis of the full-length PRO7171 sequence shown in FIG. 116 (SEQ ID NO: 116) evidences the presence of a variety of important polypeptide domains as shown in FIG. 116, wherein the locations given for those important polypeptide domains are approximate as described above. Clone

[0914] DNA108670-2744 has been deposited with ATCC on Aug. 17, 1999 and is assigned ATCC Deposit No. PTA-546.

[0915] An analysis of the Dayhoff database (version 35.45 SwissProt 35), using the ALIGN-2 sequence alignment analysis of the full-length sequence shown in FIG. 116 (SEQ ID NO: 116), evidenced sequence identity between the PRO7171 amino acid sequence and the following Dayhoff sequences: AC007504.sub.--28, AF103900.sub.--1, OPUD_BACSU, G69670, T02361, and TS11_GIALA.

Example 57

Isolation of cDNA Clones Encoding Human PRO7436 Polypeptides [UNQ2973]

[0916] DNA119535-2756 was identified by applying a proprietary signal sequence finding algorithm developed by Genentech, Inc. (South San Francisco, Calif.) upon ESTs as well as clustered and assembled EST fragments from public (e.g., Genbank) and/or private (LIFESEQ.RTM., Incyte Pharmaceuticals, Inc., Palo Alto, Calif.) databases. The signal sequence algorithm computes a secretion signal score based on the character of the DNA nucleotides surrounding the first and optionally the second methionine codon(s) (ATG) at the 5'-end of the sequence or sequence fragment under consideration. The nucleotides following the first ATG must code for at least 35 unambiguous amino acids without any stop codons. If the first ATG has the required amino acids, the second is not examined. If neither meets the requirement, the candidate sequence is not scored. In order to determine whether the EST sequence contains an authentic signal sequence, the DNA and corresponding amino acid sequences surrounding the ATG codon are scored using a set of seven sensors (evaluation parameters) known to be associated with secretion signals.

[0917] Use of the above described signal sequence algorithm allowed identification of an EST sequence from the LIFESEQ.RTM. database, Incyte Pharmaceuticals, Palo Alto, Calif., designated herein as 5325636. This EST sequence was then compared to a variety of expressed sequence tag (EST) databases which included public EST databases (e.g., Genbank) and a proprietary EST DNA database (LIFESEQ.RTM., Incyte Pharmaceuticals, Palo Alto, Calif.) to identify existing homologies. The homology search was performed using the computer program BLAST or BLAST2 (Altshul et al., Methods in Enzymology 266:460-480 (1996)). Those comparisons resulting in a BLAST score of 70 (or in some cases 90) or greater that did not encode known proteins were clustered and assembled into a consensus DNA sequence with the program "phrap" (Phil Green, University of Washington, Seattle, Wash.). The consensus sequence obtained therefrom is herein designated DNA105428.

[0918] In light of an observed sequence homology between the DNA105428 sequence and an EST sequence encompassed within clone no. 5325636 from the LIFESEQ.RTM. database, Incyte Pharmaceuticals, Palo Alto, Calif., clone no. 5325636 was purchased and the cDNA insert was obtained and sequenced. It was found herein that that cDNA insert encoded a full-length protein. The sequence of this cDNA insert is shown in FIG. 117 and is herein designated as DNA119535-2756.

[0919] Clone DNA119535-2756 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 211-213 and ending at the stop codon at nucleotide positions 1111-1113 (FIG. 117; SEQ ID NO:117). The predicted polypeptide precursor is 300 amino acids long (FIG. 118; SEQ ID NO:118). The full-length PRO7436 protein shown in FIG. 118 has an estimated molecular weight of about 32,638 daltons and a pI of about 6.02. Analysis of the full-length PRO7436 sequence shown in FIG. 118 (SEQ ID NO: 118) evidences the presence of a variety of important polypeptide domains as shown in FIG. 118, wherein the locations given for those important polypeptide domains are approximate as described above. Clone DNA119535-2756 has been deposited with ATCC on Aug. 31, 1999 and is assigned ATCC Deposit No. PTA-613.

[0920] An analysis of the Dayhoff database (version 35.45 SwissProt 35), using the ALIGN-2 sequence alignment analysis of the full-length sequence shown in FIG. 118 (SEQ ID NO: 118), evidenced sequence identity between the PRO7436 amino acid sequence and the following Dayhoff sequences: AC005955.sub.--1, CGM1_HUMAN, P_R22041, CCEM_HUMAN, P_R06434, P_P93996, CE10_MOUSE, HOM6PSG2.sub.--1, PSG6_HUMAN, and ECTO_RAT.

Example 58

Isolation of cDNA Clones Encoding Human PRO9912 Polypeptides [UNQ3077]

[0921] An expressed sequence tag (EST) DNA database LIFESEQ (Incyte Pharmaceuticals, Palo Alto, Calif.) was searched and an EST was identified which showed homology to autotaxin.

[0922] EST clone no. 2921845 was then purchased from LIFESEQ (Incyte Pharmaceuticals, Palo Alto, Calif.) and the cDNA insert of that clone was obtained and sequenced in entirety. The entire nucleotide sequence of the clone, designated herein as DNA108700-2802, is shown in FIG. 119 (SEQ ID NO: 119). The DNA108700-2802 clone contains a single open reading frame with an apparent translational initiation site at nucleotide positions 4-6 and a stop signal at nucleotide positions 1378-1380 (FIG. 119, SEQ ID NO:119). The predicted polypeptide precursor is 458 amino acids long, has a calculated molecular weight of approximately 51506 daltons and an estimated pI of approximately 6.79. Analysis of the full-length PRO9912 sequence shown in FIG. 120 (SEQ ID NO:120) evidences the presence of a variety of important polypeptide domains as shown in FIG. 120, wherein the locations given for those important polypeptide domains are approximate as described above. Clone DNA108700-2802 has been deposited with ATCC on Dec. 22, 1999 and is assigned ATCC deposit no. PTA-1093.

[0923] An analysis of the Dayhoff database (version 35.45 SwissProt 35), using the ALIGN-2 sequence alignment analysis of the full-length sequence shown in FIG. 120 (SEQ ID NO:120), evidenced sequence identity between the PRO9912 amino acid sequence and the following Dayhoff sequences: HS8B1.sub.--1, P_W75859, AB020686.sub.--1, P_Y17529, P_Y34324, T09933, PDNP3.sub.--1, PC1_HUMAN, HUMATXT.sub.--1 and P_R86595.

Example 59

Isolation of cDNA Clones Encoding Human PRO9917 Polypeptides [UNQ3079]

[0924] An expressed sequence tag (EST) DNA database LIFESEQ (Incyte Pharmaceuticals, Palo Alto, Calif.) was searched and an EST was identified which showed homology to a human prostate stem cell antigen.

[0925] EST clone no. 2498349 was then purchased from Incyte Pharmaceuticals, Palo Alto, Calif., and the cDNA insert of that clone was obtained and sequenced in entirety.

[0926] The entire nucleotide sequence of the clone, designated herein as DNA119474-2803, is shown in FIG. 121 (SEQ ID NO: 121). The DNA119474-2803 clone contains a single open reading frame with an apparent translational initiation site at nucleotide positions 121-123 and a stop signal at nucleotide positions 544-546 (FIG. 121, SEQ ID NO:121). The predicted polypeptide precursor is 141 amino acids long, has a calculated molecular weight of approximately 15240 daltons and an estimated pI of approximately 8.47. Analysis of the full-length PRO9917 sequence shown in FIG. 122 (SEQ ID NO:122) evidences the presence of a variety of important polypeptide domains as shown in FIG. 122, wherein the locations given for those important polypeptide domains are approximate as described above. Chromosome mapping evidences that the PRO9917-encoding nucleic acid maps to 2q21-q22 in humans. Clone DNA119474-2803 has been deposited with ATCC on Dec. 22, 1999 and is assigned ATCC deposit no. PTA-1097.

[0927] An analysis of the Dayhoff database (version 35.45 SwissProt 35), using the ALIGN-2 sequence alignment analysis of the full-length sequence shown in FIG. 122 (SEQ ID NO:122), evidenced sequence identity between the PRO9917 amino acid sequence and the following Dayhoff sequences: PSCA.sub.--1, P_W80956, AF043498.sub.--1, P_W70522, P_W86024, P_W62066, P_Y13938, P_Y13347, D45835 and HSU08839.sub.--1. Interestingly, the PRO9917 polypeptide lacks the GPI tail that almost all members of the Prostate Stem Cell Antigen (PSCA) family have.

Example 60

Isolation of cDNA Clones Encoding Human PRO19646 Polypeptides [UNQ5827]

[0928] The extracellular domain (ECD) sequences (including the secretion signal sequence, if any) from about 950 known secreted proteins from the Swiss-Prot public database were used to search EST databases. The EST databases included (1) public EST databases (e.g., GenBank), (2) a proprietary EST database (LIFESEQ.RTM., Incyte Pharmaceuticals, Palo Alto, Calif.), (3) a proprietary EST database from Genentech. The search was performed using the computer program BLAST or BLAST2 [Altschul et al., Methods in Enzymology, 266:460-480 (1996)] as a comparison of the ECD protein sequences to a 6 frame translation of the EST sequences. Those comparisons resulting in a BLAST score of 70 (or in some cases, 90) or greater that did not encode known proteins were clustered and assembled into consensus DNA sequences with the program "phrap" (Phil Green, University of Washington, Seattle, Wash.).

[0929] A consensus DNA sequence was assembled relative to other EST sequences using phrap as described above. This consensus sequence is herein designated DNA144267. In some cases, the consensus sequence derives from an intermediate consensus DNA sequence which was extended using repeated cycles of BLAST and phrap to extend that intermediate consensus sequence as far as possible using the sources of EST sequences discussed above.

[0930] Based on the DNA144267 consensus sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO19646. Forward and reverse PCR primers generally range from 20 to 30 nucleotides and are often designed to give a PCR product of about 100-1000 bp in length. The probe sequences are typically 40-55 bp in length. In some cases, additional oligonucleotides are synthesized when the consensus sequence is greater than about 1-1.5 kbp. In order to screen several libraries for a full-length clone, DNA from the libraries was screened by PCR amplification, as per Ausubel et al., Current Protocols in Molecular Biology, supra, with the PCR primer pair. A positive library was then used to isolate clones encoding the gene of interest using the probe oligonucleotide and one of the primer pairs.

[0931] PCR primers (forward and reverse) were synthesized:

TABLE-US-00060 (SEQ ID NO: 237) forward PCR primer 5' -- 3' GTCGCCCCATTTCCTGCAACAG (SEQ ID NO: 238) reverse PCR primer 5' -- 3' GGGCCTGCTCTCCCTCTGAAGC

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA144267 sequence which had the following nucleotide sequence

TABLE-US-00061 hybridization probe (SEQ ID NO: 239) 5' -- 3' GTGCTGGGCTCTGGAGCCACACTGCGTCTTCCGTC

[0932] RNA for construction of the cDNA libraries was isolated from human [identify tissue type] tissue. The cDNA libraries used to isolate the cDNA clones were constructed by standard methods using commercially available reagents such as those from Invitrogen, San Diego, Calif. The cDNA was primed with oligo dT containing a NotI site, linked with blunt to SalI hemikinased adaptors, cleaved with Not', sized appropriately by gel electrophoresis, and cloned in a defined orientation into a suitable cloning vector (such as pRK5B or pRK5D; pRK5B is a precursor of pRK5D that does not contain the SfiI site; see, Holmes et al., Science, 253:1278-1280 (1991)) in the unique XhoI and NotI sites.

[0933] DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for a full-length PRO19646 polypeptide (designated herein as DNA145841-2868 [FIG. 127, SEQ ID NO: 127]) and the derived protein sequence for that PRO19646 polypeptide.

[0934] The full length clone identified above contained a single open reading frame with an apparent translational initiation site at nucleotide positions 199-201 and a stop signal at nucleotide positions 2322-2324 (FIG. 127, SEQ ID NO:127). The predicted polypeptide precursor is 708 amino acids long, has a calculated molecular weight of approximately 75093 daltons and an estimated pI of approximately 6.65. Analysis of the full-length PRO19646 sequence shown in FIG. 128 (SEQ ID NO:128) evidences the presence of a variety of important polypeptide domains as shown in FIG. 128, wherein the locations given for those important polypeptide domains are approximate as described above. Clone DNA145841-2868 has been deposited with ATCC on Apr. 11, 2000 and is assigned ATCC deposit no. PTA-1678.

[0935] An analysis of the Dayhoff database (version 35.45 SwissProt 35), using the ALIGN-2 sequence alignment analysis of the full-length sequence shown in FIG. 128 (SEQ ID NO:128), evidenced sequence identity between the PRO19646 amino acid sequence and the following Dayhoff sequences: DMC163A10.sub.--1, ICCR_DROME, NM.sub.--004646.sub.--1, AF210316.sub.--1, PGBM_HUMAN, NM.sub.--002821.sub.--1, P_W83927, HSU33G35.sub.--1, MAG_HUMAN, NM.sub.--001771.sub.--1.

Example 61

Isolation of cDNA Clones Encoding Human PRO19820 Polypeptides [UNQ5926]

[0936] DNA149911-2885 was identified by applying a proprietary signal sequence finding algorithm developed by Genentech, Inc. (South San Francisco, Calif.) upon genomic DNA from public (e.g., GenBank) and/or private databases. In this instance, a genomic sequence from GenBank (Accession No:) was analyzed using the gene prediction program GENSCAN, licensed from Stanford University. GENSCAN analysis predicts gene coding regions by identifying the potential exons and removing introns, creating DNA sequences which are then subjected to the signal algorithm. The signal sequence algorithm computes a secretion signal score based on the character of the DNA nucleotides surrounding the first and optionally the second methionine codon(s) (ATG) at the 5'-end of the sequence or sequence fragment under consideration. The nucleotides following the first ATG must code for at least 35 unambiguous amino acids without any stop codons. In order to determine whether the sequence contains an authentic signal sequence, the DNA and corresponding amino acid sequences surrounding the ATG codon are scored using a set of seven sensors (evaluation parameters) known to be associated with secretion signals.

[0937] Use of the above described signal sequence algorithm allowed identification of a sequence from the GenBank database, designated herein as DNA144336.

[0938] Based on the DNA144336 sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO19820. Forward and reverse PCR primers generally range from 20 to 30 nucleotides and are often designed to give a PCR product of about 100-1000 bp in length. The probe sequences are typically 40-55 bp in length. In some cases, additional oligonucleotides are synthesized when the consensus sequence is greater than about 1-1.5 kbp. In order to screen several libraries for a full-length clone, DNA from the libraries was screened by PCR amplification, as per Ausubel et al., Current Protocols in Molecular Biology, supra, with the PCR primer pair. A positive library was then used to isolate clones encoding the gene of interest using the probe oligonucleotide and one of the primer pairs.

[0939] PCR primers (forward and reverse) were synthesized:

TABLE-US-00062 forward PCR primer 5' - AGCCCCAGGGAGCACAGGCT- 3' (SEQ ID NO: 240) reverse PCR primer 5' - GCTCGTCACGGCCATCTTCACC- 3' (SEQ ID NO: 241)

[0940] Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA144389 sequence which had the following nucleotide sequence

TABLE-US-00063 hybridization probe (SEQ ID NO: 242) 5' - TGCGACAGCGGCATCAGGCGGTTCTTC - 3'

[0941] RNA for construction of the cDNA libraries was isolated from human mixed tissue. The cDNA libraries used to isolate the cDNA clones were constructed by standard methods using commercially available reagents such as those from Invitrogen, San Diego, Calif. The cDNA was primed with oligo dT containing a NotI site, linked with blunt to SalI hemikinased adaptors, cleaved with NotI, sized appropriately by gel electrophoresis, and cloned in a defined orientation into a suitable cloning vector (such as pRK5B or pRK5D; pRK5B is a precursor of pRK5D that does not contain the SfiI site; see, Holmes et al., Science, 253:1278-1280 (1991)) in the unique XhoI and NotI sites.

[0942] DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for a full-length PRO19820 polypeptide (designated herein as DNA149911-2885 [FIG. 131, SEQ ID NO: 131]) and the derived protein sequence for that PRO19820 polypeptide.

[0943] Clone DNA149911-2885 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 9-11 and ending at the stop codon at nucleotide positions 342-344 (FIG. 131). The predicted polypeptide precursor is 111 amino acids long (FIG. 132; SEQ ID NO:132). The full-length PRO19820 protein shown in FIG. 132 has an estimated molecular weight of about 12447 daltons and a pI of about 8.31. Analysis of the full-length PRO19820 sequence shown in FIG. 132 (SEQ ID NO:132) evidences the presence of a variety of important polypeptide domains as shown in FIG. 132, wherein the locations given for those important polypeptide domains are approximate as described above. Clone DNA149911-2885 has been deposited with ATCC on Apr. 25, 2000 and is assigned ATCC deposit no. PTA-1776.

[0944] An analysis of the Dayhoff database (version 35.45 SwissProt 35), using the ALIGN-2 sequence alignment analysis of the full-length sequence shown in FIG. 132 (SEQ ID NO:132), evidenced sequence identity between the PRO19820 amino acid sequence and the following Dayhoff sequences: P_Y41705, NM.sub.--000727.sub.--1, G70864, CCG1_HUMAN, MNT_HUMAN, P_Y06527, T13049, P_W47524, AF030100.sub.--1, and RNAJ696.sub.--1.

Example 62

Isolation of cDNA Clones Encoding Human PRO21201 Polypeptides [UNQ6098]

[0945] DNA168028-2956 was identified by applying a proprietary signal sequence finding algorithm developed by Genentech, Inc. (South San Francisco, Calif.) upon genomic DNA from public (e.g., GenBank) and/or private databases. In this instance, a genomic sequence from GenBank (Accession No: Z98200) was analyzed using the gene prediction program GENS CAN, licensed from Stanford University. GENS CAN analysis predicts gene coding regions by identifying the potential exons and removing introns, creating DNA sequences which are then subjected to the signal algorithm. The signal sequence algorithm computes a secretion signal score based on the character of the DNA nucleotides surrounding the first and optionally the second methionine codon(s) (ATG) at the 5'-end of the sequence or sequence fragment under consideration. The nucleotides following the first ATG must code for at least 35 unambiguous amino acids without any stop codons. In order to determine whether the sequence contains an authentic signal sequence, the DNA and corresponding amino acid sequences surrounding the ATG codon are scored using a set of seven sensors (evaluation parameters) known to be associated with secretion signals.

[0946] Use of the above described signal sequence algorithm allowed identification of a sequence from the GenBank database, designated herein as DNA144330.

[0947] Based on the DNA144330 sequence, oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO21201. Forward and reverse PCR primers generally range from 20 to 30 nucleotides and are often designed to give a PCR product of about 100-1000 bp in length. The probe sequences are typically 40-55 bp in length. In some cases, additional oligonucleotides are synthesized when the consensus sequence is greater than about 1-1.5 kbp. In order to screen several libraries for a full-length clone, DNA from the libraries was screened by PCR amplification, as per Ausubel et al., Current Protocols in Molecular Biology, supra, with the PCR primer pair. A positive library was then used to isolate clones encoding the gene of interest using the probe oligonucleotide and one of the primer pairs.

[0948] PCR primers (forward and reverse) were synthesized:

TABLE-US-00064 forward PCR primer 5' - TCCACGACCTCCTGTCGGAGC - 3' (SEQ ID NO: 243) reverse PCR primer 5' - AGACCCTGTGCGGACTGCTGC - 3' (SEQ ID NO: 244)

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA144330 sequence which had the following nucleotide sequence

TABLE-US-00065 hybridization probe 5' - AGCCCCGACCACAGCAGCAGCCCC - 3' (SEQ ID NO: 245)

[0949] RNA for construction of the cDNA libraries was isolated from a mixture of human tissues. The cDNA libraries used to isolate the cDNA clones were constructed by standard methods using commercially available reagents such as those from Invitrogen, San Diego, Calif. The cDNA was primed with oligo dT containing a NotI site, linked with blunt to SalI hemikinased adaptors, cleaved with NotI, sized appropriately by gel electrophoresis, and cloned in a defined orientation into a suitable cloning vector (such as pRK5B or pRK5D; pRK5B is a precursor of pRK5D that does not contain the SfiI site; see, Holmes et al., Science, 253:1278-1280 (1991)) in the unique XhoI and NotI sites.

[0950] DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for a full-length PRO21201 polypeptide (designated herein as DNA168028-2956 [FIG. 133, SEQ ID NO: 133]) and the derived protein sequence for that PRO21201 polypeptide.

[0951] Clone DNA168028-2956 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 78-80 and ending at the stop codon at nucleotide positions 1080-1082 (FIG. 133). The predicted polypeptide precursor is 334 amino acids long (FIG. 134; SEQ ID NO:134). The full-length PRO21201 protein shown in FIG. 134 has an estimated molecular weight of about 37257 daltons and a pI of about 5.95. Analysis of the full-length PRO21201 sequence shown in FIG. 134 (SEQ ID NO:134) evidences the presence of a variety of important polypeptide domains as shown in FIG. 134, wherein the locations given for those important polypeptide domains are approximate as described above. Clone DNA168028-2956 has been deposited with ATCC on Jul. 25, 2000 and is assigned ATCC deposit no. PTA-2304.

[0952] An analysis of the Dayhoff database (version 35.45 SwissProt 35), using the ALIGN-2 sequence alignment analysis of the full-length sequence shown in FIG. 134 (SEQ ID NO:134), evidenced sequence identity between the PRO21201 amino acid sequence and the following Dayhoff sequences: NM.sub.--014028.sub.--1, AF077205.sub.--1, YR53_CAEEL and T22084.

Example 63

Isolation of cDNA Clones Encoding Human PRO20026 Polypeptides [UNQ6115]

[0953] The extracellular domain (ECD) sequences (including the secretion signal sequence, if any) from about 950 known secreted proteins from the Swiss-Prot public database were used to search EST databases. The EST databases included a proprietary EST database (LIFESEQ.RTM., Incyte Pharmaceuticals, Palo Alto, Calif.). The search was performed using the computer program BLAST or BLAST2 [Altschul et al., Methods in Enzymology, 266:460-480 (1996)] as a comparison of the ECD protein sequences to a 6 frame translation of the EST sequences. Those comparisons resulting in a BLAST score of 70 (or in some cases, 90) or greater that did not encode known proteins were clustered and assembled into consensus DNA sequences with the program "phrap" (Phil Green, University of Washington, Seattle, Wash.).

[0954] A consensus DNA sequence was assembled relative to other EST sequences using phrap as described above. This consensus sequence is herein designated DNA149870. In some cases, the DNA149870 consensus sequence derives from an intermediate consensus DNA sequence which was extended using repeated cycles of BLAST and phrap to extend that intermediate consensus sequence as far as possible using the sources of EST sequences discussed above.

[0955] Based on the DNA149870 consensus sequence, flip cloning was performed. Oligonucleotides were synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO20026. Forward and reverse PCR primers generally range from 20 to 30 nucleotides and are often designed to give a PCR product of about 100-1000 bp in length. The probe sequences are typically 40-55 bp in length. In some cases, additional oligonucleotides are synthesized when the consensus sequence is greater than about 1-1.5 kbp. In order to screen several libraries for a full-length clone, DNA from the libraries was screened by Flip PCR amplification, as per Schanke et al., BioTechniques, 16:414-416 (1994), with the PCR primer pair. A positive library was then used to isolate clones encoding the gene of interest using the probe oligonucleotide and one of the primer pairs.

[0956] PCR primers (forward and reverse) were synthesized:

TABLE-US-00066 forward PCR primer: 5'-CGTTGTTTGTCAGTGGAGAGCAGGG-3' (SEQ ID NO: 246) reverse PCR primer 5'-CAGGAACACCTGAGGCAGAAGCG-3' (SEQ ID NO: 247)

Additionally, a synthetic oligonucleotide hybridization probe was constructed from the consensus DNA149870 sequence which had the following nucleotide sequence

TABLE-US-00067 hybridization probe (SEQ ID NO: 248) 5'-CTATCTCCCTGCCAGGAGGCCGGAGTGGGGGAGGTCAGAC-3'

[0957] RNA for construction of the cDNA libraries was isolated from human tissue. The cDNA libraries used to isolate the cDNA clones were constructed by standard methods using commercially available reagents such as those from Invitrogen, San Diego, Calif. The cDNA was primed with oligo dT containing a NotI site, linked with blunt to SalI hemikinased adaptors, cleaved with Nod, sized appropriately by gel electrophoresis, and cloned in a defined orientation into a suitable cloning vector (such as pRKB or pRKD; pRK5B is a precursor of pRK5D that does not contain the SfiI site; see, Holmes et al., Science, 253:1278-1280 (1991)) in the unique XhoI and Nod sites.

[0958] DNA sequencing of the clones isolated as described above gave the full-length DNA sequence for a full-length PRO20026 polypeptide (designated herein as DNA154095-2998 [FIG. 135, SEQ ID NO: 135]) and the derived protein sequence for that PRO20026 polypeptide.

[0959] The full length clone identified above contained a single open reading frame with an apparent translational initiation site at nucleotide positions 70-72 and a stop signal at nucleotide positions 2254-2256 (FIG. 135, SEQ. ID NO: 135). The predicted polypeptide precursor is 728 amino acids long, has a calculated molecular weight of approximately 81,310 daltons and an estimated pI of approximately 6.84. Analysis of the full-length PRO20026 sequence shown in FIG. 136 (SEQ ID NO: 136) evidences the presence of a variety of important polypeptide domains as shown in FIG. 136, wherein the locations given for those important polypeptide domains are approximate as described above. Clone DNA154095-2998 has been deposited with ATCC on Oct. 10, 2000 and is assigned ATCC Deposit No. PTA-2591.

[0960] An analysis of the Dayhoff database shows that PRO20026 has sequence similarity to an IL-17 receptor protein and PRO2006 is also designated herein as IL-17RH4. Specifically, an analysis of the Dayhoff database (version 35.45 SwissProt 35), using the ALIGN-2 sequence alignment analysis of the full-length sequence shown in FIG. 136 (SEQ ID NO: 136), evidenced sequence identity between the PRO20026 amino acid sequence and the following Dayhoff sequences: T42695, P_W04185, P_W92409, P_W61272, NM.sub.--014339.sub.--1, HSU58917.sub.--1, MMU31993.sub.--1, GEN13979, P_W04184, P_W61271.

Example 64

Isolation of cDNA Clones Encoding Human PRO23202 Polypeptides [UNQ6507]

[0961] An expressed sequence tag (EST) DNA database (LIFESEQ.RTM., Incyte Pharmaceuticals, Palo Alto, Calif.) was searched and an EST was identified by GEPIS. Gene expression profiling in silico (GEPIS) is a bioinformatics tool that characterizes genes of interest for new therapeutic targets. GEPIS takes advantage of the vast amount of EST sequence and library information to determine gene expression profiles. GEPIS is based on the assumption that the expression level of a gene is proportionally correlated with the number of its occurrences in EST databases, and it works by integrating the Incyte EST relational database and Genentech proprietary information in a stringent and statistically meaningful way. In this example, it is used to identify and cross-validate new tumor antigens, although GEPIS can be configured to either perform very specific analyses or broad screening tasks. For the initial screen, GEPIS is used to go from libraries to sequence. The entire Incyte database was used to cluster sequence based on its library information. Breast, colon, lung and prostate were the target organs specified. The sequences found in this initial cluster were then subjected to a screen for secreted and transmembrane containing domains.

[0962] The remaining sequences were then screened for novelty and those individual sequences identified. In a final step, each individual sequence was then put through a GEPIS screen, this time going from sequence to library, confirming its expression profile in the original target tissue. Using this type of screening bioinformatics, DNA182753 was identified, and PCR primers designed using this sequence were used to screen libraries for the full length clone.

[0963] RNA for construction of cDNA libraries was then isolated from human prostate tissue. The cDNA libraries used to isolate the cDNA clones encoding human PRO23203 were constructed by standard methods using commercially available reagents such as those from Invitrogen, San Diego, Calif. The cDNA was primed with oligo dT containing a Nod site, linked with blunt to Sail hemikinased adaptors, cleaved with Nod, sized appropriately by gel electrophoresis, and cloned in a defined orientation into a suitable cloning vector (such as pRKB or pRKD; pRK5B is a precursor of pRK5D that does not contain the SfiI site; see, Holmes et al., Science, 253:1278-1280 (1991)) in the unique XhoI and NotI.

[0964] Oligonucleotides probes based upon the above described EST sequence were then synthesized: 1) to identify by PCR a cDNA library that contained the sequence of interest, and 2) for use as probes to isolate a clone of the full-length coding sequence for PRO23203. Forward and reverse PCR primers generally range from 20 to 30 nucleotides and are often designed to give a PCR product of about 100-1000 bp in length. The probe sequences are typically 40-55 bp in length. In order to screen several libraries for a full-length clone, DNA from the libraries was screened by PCR amplification, as per Ausubel et al., Current Protocols in Molecular Biology, supra, with the PCR primer pair. A positive library was then used to isolate clones encoding the gene of interest using the probe oligonucleotide and one of the primer pairs.

[0965] The oligonucleotide probes employed were as follows:

TABLE-US-00068 forward PCR primer (SEQ ID NO: 249) 5'-GATATTTGTTTCTCAACATGGCTTATCAGCAGG-3' reverse PCR primer (SEQ ID NO: 250) 5'-TCTCTGACCTTCTCATCGGTAAGCAGAGG-3' hybridization probe (SEQ ID NO: 251) 5'-TCTTTTGCAGCTTTGCAGATACCCAGACTGAGCTGGAACTGGA-3'

[0966] A full length clone [herein designated DNA185171-2994] was identified that contained a single open reading frame with an apparent translational initiation site at nucleotide positions 188-190 and a stop signal at nucleotide positions 1550-1552 (FIG. 139, SEQ ID NO:139). The predicted polypeptide precursor is 454 amino acids long, has a calculated molecular weight of approximately 52008 daltons and an estimated pI of approximately 8.83. Analysis of the full-length PRO23203 sequence shown in FIG. 140 (SEQ ID NO:140) evidences the presence of a variety of important polypeptide domains as shown in FIG. 140, wherein the locations given for those important polypeptide domains are approximate as described above. Clone DNA185171-2994 has been deposited with ATCC on Sep. 26, 2000 and is assigned ATCC deposit no. PTA-2513.

[0967] An analysis of the protein database (version 35.45 SwissProt 35), using the ALIGN-2 sequence alignment analysis of the full-length sequence shown in FIG. 140 (SEQ ID NO:140), evidenced sequence identity between the PRO23203 amino acid sequence and the following sequences:AK001691.sub.--1.

Example 65

Isolation of cDNA Clones Encoding Human PRO35250 Polypeptides [UNQ9574]

[0968] DNA 171732-3100 was identified by applying a proprietary signal sequence finding algorithm developed by Genentech, Inc. (South San Francisco, Calif.) upon ESTs as well as clustered and assembled EST fragments from public (e.g., GenBank) and/or private (LIFESEQ.RTM., Incyte Pharmaceuticals, Inc., Palo Alto, Calif.) databases. The signal sequence algorithm computes a secretion signal score based on the character of the DNA nucleotides surrounding the first and optionally the second methionine codon(s) (ATG) at the 5'-end of the sequence or sequence fragment under consideration. The nucleotides following the first ATG must code for at least 35 unambiguous amino acids without any stop codons. If the first ATG has the required amino acids, the second is not examined. If neither meets the requirement, the candidate sequence is not scored. In order to determine whether the EST sequence contains an authentic signal sequence, the DNA and corresponding amino acid sequences surrounding the ATG codon are scored using a set of seven sensors (evaluation parameters) known to be associated with secretion signals.

[0969] Use of the above described signal sequence algorithm allowed identification of an EST sequence from the LIFESEQ.RTM. (Incyte Pharmaceuticals, Palo Alto, Calif.) database, designated herein as 248197.2. The source of the EST sequence was a library prepared from right temporal lobe tissue removed from a 45-year-old black male during a brain lobectomy. cDNA synthesis was initiated using a Nod-anchored oligo(dT) primer. Double-stranded cDNA was blunted, ligated to EcoRI adaptors, digested with Nod, size-selected, and cloned into the NotI and EcoRI sites of the pINCY vector (Incyte). This EST sequence was then compared to a variety of expressed sequence tag (EST) databases which included public EST databases (e.g., GenBank) and a proprietary EST DNA database (LIFESEQ.RTM., Incyte Pharmaceuticals, Palo Alto, Calif.) to identify existing homologies. The homology search was performed using the computer program BLAST or BLAST2 (Altshul et al., Methods in Enzymology 266:460-480 (1996)). Those comparisons resulting in a BLAST score of 70 (or in some cases 90) or greater that did not encode known proteins were clustered and assembled into a consensus DNA sequence with the program "phrap" (Phil Green, University of Washington, Seattle, Wash.). The consensus sequence obtained therefrom is herein designated DNA130657.

[0970] In light of an observed sequence homology between the DNA130657 sequence and an EST sequence encompassed within clone no. 4028188 from the LIFESEQ.RTM. (Incyte Pharmaceuticals, Palo Alto, Calif.) database, clone no. 4028188 was purchased and the cDNA insert was obtained and sequenced. It was found herein that the cDNA insert encoded a full-length protein. The sequence of this cDNA insert is shown in FIG. 141 and is herein designated as DNA171732-3100.

[0971] Clone DNA171732-3100 contains a single open reading frame with an apparent translational initiation site at nucleotide positions 52-54 and ending at the stop codon at nucleotide positions 604-606 (FIG. 141; SEQ ID NO:141). The predicted polypeptide precursor is 184 amino acids long (FIG. 142; SEQ ID NO:142). The full-length PRO35250 protein shown in FIG. 142 has an estimated molecular weight of about 19,806 daltons and a pI of about 4.74. Analysis of the full-length PRO35250 sequence shown in FIG. 142 (SEQ ID NO:142) evidences the presence of a variety of important polypeptide domains as shown in FIG. 142, wherein the locations given for those important polypeptide domains are approximate as described above. Clone DNA171732-3100 has been deposited with ATCC on Apr. 24, 2001 and is assigned ATCC deposit no. PTA-3329.

[0972] An analysis of the Dayhoff database (version 35.45 SwissProt 35), using the ALIGN-2 sequence alignment analysis of the full-length sequence shown in FIG. 142 (SEQ ID NO:142), evidenced sequence identity between the PRO35250 amino acid sequence and the following Dayhoff sequence: AK003305.sub.--1.

Example 66

Generation and Analysis of Mice Comprising PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 Gene Disruptions

[0973] To investigate the role of PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides, disruptions in PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 genes were produced by homologous recombination or retroviral insertion techniques. Specifically, transgenic mice comprising disruptions in PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 genes (i.e., knockout mice) were created by either gene targeting or gene trapping. Mutations were confirmed by southern blot analysis to confirm correct targeting on both the 5' and 3' ends. Gene-specific genotyping was also performed by genomic PCR to confirm the loss of the endogenous native transcript as demonstrated by RT-PCR using primers that anneal to exons flanking the site of insertion. Targeting vectors were electroporated into 129 strain ES cells and targeted clones were identified. Targeted clones were microinjected into host blastocysts to produce chimeras. Chimeras were bred with C57 animals to produce F1 heterozygotes. Heterozygotes were intercrossed to produce F2 wildtype, heterozygote and homozygote cohorts which were used for phenotypic analysis. Rarely, if not enough F1 heterozygotes were produced, the F1 hets were bred to wildtype C57 mice to produce sufficient heterozygotes to breed for cohorts to be analyzed for a phenotype. All phenotypic analysis was performed from 12-16 weeks after birth.

Overall Summary of Phenotypic Results

[0974] 66.1. Generation and Analysis of Mice Comprising DNA284870 (UNQ128) Gene Disruptions

[0975] In these knockout experiments, the gene encoding PRO69122 polypeptides (designated as DNA284870) (UNQ128) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: AK005023 Mus musculus adult male liver cDNA, RIKEN full-length enriched library, clone:1300016D21 product:Sell (suppressor of lin-12) 1 homolog (C. elegans); protein reference: Q9Z2G6 ACCESSION:Q9Z2G6 NID: Mus musculus (Mouse). Sel-1 homolog precursor (Suppressor of lin-12-like protein) (Sel-1L); the human gene sequence reference: NM.sub.--005065 ACCESSION:NM.sub.--005065 NID:19923668 Homo sapiens Homo sapiens sel-1 suppressor of lin-12-like (C. elegans) (SEL1L); the human protein sequence corresponds to reference: Q9UBV2 ACCESSION:Q9UBV2 NID: Homo sapiens (Human). SEL-1 HOMOLOG PRECURSOR (SUPPRESSOR OF LIN-12-LIKE PROTEIN) (SEL-1L).

[0976] The mouse gene of interest is Sel1h (Sell [suppressor of lin-12] 1 homolog [C. elegans]), ortholog of human SEL1L (sel-1 suppressor of lin-12-like [C. elegans]). Aliases include IBD2; SEL1-LIKE; sel-1 (suppressor of lin-12, C. elegans)-like; and Suppressor of lin 12 (sel-1), C. elegans, homolog of.

[0977] SEL1L is an intracellular vesicle-associated protein, consisting of a signal peptide, a fibronectin type II domain, a transmembrane segment, and a proline-rich C terminus. Although the function of this protein is unknown, SEL1L has been proposed to play a role in processes such as Notch signaling, intracellular protein trafficking, secretion, cell growth inhibition, and tumor aggressiveness; the gene is expressed during pancreas development and in neural tube and dorsal root ganglia (Donoviel et al, Mech Dev 78(1-2):203-7 (1998); Cattaneo et al, Gene 326:149-56 (2004); Chiaramonte et al, Anticancer Res 22(6C):4211-4 (2002); Orlandi et al, Cancer Res 62(2):567-74 (2002); Biunno et al, Genomics 46(2):284-6 (1997); Grant and Greenwald, Development 124(3):637-44 (1997)).

[0978] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00069 wt het hom Total Observed 16 36 0 52 Expected 13.0 26.0 13.0 52

Chi-Sq.=33.49 Significance=5.3424262E-8 (hom/n)=0.0 Avg. Litter Size=8

Mutation Information

[0979] Mutation Type: Homologous Recombination (standard) Description: Coding exon 1 was targeted (NCBI accession NM.sub.--011344.1). Wild-type Expression Panel: Expression of the target gene was detected in embryonic stem (ES) cells and in all 13 adult tissue samples tested by RT-PCR. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[0980] 66.1.1. Phenotypic Analysis (for Disrupted Gene: DNA284870 (UNQ128)

[0981] (a) Overall Phenotypic Summary:

[0982] Mutation of the gene encoding the ortholog of human sel-1 suppressor of lin-12-like (C. elegans) (SEL1L) resulted in lethality of (-/-) mutants. Gene disruption was confirmed by Southern blot.

[0983] (b) Microarray Analysis

[0984] Tissue microarray analysis shows UNQ128 to be strongly expressed in the pancreas and down regulated in pancreatic carcinomas. In addition, UNQ128 is also overexpressed in breast tumors compared to normal breast tissue.

[0985] (c) Pathology

Microscopic: Not tested due to embryonic lethality. At 12.5 days, there were 40 embryos observed: 21(+/-) embryos, 2 (+/+) embryos, 4 resorption moles, 10 to-be-determined, and 3 inconclusive. Gene Expression LacZ activity was not detected in the panel of tissues by immunohistochemistry. Transverse sections of LacZ wholemounts in heterozygous embryos at 12.5 dpc shows expression in the inner layer of the retina; forelimb muscle; endothelium of the cranial vasculature and floor plate expression in the neural tube which is indicative of a role in neural patterning.

[0986] Discussion Related to Embryonic Developmental Abnormality of Lethality:

[0987] Embryonic lethality in knockout mice usually results from various serious developmental problems including but not limited to neurodegenerative diseases, angiogenic disorders, inflammatory diseases, or where the gene/protein has an important role in basic cell signaling processes in many cell types. In addition, embryonic lethals are useful as potential cancer models. Likewise, the corresponding heterozygous (+/-) mutant animals are particularly useful when they exhibit a phenotype and/or a pathology report which reveals highly informative clues as to the function of the knocked-out gene. For instance, EPO knockout animals were embryonic lethals, but the pathology reports on the embryos showed a profound lack of RBCs.

[0988] 66.2. Generation and Analysis of Mice Comprising DNA30871-1157 (UNQ178) Gene Disruptions

[0989] In these knockout experiments, the gene encoding PRO204 polypeptides (designated as DNA30871-1157) (UNQ178) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: NM.sub.--019790 Mus musculus transmembrane protein with EGF-like and two follistatin-like domains 2 (Tmeff2); protein reference: Q9QYM9 ACCESSION:Q9QYM9 NID: Mus musculus (Mouse). TMEFF2 PROTEIN PRECURSOR; the human gene sequence reference: NM.sub.--016192 ACCESSION:NM.sub.--016192 NID:12383050 Homo sapiens Homo sapiens transmembrane protein with EGF-like and two follistatin-like domains 2 (TMEFF2); the human protein sequence corresponds to reference:Q9UIK5 ACCESSION:Q9UIK5 NID: Homo sapiens (Human). TMEFF2 PROTEIN PRECURSOR (TRANSMEMBRANE PROTEIN TENB2) (TPEF) (TRANSMEMBRANE PROTEIN WITH EGF-LIKE AND TWO FOLLISTATIN-LIKE DOMAINS 2).

[0990] The mouse gene of interest is Tmeff2 (transmembrane protein with EGF-like and two follistatin-like domains 2), ortholog of human TMEFF2. Aliases include 4832418D20Rik, TR, HPP1, TPEF, TENB2, tomoregulin, transmembrane protein TENB2, and putative transmembrane protein with EGF-like and two follistatin-like domains 2.

[0991] TMEFF2 is a type I plasma membrane protein that may function as a protease inhibitor or signal transducing receptor. The protein contains a signal peptide, two Kazal-type serine protease inhibitor domains (Pfam accession PF00050), an EGF-like domain, a transmembrane segment, and a cytoplasmic C-terminal G protein-activating motif. TMEFF2 undergoes ectodomain shedding to produce a secreted form, consisting of the protease domains and the EGF-like domain. The extracellular segment of TMEFF2 is capable of stimulating tyrosine phosphorylation of receptor tyrosine kinase ERBB4, suggesting that TMEFF2 functions as a signal-transducing ligand. Moreover, the TMEFF2 extracellular segment can increase survival of cultured neurons, suggesting that TMEFF2 functions as a survival factor. TMEFF2 gene is hypermethylated in several types of cancer, and ectopic TMEFF2 gene expression in prostate cancer cell lines inhibits growth, suggesting that TMEFF2 functions as a tumor suppressor. TMEFF2 is primarily expressed in distinct subsets of neurons in brain but is also expressed in colon, bladder, prostate, and several other tissues. A monoclonal antibody reactive with TMEFF2 and conjugated with the cytotoxic agent auristatin-E has been validated in mice as a treatment for prostate cancer (Uchida et al, Biochem Biophys Res Commun 266(2):593-602 (1999); Horie et al, Genomics 67(2):146-52 (2000); Liang et al, Cancer Res 60(17):4907-12 (2000); Lin et al, Life Sci 73(13):1617-27 (2003); Gery et al, Oncogene 21(31):4739-46 (2002); Gery and Koeffler, J Mol Biol 328(5):977-83 (2003); Afar et al, Mol Cancer Ther 3(8):921-32 (2004)).

[0992] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00070 wt het hom Total Observed 23 39 20 82 Expected 20.5 41.0 20.5 82

Chi-Sq.=1.02 Significance=0.6004956 (hom/n)=0.29 Avg. Litter Size=8

Mutation Information

[0993] Mutation Type Homologous Recombination (standard) Description: Coding exons 1 and 2 were targeted (NCBI accession NM.sub.--019790.2). 1. Wild-type Expression Panel: Expression of the target gene was detected in embryonic stem (ES) cells and in all 13 adult tissue samples tested by RT-PCR, except bone. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[0994] 66.2.1. Phenotypic Analysis (for Disrupted Gene: DNA30871-1157 (UNQ178)

[0995] (a) Overall Phenotypic Summary:

[0996] Mutation of the gene encoding the ortholog of human transmembrane protein with EGF-like and two follistatin-like domains 2 (TMEFF2) resulted in small (-/-) mice that failed to thrive. The homozygous mutant mice were small and sickly, with several dying by 3 weeks of age. The remaining homozygous mutants were transferred to necropsy, where microscopic analysis revealed leukopenia and bone marrow hypoplasia. In addition, there was widespread apoptosis and loss of T lymphocytes in the thymic cortex and depletion of T cell areas in the spleen. Leukopenia and bone marrow hypoplasia were noted in the (-/-) mice. Gene disruption was confirmed by Southern blot.

[0997] (b) Pathology Assay-Specific Summary

Gross: The homozygous mutant mice were small and failed to thrive, exhibiting body weights less than half that of normal age-matched wild-type mice. Most organs were small in proportion to reduced overall weight in the (-/-) mice. The spleen and thymus were especially reduced in size compared with the wildtype littermate controls. Microscopic: The (-/-) mice exhibited leukopenia, due to both lymphopenia and granulocytopenia, and granulocytic hypoplasia of bone marrow. The bone marrow was diffusely hypoplastic in (-/-) mice, with normal amounts of erythropoiesis but markedly decreased numbers of myeloid granulocytic cell precursors, suggesting that decreased granulocytopoiesis caused the leukopenia. There was widespread apoptosis and loss of T lymphocytes in the thymic cortex and depletion of T cell areas in the spleen. Thymic involution is a common finding in stressed or severely ill mice and often results in lymphopenia. Gene Expression LacZ activity was not detected in the panel of tissues by immunohistochemical analysis.

[0998] (c) Bone Metabolism & Body Diagnostics

[0999] (1) Tissue Mass & Lean Body Mass Measurements--Dexa

[1000] Dexa Analysis--Test Description:

[1001] Procedure: A cohort of 4 wild type and 4 heterozygotes and 8 homozygotes were tested in this assay. Dual Energy X-ray Absorptiometry (DEXA) has been used successfully to identify changes in total tissue mass (TTM).

[1002] The mouse was anesthetized by intraperitoneal injection of Avertin (1.25% 2,2,2,-tribromoethanol, 20 ml/kg body weight), body length and weight were measured, and then the mouse was placed in a prone position on the platform of the PIXImus.TM. Densitometer (Lunar Inc.) for a DEXA scan. Using Lunar PIXImus software, the bone mineral density (BMD) and fat composition (% fat) and total tissue mass (TTM) were determined in the regions of interest (ROI, i.e., whole body, vertebrae, and both femurs).

[1003] Results: Obvious: The (-/-) mice were small and sickly, with several dying by 3 weeks of age. Of the surviving (-/-) mutants, 6 were transferred to necropsy at 3 weeks of age and the rest were euthanized for pathology at 3.5 weeks of age.

[1004] 66.3. Generation and Analysis of Mice Comprising DNA32286-1191 (UNQ188) Gene Disruptions

[1005] In these knockout experiments, the gene encoding PRO214 polypeptides (designated as DNA32286-1191) (UNQ188) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: NM.sub.--133930 ACCESSION:NM.sub.--133930 NID: gi 19527147 ref NM.sub.--133930.1 Mus musculus cysteine-rich with EGF-like domains 1 (Creld1); protein reference:Q91XD7 ACCESSION:Q91XD7 NID: Mus musculus (Mouse). UNKNOWN; the human gene sequence reference: NM.sub.--015513 ACCESSION:NM.sub.--015513 NID: gi 22095396 ref NM.sub.--015513.2 Homo sapiens cysteine-rich with EGF-like domains 1 (CRELD1); the human protein sequence corresponds to reference:Q9Y409 ACCESSION:Q9Y409 NID: Homo sapiens (Human). HYPOTHETICAL 44.9 KDA PROTEIN.

[1006] The mouse gene of interest is Creld1 (cysteine-rich with EGF-like domains 1), ortholog of human CRELD1. Aliases include AVSD2, CIRRIN, DKFZP566D213, and atrioventricular septal defect 2. CRELD1 is a type III plasma membrane protein that may function as a cell adhesion molecule. The protein contains a signal peptide, a tryptophan- and glutamate-rich (WE) domain, a tandem array of EGF-like repeats, and two C-terminal transmembrane segments separated by a short cytoplasmic domain. Mutations in the CRELD1 gene may increase the risk of developing atrioventricular septal defect (Robinson et al, Am J Hum Genet. 72(4):1047-52 (2003); Rupp et al, Gene 293(1-2):47-57 (2002)).

[1007] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00071 wt het hom Total Observed 16 30 0 46 Expected 11.5 23.0 11.5 46

Chi-Sq.=34.36 Significance=3.4579656E-8 (hom/n)=0.0 Avg. Litter Size=8

Mutation Information

[1008] Mutation Type: Homologous Recombination (standard) Description: Coding exons 1 and 2 were targeted (NCBI accession NM.sub.--133930.1). 1. Wild-type Expression Panel: Expression of the target gene was detected in all 13 adult tissue samples tested by RT-PCR, except adipose and stomach, small intestine, and colon. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[1009] 66.3.1. Phenotypic Analysis (for Disrupted Gene: DNA32286-1191 (UNQ188)

[1010] (a) Overall Phenotypic Summary:

[1011] Mutation of the gene encoding the ortholog of human cysteine-rich with EGF-like domains 1 (CRELD1) resulted in lethality of (-/-) mutants. Gene disruption was confirmed by Southern blot.

[1012] (b) Pathology

Microscopic: Not tested due to embryonic lethality. At 12.5 days, there were 50 embryos observed: 19 (+/-) embryos, 13 (+/+) embryos, 16 resorption moles, and 2 inconclusive.

[1013] Discussion Related to Embryonic Developmental Abnormality of Lethality:

[1014] Embryonic lethality in knockout mice usually results from various serious developmental problems including but not limited to neuro-degenerative diseases, angiogenic disorders, inflammatory diseases, or where the gene/protein has an important role in basic cell signaling processes in many cell types. In addition, embryonic lethals are useful as potential cancer models. Likewise, the corresponding heterozygous (+/-) mutant animals are particularly useful when they exhibit a phenotype and/or a pathology report which reveals highly informative clues as to the function of the knocked-out gene. For instance, EPO knockout animals were embryonic lethals, but the pathology reports on the embryos showed a profound lack of RBCs.

[1015] UNQ188 deficient mice have heart defects and die about mid-gestation from cardiac insufficiency. Ex vivo analysis shows that UNQ188 is required for endothelial cell migration during heart development, defining the developmental pathway for UNQ188 function in the embryonic heart.

[1016] 66.4. Generation and Analysis of Mice Comprising DNA33107-1135 (UNQ196) Gene Disruptions

[1017] In these knockout experiments, the gene encoding PRO222 polypeptides (designated as DNA33107-1135) (UNQ196) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: NM.sub.--144796 Mus musculus RIKEN cDNA E430021N18 gene (E430021N18Rik); protein reference: Q8BH32 ACCESSION:Q8BH32 NID: Mus musculus (Mouse). Mus musculus 16 days neonate cerebellum cDNA, RIKEN full-length enriched library, clone:9630004A14 product:hypothetical Sushi domain/SCR repeat/CCP module containing protein, full insert sequence (Mus musculus 2 days neonate thymus thymic cells cDNA, RIKEN full-length enriched library, clone:E430021N18 product:hypothetical Sushi domain/SCR repeat/CCP module containing protein, full insert sequence); the human gene sequence reference: AY358495 Homo sapiens clone DNA33107 YHGM196 (UNQ196); the human protein sequence corresponds to reference: Q6UX62 ACCESSION:Q6UX62 NID: Homo sapiens (Human). YHGM196.

[1018] The mouse gene of interest is RIKEN cDNA E430021N18 gene, ortholog of human "clone DNA33107 YHGM196" (YHGM196). Aliases include MGC30368 and UNQ196.

[1019] YHGM196 is a putative type I plasma membrane protein, consisting of a signal peptide, four sushi domains, a transmembrane segment, and a cytoplasmic C terminus. The function of this protein is not known; however, sushi domains are frequently found in cell adhesion molecules and complement (Pfam accession PF00084).

[1020] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00072 wt het hom Total Observed 14 43 19 76 Expected 19.0 38.0 19.0 76

Chi-Sq.=0.04 Significance=0.9801987 (hom/n)=0.25 Avg. Litter Size=9 Mutation Type Homologous Recombination (standard) Description: Coding exon 1 (NCBI accession NM.sub.--144796.2) and the preceding noncoding exon (NCBI accession BM944003) were targeted. 1. Wild-type Expression Panel: Expression of the target gene was detected in embryonic stem (ES) cells and in all 13 adult tissue samples tested by RT-PCR, except skeletal muscle; bone; and stomach, small intestine, and colon. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[1021] 66.4.1. Phenotypic Analysis (for Disrupted Gene: DNA33107-1135 (UNQ196)

[1022] (a) Overall Phenotypic Summary:

[1023] Mutation of the gene encoding the ortholog of human "clone DNA33107 YHGM196" (YHGM196) resulted in decreased systolic blood pressure in the (-/-) mice. In addition, the mutant (-/-) mice showed increased mean serum IgG3 levels compared with the control (+/+) littermates. Gene disruption was confirmed by Southern blot.

[1024] (b) Microarray Analysis

[1025] Microarray analysis reveals that UNQ196 is overexpressed or upregulated in breast cancer compared to normal breast tissue. In addition, UNQ196 is expressed in the embryonic mammary gland.

[1026] (c) Immunology Phenotypic Analysis

[1027] Immune related and inflammatory diseases are the manifestation or consequence of fairly complex, often multiple interconnected biological pathways which in normal physiology are critical to respond to insult or injury, initiate repair from insult or injury, and mount innate and acquired defense against foreign organisms. Disease or pathology occurs when these normal physiological pathways cause additional insult or injury either as directly related to the intensity of the response, as a consequence of abnormal regulation or excessive stimulation, as a reaction to self, or as a combination of these.

[1028] Though the genesis of these diseases often involves multistep pathways and often multiple different biological systems/pathways, intervention at critical points in one or more of these pathways can have an ameliorative or therapeutic effect. Therapeutic intervention can occur by either antagonism of a detrimental process/pathway or stimulation of a beneficial process/pathway.

[1029] T lymphocytes (T cells) are an important component of a mammalian immune response. T cells recognize antigens which are associated with a self-molecule encoded by genes within the major histocompatibility complex (MHC). The antigen may be displayed together with MHC molecules on the surface of antigen presenting cells, virus infected cells, cancer cells, grafts, etc. The T cell system eliminates these altered cells which pose a health threat to the host mammal. T cells include helper T cells and cytotoxic T cells. Helper T cells proliferate extensively following recognition of an antigen-MHC complex on an antigen presenting cell. Helper T cells also secrete a variety of cytokines, i.e., lymphokines, which play a central role in the activation of B cells, cytotoxic T cells and a variety of other cells which participate in the immune response.

[1030] In many immune responses, inflammatory cells infiltrate the site of injury or infection. The migrating cells may be neutrophilic, eosinophilic, monocytic or lymphocytic as can be determined by histologic examination of the affected tissues. Current Protocols in Immunology, ed. John E. Coligan, 1994, John Wiley & Sons, Inc.

[1031] Many immune related diseases are known and have been extensively studied. Such diseases include immune-mediated inflammatory diseases (such as rheumatoid arthritis, immune mediated renal disease, hepatobiliary diseases, inflammatory bowel disease (IBD), psoriasis, and asthma), non-immune-mediated inflammatory diseases, infectious diseases, immunodeficiency diseases, neoplasia, and graft rejection, etc. In the area of immunology, targets were identified for the treatment of inflammation and inflammatory disorders.

[1032] In the area of immunology, targets have been identified herein for the treatment of inflammation and inflammatory disorders. Immune related diseases, in one instance, could be treated by suppressing the immune response. Using neutralizing antibodies that inhibit molecules having immune stimulatory activity would be beneficial in the treatment of immune-mediated and inflammatory diseases. Molecules which inhibit the immune response can be utilized (proteins directly or via the use of antibody agonists) to inhibit the immune response and thus ameliorate immune related disease.

[1033] The following test was performed:

[1034] Serum Immunoglobulin Isotyping Assay:

[1035] The Serum Immunoglobulin Isotyping Assay is performed using a Cytometric Bead Array (CBA) kit. This assay is used to rapidly identify the heavy and light chain isotypes of a mouse monoclonal antibody in a single sample. The values expressed are "relative fluorescence units" and are based on the detection of kappa light chains. Any value <6 is not significant.

[1036] Results:

[1037] The (-/-) mice exhibited increased mean serum IgG3 levels compared to their gender-matched (+/+) littermate controls, the (+/+) mice for the project run and the historical median.

[1038] The serum immunoglobulin isotyping assay revealed that homozygous adults exhibited increased serum IgG3 levels. Thus, homozygotes showed elevated serum immunoglobulins compared with the (+/+) littermates. IgG3 immunoglobulins have neutralization effects and to a lesser extent are important for activation of the complement system. These immunological abnormalities suggest that antagonists or inhibitors of PRO222 polypeptides would stimulate the immune system and would find utility in the cases wherein this effect would be beneficial to the individual such as in the case of leukemia, and other types of cancer, and in immunocompromised patients, such as AIDS sufferers. Accordingly, PRO222 polypeptides or agonists thereof acting as a negative regulator would inhibit the immune response and would be useful candidates for suppressing harmful immune responses, e.g. in the case of graft rejection or graft-versus-host diseases.

[1039] (d) Cardiology--Blood Pressure

Test Description: Systolic blood pressure is measured via a noninvasive tail-cuff method for four days on the Visitech BP-2000 Blood Pressure Analysis System. The blood pressure is measured ten times each day for four days. The four days are then averaged to obtain a mouse's conscious systolic blood pressure.

[1040] Results

[1041] The (-/-) mice exhibited decreased mean systolic blood pressure (1 SD below the historic means) when compared with that of their gender-matched (+/+) littermates and the historical mean.

[1042] 66.5. Generation and Analysis of Mice Comprising DNA35557-1137 (UNQ208) Gene Disruptions

[1043] In these knockout experiments, the gene encoding PRO234 polypeptides (designated as DNA3557-1137) (UNQ208) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: XM.sub.--146887 PREDICTED: Mus musculus RIKEN cDNA E030012M19 gene (E030012M19Rik); protein reference: XP.sub.--146887 similar to layilin [Mus musculus]; the human gene sequence reference: NM.sub.--178834 Homo sapiens layilin (LOC143903); the human protein sequence corresponds to reference: Q96NF3 ACCESSION:Q96NF3 NID: Homo sapiens (Human). cDNA FLJ30977 FIS, CLONE HHDPC2000095, HIGHLY SIMILAR TO CRICETULUS GRISEUS LAYILIN.

[1044] The mouse gene of interest is RIKEN cDNA E030012M19 gene, ortholog of human layilin. Aliases include Gm511.

[1045] Layilin is a type I integral plasma membrane protein that likely functions as a cell adhesion molecule or receptor. The protein binds with the extracellular matrix protein hyaluronan and associates with cytoskeletal adaptor protein talin. Layilin likely plays a role in processes such as cell adhesion, motility, and wound healing (Borowsky and Hynes, J Cell Biol 143(2):429-42 (1998); Bono et al, Mol Biol Cell 12(4):891-900 (2001)).

[1046] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00073 wt het hom Total Observed 23 39 10 72 Expected 18 36 18 72

Mutation Type: Homologous Recombination (standard) Description: Coding exons 1 through 3 were targeted (NCBI accession XM.sub.--146887.3). Chi-Sq.=3.56 Significance=0.16863815 (hom/n)=0.23 Avg. Litter Size=9 1. Wild-type Expression Panel: Expression of the target gene was detected in embryonic stem (ES) cells and in all 13 adult tissue samples tested by RT-PCR, except skeletal muscle and bone. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[1047] 66.5.1. Phenotypic Analysis (for Disrupted Gene: DNA35557-1137 (UNQ208)

[1048] (a) Overall Phenotypic Summary:

[1049] Mutation of the gene encoding the ortholog of human layilin resulted in about half the expected numbers of homozygotes genotyped. The male (-/-) mice also exhibited decreased mean lean body mass. In addition, the male knockout mice showed decreased bone mineral content (BMC) and decreased bone mineral density (BMD) in total body, femurs, and vertebrae. Gene disruption was confirmed by Southern blot.

[1050] (b) Bone Metabolism & Body Diagnostics/Radiology Phenotypic Analysis

[1051] In the area of bone metabolism, targets were identified herein for the treatment of arthritis, osteoporosis, osteopenia and osteopetrosis as well as identifying targets that promote bone healing. Tests included: [1052] DEXA for measurement of bone mineral density on femur and vertebra [1053] MicroCT for very high resolution and very high sensitivity measurements of bone mineral density for both trabecular and cortical bone.

[1054] Dexa Analysis--Test Description:

[1055] Procedure: A cohort of 4 wild type, 4 heterozygotes and 8 homozygotes were tested in this assay. Dual Energy X-ray Absorptiometry (DEXA) has been used successfully to identify changes in bone. Anesthetized animals were examined and bone mineral content (BMC), BMC/LBM ratios, volumetric bone mineral density (vBMD), total body BMD, femur BMD and vertebra BMD were measured.

[1056] The mouse was anesthetized by intraperitoneal injection of Avertin (1.25% 2,2,2,-tribromoethanol, 20 ml/kg body weight), body length and weight were measured, and then the mouse was placed in a prone position on the platform of the PIXImus.TM. Densitometer (Lunar Inc.) for a DEXA scan. Using Lunar PIXImus software, the bone mineral density (BMD) and fat composition (% fat) and total tissue mass (TTM) were determined in the regions of interest (ROI) [i.e., whole body, vertebrae, and both femurs].

[1057] Results:

[1058] Mutant (-/-) mice deficient in the gene encoding PRO234 polypeptides show a phenotype consistent with tissue wasting diseases marked by decreased lean body mass. In addition, the male knockout mice showed decreased bone mineral content (BMC) and decreased bone mineral density (BMD) in total body, femurs and vertebrae. Thus, the (-/-) mice showed signs of tissue wasting disease and bone metabolism abnormalities which are commonly associated with osteoporosis. PRO234 polypeptides or agonists thereof would be useful for bone healing or for treating bone related disorders such as osteoporosis, whereas antagonists or inhibitors of PRO234 polypeptides would mimic the negative bone phenotype.

[1059] 66.6. Generation and Analysis of Mice Comprising DNA36350-1158 (UNQ232) Gene Disruptions

[1060] In these knockout experiments, the gene encoding PRO265 polypeptides (designated as DNA36350-1158) (UNQ232) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: NM.sub.--201518 Mus musculus fibronectin leucine rich transmembrane protein 2 (Flrt2); protein reference: Q8BLU0 ACCESSION:Q8BLU0 NID: Mus musculus (Mouse). Mus musculus adult male aorta and vein cDNA, RIKEN full-length enriched library, clone:A530098L04 product:KIAA0405 (LEUCINE-RICH REPEAT TRANSMEMBRANE PROTEIN FLRT2) homolog (Fibronectin leucine rich transmembrane protein 2); the human gene sequence reference: NM.sub.--013231 Homo sapiens fibronectin leucine rich transmembrane protein 2 (FLRT2); the human protein sequence corresponds to reference: O43155 ACCESSION:O43155 NID: Homo sapiens (Human). Leucine-rich repeat transmembrane protein FLRT2 precursor (Fibronectin-like domain-containing leucine-rich transmembrane protein 2) (UNQ232/PRO265).

[1061] The mouse gene of interest is Flrt2 (fibronectin leucine rich transmembrane protein 2), ortholog of human FLRT2. Aliases include KIAA0405.

[1062] FLRT2 is a putative type I plasma membrane protein expressed in pancreas, skeletal muscle, brain, and heart. The protein contains a signal peptide, several leucine-rich repeats, a fibronectin domain, a transmembrane segment, and a short cytoplasmic C terminus. FLRT2 is likely to function in receptor signaling (Lacy et al, Genomics 62(3):417-26 (1999); FLRT3 promotes neurite outgrowth and is upregulated upon nerve damage [Bottcher et al, Nat Cell Biol 6(1):38-44 (2004)].

[1063] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00074 wt het hom Total Observed 25 46 2 73 Expected 18.25 36.5 18.25 73

Chi-Sq.=39.54 Significance=2.5941669E-9 (hom/n)=0.03 Avg. Litter Size=8

Mutation Information

[1064] Mutation Type Homologous Recombination (standard) Description: Coding exon 1 was targeted (NCBI accession NM.sub.--201518.1). 1. Wild-type Expression Panel: Expression of the target gene was detected in all 13 adult tissue samples tested by RT-PCR, except skeletal muscle and bone. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[1065] 66.6.1. Phenotypic Analysis (for Disrupted Gene: DNA36350-1158 (UNQ232)

[1066] (a) Overall Phenotypic Summary:

[1067] Mutation of the gene encoding the ortholog of human fibronectin leucine rich transmembrane protein 2 (FLRT2) resulted in greatly reduced viability of (-/-) mutants. Genetic data indicate that this mutation resulted in greatly reduced viability of the homozygous mutants. Three of the identified (-/-) mice were embryonic submissions. The 2 surviving mutant mice were smaller than their wild-type littermates and exhibited numerous abnormalities, including a hearing impairment. Microscopic analysis revealed cardiomyopathy in the homozygous mutants, leading to heart failure. In addition, the female homozygous and heterozygous mice exhibited increased skin fibroblast proliferation rates. In addition, the surviving knockout mice exhibited several immunological abnormalities marked by increased mean serum IgG2a and IgG1 levels. However, a single (-/-) mouse also exhibited decreased serum TNF-alpha, MCP-1 and IL-6 responses to LPS challenge. The surviving (-/-) mice also exhibited decreased total tissue mass, decreased percentage of body fat and decreased fat mass. The female knockout mice showed decreased volumetric bone mineral density (vBMD) and total body mineral bone density (BMD). The male (-/-) mice exhibited increased micro-CT bone measurements. The single female (-/-) mouse also showed a dilated optic disc. Gene disruption was confirmed by Southern blot.

[1068] (b) Pathology

Microscopic: At 12.5 days, there were 51 embryos observed: 3 (-/-) embryos, 22 (+/-) embryos, 11 (+/+) embryos, 8 resorption moles, and 7 inconclusive. The 3 (-/-) embryos available for analysis exhibited cardiomyopathy, characterized by tightly packed myocytes with highly condensed eosinophilic sarcoplasm. These small dense myocytes were arranged in thin bands that formed the thin walls and trabeculae of the ventricles and atria. The myocytes were surrounded by increased numbers of large primitive endocardial cells that partially filled the ventricular lumen. There was diffuse vascular congestion in the abdominal organs with dilatation of vessels in the embryo, suggesting that congestive heart failure resulted from defective myocardial development. The living (-/-) embryos were generally smaller than their (+/+) littermates, but there was also evidence of embryonic death and resorption at necropsy. The defective structure and arrangement of the cardiac myocytes apparently led to a progressive decrease in prenatal cardiac function, development of heart failure, and embryonic death. Gene Expression: LacZ activity was detected in the parathyroid among the panel of tissues analyzed by immunohistochemistry.

[1069] (c) Phenotypic Analysis: CNS/Neurology

[1070] In the area of neurology, analysis focused herein on identifying in vivo validated targets for the treatment of neurological and psychiatric disorders including depression, generalized anxiety disorders, attention deficit hyperactivity disorder, obsessive compulsive disorder, schizophrenia, cognitive disorders, hyperalgesia and sensory disorders. Neurological disorders include the category defined as "anxiety disorders" which include but are not limited to: mild to moderate anxiety, anxiety disorder due to a general medical condition, anxiety disorder not otherwise specified, generalized anxiety disorder, panic attack, panic disorder with agoraphobia, panic disorder without agoraphobia, posttraumatic stress disorder, social phobia, specific phobia, substance-induced anxiety disorder, acute alcohol withdrawal, obsessive compulsive disorder, agoraphobia, bipolar disorder I or II, bipolar disorder not otherwise specified, cyclothymic disorder, depressive disorder, major depressive disorder, mood disorder, substance-induced mood disorder. In addition, anxiety disorders may apply to personality disorders including but not limited to the following types: paranoid, antisocial, avoidant behavior, borderline personality disorders, dependent, histronic, narcissistic, obsessive-compulsive, schizoid, and schizotypal.

[1071] Procedure:

[1072] Behavioral screens were performed on a cohort of 4 wild type, 4 heterozygous and 2 homozygous mutant mice. All behavioral tests were done between 12 and 16 weeks of age unless reduced viability necessitates earlier testing.

[1073] Prepulse Inhibition of the Acoustic Startle Reflex

[1074] Prepulse inhibition of the acoustic startle reflex occurs when a loud 120 decibel (dB) startle-inducing tone is preceded by a softer (prepulse) tone. The PPI paradigm consists of six different trial types (70 dB background noise, 120 dB alone, 74 dB+120 dB-pp 4, 78 dB+120 dB-pp 8, 82 dB+120 dB-pp 12, and 90 dB+120 dB-pp 20) each repeated in pseudo random order six times for a total of 36 trials. The max response to the stimulus (V max) is averaged for each trial type. Animals with a 120 dB average value equal to or below 100 are excluded from analysis. The percent that the prepulse inhibits the animal's response to the startle stimulus is calculated and graphed.

[1075] Results:

Sensorimotor Gating/Attention: Both of the mutant (-/-) mice failed to exhibit a startle response, suggesting hearing impairment in the mutants.

[1076] (d) Immunology Phenotypic Analysis

[1077] Immune related and inflammatory diseases are the manifestation or consequence of fairly complex, often multiple interconnected biological pathways which in normal physiology are critical to respond to insult or injury, initiate repair from insult or injury, and mount innate and acquired defense against foreign organisms. Disease or pathology occurs when these normal physiological pathways cause additional insult or injury either as directly related to the intensity of the response, as a consequence of abnormal regulation or excessive stimulation, as a reaction to self, or as a combination of these.

[1078] Though the genesis of these diseases often involves multistep pathways and often multiple different biological systems/pathways, intervention at critical points in one or more of these pathways can have an ameliorative or therapeutic effect. Therapeutic intervention can occur by either antagonism of a detrimental process/pathway or stimulation of a beneficial process/pathway.

[1079] T lymphocytes (T cells) are an important component of a mammalian immune response. T cells recognize antigens which are associated with a self-molecule encoded by genes within the major histocompatibility complex (MHC). The antigen may be displayed together with MHC molecules on the surface of antigen presenting cells, virus infected cells, cancer cells, grafts, etc. The T cell system eliminates these altered cells which pose a health threat to the host mammal. T cells include helper T cells and cytotoxic T cells. Helper T cells proliferate extensively following recognition of an antigen-MHC complex on an antigen presenting cell. Helper T cells also secrete a variety of cytokines, i.e., lymphokines, which play a central role in the activation of B cells, cytotoxic T cells and a variety of other cells which participate in the immune response.

[1080] In many immune responses, inflammatory cells infiltrate the site of injury or infection. The migrating cells may be neutrophilic, eosinophilic, monocytic or lymphocytic as can be determined by histologic examination of the affected tissues. Current Protocols in Immunology, ed. John E. Coligan, 1994, John Wiley & Sons, Inc.

[1081] Many immune related diseases are known and have been extensively studied. Such diseases include immune-mediated inflammatory diseases (such as rheumatoid arthritis, immune mediated renal disease, hepatobiliary diseases, inflammatory bowel disease (IBD), psoriasis, and asthma), non-immune-mediated inflammatory diseases, infectious diseases, immunodeficiency diseases, neoplasia, and graft rejection, etc. In the area of immunology, targets were identified for the treatment of inflammation and inflammatory disorders.

[1082] In the area of immunology, targets have been identified herein for the treatment of inflammation and inflammatory disorders. Immune related diseases, in one instance, could be treated by suppressing the immune response. Using neutralizing antibodies that inhibit molecules having immune stimulatory activity would be beneficial in the treatment of immune-mediated and inflammatory diseases. Molecules which inhibit the immune response can be utilized (proteins directly or via the use of antibody agonists) to inhibit the immune response and thus ameliorate immune related disease.

[1083] The following test was performed:

[1084] Serum Immunoglobulin Isotyping Assay:

[1085] The Serum Immunoglobulin Isotyping Assay is performed using a Cytometric Bead Array (CBA) kit. This assay is used to rapidly identify the heavy and light chain isotypes of a mouse monoclonal antibody in a single sample. The values expressed are "relative fluorescence units" and are based on the detection of kappa light chains. Any value <6 is not significant.

[1086] Results:

[1087] Serum Immunoglobulin isotyping resulted in the observation that (-/-) mice exhibited an increase in mean serum IgG2a and IgG1 levels compared to the (+/+) littermates, the (+/+) mice within the project run, and the historical means.

[1088] Mutant (-/-) mice exhibited elevation of IgG2a and IgG1 serum immunoglobulins compared to their gender-matched (+/+) littermates. These immunoglobulins have neutralization effects and to a lesser extent are important for activation of the complement system. The observed phenotype suggests that the PRO265 polypeptide is a negative regulator of inflammatory responses. These immunological abnormalities suggest that inhibitors (antagonists) of PRO265 polypeptides would be important agents which could stimulate the immune system and would find utility in the cases wherein this effect would be beneficial to the individual such as in the case of leukemia, and other types of cancer, and in immunocompromised patients, such as AIDS sufferers. Accordingly, PRO265 polypeptides or agonists thereof would be useful in inhibiting the immune response and would be useful candidates for suppressing harmful immune responses, e.g. in the case of graft rejection or graft-versus-host diseases.

[1089] Acute Phase Response:

[1090] Test Description: Bacterial lipopolysaccharide (LPS) is an endotoxin, and as such is a potent inducer of an acute phase response and systemic inflammation. The Level I LPS mice were injected intraperitoneally (i.p.) with a sublethal dose of LPS in 200 .mu.L sterile saline using a 26 gauge needle. The doses were based on the average weight of the mice tested at 1 .mu.g/g body weight 3 hours after injection; a 100 ul blood sample was then taken and analyzed for the presence of TNFa, MCP-1, and IL-6 on the FACSCalibur instrument.

[1091] Results:

[1092] The (-/-) mice exhibited decreased mean serum TNF-alpha, MCP-1 and IL-6 responses to LPS challenge when compared with their (+/+) littermates and the historical means.

[1093] In summary, the LPS endotoxin challenge demonstrated that knockout mice deficient in the gene encoding PRO265 polypeptides exhibit immunological abnormalities when compared with their wild-type littermates. In particular, the mutant mice exhibited a decreased ability to elicit an immunological response (TNF-alpha, MCP-1 and IL-6 production) when challenged with the LPS endotoxin indicating a decreased inflammatory response. TNF-alpha, MCP-1 and IL-6 contributes to the later stages of B cell activation. In addition, IL-6 plays a critical role in inducing the acute phase response and systemic inflammation.

[1094] (e) Phenotypic Analysis: Metabolism--Blood Chemistry

[1095] In the area of metabolism, targets may be identified for the treatment of diabetes. Blood chemistry phenotypic analysis includes blood glucose measurements. The COBAS Integra 400 (mfr: Roche) was used for running blood chemistry tests on the mice. In addition to measuring blood glucose levels the following blood chemistry tests are also routinely performed: Alkaline Phosphatase; Alanine Amino-Transferase; Albumin; Bilirubin; Phosphorous; Creatinine; BUN=Blood Urea Nitrogen; Calcium; Uric Acid; Sodium; Potassium; and Chloride. In the area of metabolism, targets may be identified for the treatment of diabetes.

[1096] Results:

[1097] The single male and female (-/-) mice available for analysis exhibited increased uric acid and potassium levels when compared with their gender-matched (+/+) littermate controls and historical means. Thus, mutant (-/-) mice exhibit a negative phenotype associated with notably elevated uric acid in the blood which is indicative of renal calculi (and associated kidney diseases) which is common in a type of gout (abnormal purine metabolism). The heterozygous (+/-) mice also trended higher than the wild-type (+/+) littermate controls. PRO265 polypeptides and agonists thereof would be useful in the treatment of such diseases associated with formation of renal calculi and/or abnormal purine metabolism. In addition, the mutant mice showed decreased mean serum glucose levels which could be associated with the reduced viability of these mice.

[1098] (f) Adult Skin Cell Proliferation:

[1099] Procedure: Skin cells were isolated from 16 week old animals (wild type, heterozygous and 1 homozygous). These were developed into primary fibroblast cultures and the fibroblast proliferation rates were measured in a strictly controlled protocol. The ability of this assay to detect hyper-proliferative and hypo-proliferative phenotypes has been demonstrated with p53 and Ku80. Proliferation was measured using Brdu incorporation.

[1100] Specifically, in these studies the skin fibroblast proliferation assay was used. An increase in the number of cells in a standardized culture was used as a measure of relative proliferative capacity. Primary fibroblasts were established from skin biopsies taken from wild type and mutant mice. Duplicate or triplicate cultures of 0.05 million cells were plated and allowed to grow for six days. At the end of the culture period, the number of cells present in the culture was determined using a electronic particle counter.

[1101] Results:

[1102] One third (1/3) of the heterozygous (+/-) mice exhibited an increased mean skin fibroblast proliferation rate when compared with their gender-matched (+/+) littermates. In addition, the single (-/-) mouse also showed elevated proliferation.

[1103] Thus, both homozygous and heterozygous mutant mice demonstrated a hyper-proliferative phenotype. As suggested by these observations, PRO265 polypeptides or agonists thereof could function as tumor suppressors and would be useful in decreasing abnormal cell proliferation.

[1104] (g) Bone Metabolism & Body Diagnostics

[1105] (1) Tissue Mass & Lean Body Mass Measurements--Dexa

[1106] Dexa Analysis--Test Description:

[1107] Procedure: A cohort of 4 wild type, 4 heterozygotes and 1 homozygote were tested in this assay. Dual Energy X-ray Absorptiometry (DEXA) has been used successfully to identify changes in total tissue mass (TTM).

[1108] The mouse was anesthetized by intraperitoneal injection of Avertin (1.25% 2,2,2,-tribromoethanol, 20 ml/kg body weight), body length and weight were measured, and then the mouse was placed in a prone position on the platform of the PIXImus.TM. Densitometer (Lunar Inc.) for a DEXA scan. Using Lunar PIXImus software, the bone mineral density (BMD) and fat composition (% fat) and total tissue mass (TTM) were determined in the regions of interest (ROI, i.e., whole body, vertebrae, and both femurs).

[1109] Body Measurements (Body Length & Weight):

[1110] Body Measurements: A measurement of body length and weight was performed at approximately 16 weeks of age.

[1111] Results:

[1112] The single male (-/-) mouse exhibited decreased mean body weight and mean body length (2-3 SD below the mean) when compared with their gender-matched (+/+) littermates and the historical mean.

[1113] Fertility:

[1114] The single male (-/-) mouse available for analysis produced no pups after mating twice with female (+/+) mice thus demonstrating impaired fertility.

[1115] (2) Bone Metabolism: Radiology Phenotypic Analysis

[1116] In the area of bone metabolism, targets were identified herein for the treatment of arthritis, osteoporosis, osteopenia and osteopetrosis as well as identifying targets that promote bone healing. Tests included: [1117] DEXA for measurement of bone mineral density on femur and vertebra [1118] MicroCT for very high resolution and very high sensitivity measurements of bone mineral density for both trabecular and cortical bone.

[1119] Dexa Analysis--Test Description:

[1120] Procedure: A cohort of 4 wild type, 4 heterozygotes and 2 homozygotes were tested in this assay. Dual Energy X-ray Absorptiometry (DEXA) has been used successfully to identify changes in bone. Anesthetized animals were examined and bone mineral content (BMC), BMC/LBM ratios, volumetric bone mineral density (vBMD), total body BMD, femur BMD and vertebra BMD were measured.

[1121] The mouse was anesthetized by intraperitoneal injection of Avertin (1.25% 2,2,2,-tribromoethanol, 20 ml/kg body weight), body length and weight were measured, and then the mouse was placed in a prone position on the platform of the PIXImus.TM. Densitometer (Lunar Inc.) for a DEXA scan. Using Lunar PIXImus software, the bone mineral density (BMD) and fat composition (% fat) and total tissue mass (TTM) were determined in the regions of interest (ROI) [i.e., whole body, vertebrae, and both femurs].

[1122] Bone MicroCT Analysis:

[1123] Procedure: MicroCT was also used to get very sensitive measurements of BMD. One vertebra and 1 femur were taken from a cohort of 4 wild type and 2 homozygous mice. Measurements were taken of lumbar 5 veterbra traebecular bone volume, traebecular thickness, connectivity density and midshaft femur total bone area and cortical thickness. The .mu.CT40 scans provided detailed information on bone mass and architecture. Multiple bones were placed into sample holders and scanned automatically. Instrument software was used to select regions of interest for analysis. Trabecular bone parameters were analyzed in the fifth lumbar vertebrae (LV5) at 16 micrometer resolution and cortical bone parameters were analyzed in the femur midshaft at a resolution of 20 micrometers.

[1124] Results:

DEXA: The single male and single female (-/-) mice available for analysis exhibited decreased total tissue mass, total fat mass, and percent total body fat when compared with their gender-matched (+/+) littermates and the historical means. In addition, the female knockouts also showed decreased volumetric bone mineral density (vBMD) and total body bone mineral density (BMD). Micro CT: The single male (-/-) mouse available for analysis (M-225) exhibited increased vertebral trabecular bone volume, number, and connectivity density when compared with its gender-matched (+/+) littermates and the historical means. This is interesting because the mouse is smaller in size.

[1125] The (-/-) mice analyzed by DEXA and bone micro CT analysis exhibited decreased bone measurements and decreased body mass measurements when compared with their (+/+) littermates, suggestive of abnormal bone disorders. In addition, the knockout mice exhibited decreased total tissue mass and body fat suggestive of growth related disorders and/or tissue wasting diseases such as cachexia. These results are consistent with the reduced viability of the (-/-) mice. The (-/-) mice also exhibited a negative bone phenotype with abnormal decreased bone measurements reflective of bone metabolic disorders. The negative bone and metabolic phenotype indicates that PRO265 polypeptides or agonists thereof would be useful for maintaining bone homeostasis or useful for treatment of other metabolic disorders. In addition, PRO265 polypeptides would be useful in bone healing or for the treatment of arthritis or osteoporosis, whereas antagonists (or inhibitors) of PRO265 polypeptides or its encoding gene would lead to abnormal or pathological bone disorders including inflammatory diseases associated with abnormal bone metabolism including arthritis, osteoporosis and osteopenia.

[1126] (h) Heart Rate:

Test Description: Heart rate is measured via a noninvasive tail-cuff method for four days on the Visitech BP-2000 Blood Pressure Analysis System. Heart rate is measured ten times each day for four days. The four days are then averaged to obtain a mouse's conscious heart rate.

[1127] Results:

[1128] The single surviving female (-/-) mouse available for analysis exhibited a notably decreased heart rate (.about.3 SD below the mean) when compared with its gender-matched (+/+) littermates and the historical mean. These results are consistent with the pathology report indicating a progressive decrease in cardiac function.

[1129] 66.7. Generation and Analysis of Mice Comprising DNA61601-1223 (UNQ272) Gene Disruptions

[1130] In these knockout experiments, the gene encoding PRO309 polypeptides (designated as DNA61601-1223) (UNQ272) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: NM.sub.--013781 Mus musculus SH2 domain containing 3C (Sh2d3c); protein reference: Q9QZS8 ACCESSION:Q9QZS8 NID: Mus musculus (Mouse). SH2 domain-containing EPH receptor-binding protein SHEP1 (CHAT-H); the human gene sequence reference: BC032365 ACCESSION:BC032365 NID:21619056 Homo sapiens Homo sapiens, SH2 domain-containing 3C, clone MGC:40418 IMAGE:4521962; the human protein sequence corresponds to reference: Q8N5H7 ACCESSION:Q8N5H7NID: Homo sapiens (Human). SH2 domain-containing 3C.

[1131] The mouse gene of interest is Sh2d3c (SH2 domain containing 3C), ortholog of human SH2D3C. Aliases include Chat, Nsp3, Shep1, novel SH2-containing protein 3, Cas/HEF1-associated signal transducer, SH2 domain-containing 3C, and SH2-containing Eph receptor-binding protein 1.

[1132] SH2D3C is a cytoplasmic protein that functions as a signal-transducing adaptor molecule, linking small Ras superfamily GTPases to activated receptor-tyrosine kinases. The protein consists of an SH2 domain and a Ras guanine nucleotide exchange factor domain, suggesting that SH2D3C may also function as a guanine nucleotide exchange factor. SH2D3C binds with GTPases R-Ras and Rap1A, with scaffolding protein Crk-associated substrate (Cas), and with receptor tyrosine kinase EphB2. Moreover, SH2D3C may also function as an adaptor for epidermal growth factor receptor, nerve growth factor receptor, T-cell receptors, and integrins. SH2D3C likely regulates processes such as membrane ruffling, cell migration, T-cell activation, and cytokine production (Dail et al, J Biol Chem 279(40):41892-902 (2004); Sakakibara et al, J Biol Chem 278(8):6012-7 (2003); Sakakibara et al, J Cell Sci 115 (Pt 24):4915-24 (2002); Sakakibara and Hattori, J Biol Chem 275(9):6404-10 (2000); Dodelet et al, J Biol Chem 274(45):31941-6 (1999)).

[1133] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00075 wt het hom Total Observed 21 44 13 78 Expected 19.5 39.0 19.5 78

Chi-Sq.=1.66 Significance=0.43604928 (hom/n)=0.22 Avg. Litter Size=8

Mutation Information

[1134] Mutation Type Homologous Recombination (standard) Description: Coding exons 4 through 6 were targeted (NCBI accession NM.sub.--013781.2). 1. Wild-type Expression Panel: Expression of the target gene was detected in embryonic stem (ES) cells and in all 13 adult tissue samples tested by RT-PCR. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[1135] 66.7.1. Phenotypic Analysis (for Disrupted Gene: DNA61601-1223 (UNQ272)

[1136] (a) Overall Phenotypic Summary:

[1137] Mutation of the gene encoding the ortholog of human SH2 domain containing 3C(SH2D3C) resulted in a decreased percentage of CD21hi CD23med B cells in spleen in (-/-) mice. In addition, the (-/-) mice showed decreased mean body weight, decreased mean total tissue mass and lean body mass. Male knockout (-/-) mice exhibited a notably decreased vertebrae bone mineral density (BMD). Gene disruption was confirmed by Southern blot.

[1138] (b) Bone Metabolism & Body Diagnostics

[1139] (1) Tissue Mass & Lean Body Mass Measurements--Dexa

[1140] Dexa Analysis--Test Description:

[1141] Procedure: A cohort of 4 wild type, 4 heterozygotes and 8 homozygotes were tested in this assay. Dual Energy X-ray Absorptiometry (DEXA) has been used successfully to identify changes in total tissue mass (TTM).

[1142] The mouse was anesthetized by intraperitoneal injection of Avertin (1.25% 2,2,2,-tribromoethanol, 20 ml/kg body weight), body length and weight were measured, and then the mouse was placed in a prone position on the platform of the PIXImus.TM. Densitometer (Lunar Inc.) for a DEXA scan. Using Lunar PIXImus software, the bone mineral density (BMD) and fat composition (% fat) and total tissue mass (TTM) were determined in the regions of interest (ROI, i.e., whole body, vertebrae, and both femurs).

[1143] Body Measurements (Body Length & Weight):

[1144] Body Measurements: A measurement of body weight was performed at approximately 16 weeks of age.

[1145] Results:

[1146] The male (-/-) mice exhibited decreased mean body weight when compared with their gender-matched (+/+) littermates and the historical mean.

[1147] (2) B one Metabolism: Radiology Phenotypic Analysis

[1148] In the area of bone metabolism, targets were identified herein for the treatment of arthritis, osteoporosis, osteopenia and osteopetrosis as well as identifying targets that promote bone healing. Tests included: [1149] DEXA for measurement of bone mineral density on femur and vertebra [1150] MicroCT for very high resolution and very high sensitivity measurements of bone mineral density for both trabecular and cortical bone.

[1151] Dexa Analysis--Test Description:

[1152] Procedure: A cohort of 4 wild type, 4 heterozygotes and 8 homozygotes were tested in this assay. Dual Energy X-ray Absorptiometry (DEXA) has been used successfully to identify changes in bone. Anesthetized animals were examined and bone mineral content (BMC), BMC/LBM ratios, volumetric bone mineral density (vBMD), total body BMD, femur BMD and vertebra BMD were measured.

[1153] The mouse was anesthetized by intraperitoneal injection of Avertin (1.25% 2,2,2,-tribromoethanol, 20 ml/kg body weight), body length and weight were measured, and then the mouse was placed in a prone position on the platform of the PIXImus.TM. Densitometer (Lunar Inc.) for a DEXA scan. Using Lunar PIXImus software, the bone mineral density (BMD) and fat composition (% fat) and total tissue mass (TTM) were determined in the regions of interest (ROI) [i.e., whole body, vertebrae, and both femurs].

[1154] Results:

DEXA: The male (-/-) mice exhibited decreased mean total tissue mass and lean body mass when compared with that of their gender-matched (+/+) littermates and the historical means. In addition, male knockout (-/-) mice showed a notably decreased vertebrae bone mineral density (BMD).

[1155] The (-/-) mice analyzed by DEXA exhibited notably decreased total tissue mass and lean body mass as well as decreased bone measurements when compared with their (+/+) littermates, suggestive of growth retardation in these mutants. This in conjunction with the observations of decreased body weight suggests a tissue wasting condition such as cachexia or other growth related disorders. Thus, PRO309 polypeptides or agonists thereof would be useful in the treatment or prevention of growth disorders including cachexia or other tissue wasting diseases.

[1156] (c) Immunology Phenotypic Analysis

[1157] Immune related and inflammatory diseases are the manifestation or consequence of fairly complex, often multiple interconnected biological pathways which in normal physiology are critical to respond to insult or injury, initiate repair from insult or injury, and mount innate and acquired defense against foreign organisms. Disease or pathology occurs when these normal physiological pathways cause additional insult or injury either as directly related to the intensity of the response, as a consequence of abnormal regulation or excessive stimulation, as a reaction to self, or as a combination of these.

[1158] Though the genesis of these diseases often involves multistep pathways and often multiple different biological systems/pathways, intervention at critical points in one or more of these pathways can have an ameliorative or therapeutic effect. Therapeutic intervention can occur by either antagonism of a detrimental process/pathway or stimulation of a beneficial process/pathway.

[1159] T lymphocytes (T cells) are an important component of a mammalian immune response. T cells recognize antigens which are associated with a self-molecule encoded by genes within the major histocompatibility complex (MHC). The antigen may be displayed together with MHC molecules on the surface of antigen presenting cells, virus infected cells, cancer cells, grafts, etc. The T cell system eliminates these altered cells which pose a health threat to the host mammal. T cells include helper T cells and cytotoxic T cells. Helper T cells proliferate extensively following recognition of an antigen-MHC complex on an antigen presenting cell. Helper T cells also secrete a variety of cytokines, i.e., lymphokines, which play a central role in the activation of B cells, cytotoxic T cells and a variety of other cells which participate in the immune response.

[1160] In many immune responses, inflammatory cells infiltrate the site of injury or infection. The migrating cells may be neutrophilic, eosinophilic, monocytic or lymphocytic as can be determined by histologic examination of the affected tissues. Current Protocols in Immunology, ed. John E. Coligan, 1994, John Wiley & Sons, Inc.

[1161] Many immune related diseases are known and have been extensively studied. Such diseases include immune-mediated inflammatory diseases (such as rheumatoid arthritis, immune mediated renal disease, hepatobiliary diseases, inflammatory bowel disease (IBD), psoriasis, and asthma), non-immune-mediated inflammatory diseases, infectious diseases, immunodeficiency diseases, neoplasia, and graft rejection, etc. In the area of immunology, targets were identified for the treatment of inflammation and inflammatory disorders.

[1162] In the area of immunology, targets have been identified herein for the treatment of inflammation and inflammatory disorders: Immune related diseases, in one instance, could be treated by suppressing the immune response. Using neutralizing antibodies that inhibit molecules having immune stimulatory activity would be beneficial in the treatment of immune-mediated and inflammatory diseases. Molecules which inhibit the immune response can be utilized (proteins directly or via the use of antibody agonists) to inhibit the immune response and thus ameliorate immune related disease.

[1163] The following test was performed:

[1164] Flourescence-Activated Cell-Sorting (FACS) Analysis--Tissue Specific FACS

[1165] Procedure:

[1166] FACS analysis of immune cell composition from peripheral blood was performed including CD4, CD8 and T cell receptor to evaluate T lymphocytes, CD19 for B lymphocytes, CD45 as a leukocyte marker and pan NK for natural killer cells. The FACS analysis was carried out on 2 wild type and 6 homozygous mice and included cells derived from thymus, spleen, bone marrow and lymph node.

[1167] In these studies, analyzed cells were isolated from thymus, peripheral blood, spleen, bone marrow and lymph nodes. Flow cytometry was designed to determine the relative proportions of CD4 and CD8 positive T cells, B cells, NK cells and monocytes in the mononuclear cell population. A Becton-Dicicinson FACSCalibur 3-laser FACS machine was used to assess immune status. For Phenotypic Assays and Screening, this machine records CD4+/CD8-, CD8+/CD4-, NK, B cell and monocyte numbers in addition to the CD4+/CD8+ ratio.

Test Description The mononuclear cell profile is derived by staining a single sample of lysed peripheral blood from each mouse with a panel of six lineage-specific antibodies: CD45 PerCP, anti-TCRb APC, CD4 PE, CD8 FITC, pan-NK PE, and CD19 FITC. The two FITC and PE labeled antibodies stain mutually exclusive cell types. The samples are analyzed using a Becton Dickinson FACSCalibur flow cytometer with CellQuest software

[1168] Results:

Tissue Specific FACS-Mouse: Analyzes of lymphocyte and antigen presenting cell subsets in blood, spleen, bone marrow and peritoneal lavage resulted in the following major findings: Total spleen cell numbers are lower than wildtype or heterozygous littermates. Also observed were statistically significant decreased in knockout cell numbers in the following subsets: spleen--marginal zone B cells, follicular B cells, T1/B cells, T2/marginal zone B cells, activated CD4 T cells, naive CD8 T cells, myeloid dendritic cells and plasmacytoid dendritic cells; bone marrow--total cell numbers, immature B cells, pre-B cells, pro B cells, IgM+ and IgM- plasma cells. The (-/-) mice exhibited a notably decreased percentage of CD21hi CD23med B cells in spleen when compared with that of the (+/+) mice. These results indicate that the knockout mice exhibited a decrease in a subset of B cells (marginal zone B cells) that contain a pool of memory cells and participate in the fast immune response. Thus, the mutant homozygous mice exhibited immunological abnormalities associated with decreased levels of B cell progenitor cells in the spleen.

[1169] These results show that knockout (-/-) mice exhibit immunological abnormalities compared to their wild-type (+/+) littermates. Antagonists (inhibitors) of PRO309 polypeptides would be expected to mimic this phenotype. PRO309 polypeptides or agonists thereof would be useful in the development or maturation of B cells which could then participate in fast immune responses.

[1170] 66.8. Generation and Analysis of Mice Comprising DNA40982-1235 (UNQ293) Gene Disruptions

[1171] In these knockout experiments, the gene encoding PRO332 polypeptides (designated as DNA40982-1235) (UNQ293) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: NM.sub.--172874 Mus musculus podocan (Podn); protein reference: Q7TQ62 ACCESSION:Q7TQ62 NID: Mus musculus (Mouse). Podocan protein; the human gene sequence reference: NM.sub.--153703 Homo sapiens podocan (PODN); the human protein sequence corresponds to reference: Q5VVZ3 ACCESSION:Q5VVZ3 NID: Homo sapiens (Human). Podocan. The mouse gene of interest is Podn (podocan), ortholog of human PODN. Aliases include Pc an, SLRR5A, 9430070G18, and MGC24995.

[1172] PODN is a putative secreted protein that can bind with type-1 collagen and likely functions as an extracellular matrix protein. The 611-amino acid protein is a member of the small leucine-rich repeat (SLR) family of non-collagenous extracellular matrix proteins, consisting of a cysteine-rich N terminus, 20 leucine-rich repeats, and an acidic C-terminal domain. Within the renal glomerulus, PODN is expressed in podocytes and vascular endothelial cells and is found in basement membrane. PODN is also expressed in other tissues, including heart and vascular smooth muscle cells. PODN likely modulates fibrillogenesis in glomerular basement membrane and may play a role in glomerular filtration, sclerotic glomerular lesion formation associated with HIV infection, and growth regulation of cardiovascular tissues (Ross et al, J Biol Chem 278(35):33248-55 (2003); Shimizu-Hirota et al, FEBS Lett 563(1-3):69-74 (2004)).

[1173] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00076 wt het hom Total Observed 24 46 19 89 Expected 22.25 44.5 22.25 89

Chi-Sq.=2.61 Significance=0.27117255 (hom/n)=0.24 Avg. Litter Size=9

Mutation Information

[1174] Mutation Type: Homologous Recombination (standard) Description: Coding exons 1 through 5 were targeted (NCBI accession NM.sub.--172874.2). 1. Wild-type Expression Panel: Expression of the target gene was detected in embryonic stem (ES) cells and in all 13 adult tissue samples tested by RT-PCR, except skeletal muscle. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[1175] 66.8.1. Phenotypic Analysis (for Disrupted Gene: DNA40982-1235 (UNQ293)

[1176] (a) Overall Phenotypic Summary:

[1177] Mutation of the gene encoding the ortholog of human podocan (PODN) resulted in an increased serum

[1178] IgG3 level. In addition, the mutant (-/-) mice exhibited increased bone mineral density measurements and increased mean femoral mid-shaft cross-sectional area. Gene disruption was confirmed by Southern blot.

[1179] (b) Immunology Phenotypic Analysis

[1180] Immune related and inflammatory diseases are the manifestation or consequence of fairly complex, often multiple interconnected biological pathways which in normal physiology are critical to respond to insult or injury, initiate repair from insult or injury, and mount innate and acquired defense against foreign organisms. Disease or pathology occurs when these normal physiological pathways cause additional insult or injury either as directly related to the intensity of the response, as a consequence of abnormal regulation or excessive stimulation, as a reaction to self, or as a combination of these.

[1181] Though the genesis of these diseases often involves multistep pathways and often multiple different biological systems/pathways, intervention at critical points in one or more of these pathways can have an ameliorative or therapeutic effect. Therapeutic intervention can occur by either antagonism of a detrimental process/pathway or stimulation of a beneficial process/pathway.

[1182] T lymphocytes (T cells) are an important component of a mammalian immune response. T cells recognize antigens which are associated with a self-molecule encoded by genes within the major histocompatibility complex (MHC). The antigen may be displayed together with MHC molecules on the surface of antigen presenting cells, virus infected cells, cancer cells, grafts, etc. The T cell system eliminates these altered cells which pose a health threat to the host mammal. T cells include helper T cells and cytotoxic T cells. Helper T cells proliferate extensively following recognition of an antigen-MHC complex on an antigen presenting cell. Helper T cells also secrete a variety of cytokines, i.e., lymphokines, which play a central role in the activation of B cells, cytotoxic T cells and a variety of other cells which participate in the immune response.

[1183] In many immune responses, inflammatory cells infiltrate the site of injury or infection. The migrating cells may be neutrophilic, eosinophilic, monocytic or lymphocytic as can be determined by histologic examination of the affected tissues. Current Protocols in Immunology, ed. John E. Coligan, 1994, John Wiley & Sons, Inc.

[1184] Many immune related diseases are known and have been extensively studied. Such diseases include immune-mediated inflammatory diseases (such as rheumatoid arthritis, immune mediated renal disease, hepatobiliary diseases, inflammatory bowel disease (IBD), psoriasis, and asthma), non-immune-mediated inflammatory diseases, infectious diseases, immunodeficiency diseases, neoplasia, and graft rejection, etc. In the area of immunology, targets were identified for the treatment of inflammation and inflammatory disorders.

[1185] In the area of immunology, targets have been identified herein for the treatment of inflammation and inflammatory disorders. Immune related diseases, in one instance, could be treated by suppressing the immune response. Using neutralizing antibodies that inhibit molecules having immune stimulatory activity would be beneficial in the treatment of immune-mediated and inflammatory diseases. Molecules which inhibit the immune response can be utilized (proteins directly or via the use of antibody agonists) to inhibit the immune response and thus ameliorate immune related disease.

[1186] The following test was performed:

[1187] Serum Immunoglobulin Isotyping Assay:

[1188] The Serum Immunoglobulin Isotyping Assay is performed using a Cytometric Bead Array (CBA) kit. This assay is used to rapidly identify the heavy and light chain isotypes of a mouse monoclonal antibody in a single sample. The values expressed are "relative fluorescence units" and are based on the detection of kappa light chains. Any value <6 is not significant.

[1189] Results:

[1190] The (-/-) mice exhibited increased mean serum IgG3 levels compared to their gender-matched (+/+) littermate controls.

[1191] The serum immunoglobulin isotyping assay revealed that homozygous adults exhibited increased serum IgG3 levels. Thus, homozygotes showed elevated serum immunoglobulins compared with the (+/+) littermates. IgG3 immunoglobulins have neutralization effects and to a lesser extent are important for activation of the complement system. These immunological abnormalities suggest that antagonists or inhibitors of PRO332 polypeptides would stimulate the immune system and would find utility in the cases wherein this effect would be beneficial to the individual such as in the case of leukemia, and other types of cancer, and in immunocompromised patients, such as AIDS sufferers. Accordingly, PRO332 polypeptides or agonists thereof would inhibit the immune response and would be useful candidates for suppressing harmful immune responses, e.g. in the case of graft rejection or graft-versus-host diseases.

[1192] (c) Bone Metabolism & Body Diagnostics: Radiology Phenotypic Analysis

[1193] In the area of bone metabolism, targets were identified herein for the treatment of arthritis, osteoporosis, osteopenia and osteopetrosis as well as identifying targets that promote bone healing. Tests included: [1194] DEXA for measurement of bone mineral density on femur and vertebra [1195] MicroCT for very high resolution and very high sensitivity measurements of bone mineral density for both trabecular and cortical bone.

[1196] Dexa Analysis--Test Description:

[1197] Procedure: A cohort of 4 wild type, 4 heterozygotes and 8 homozygotes were tested in this assay. Dual Energy X-ray Absorptiometry (DEXA) has been used successfully to identify changes in bone. Anesthetized animals were examined and bone mineral content (BMC), BMC/LBM ratios, volumetric bone mineral density (vBMD), total body BMD, femur BMD and vertebra BMD were measured.

[1198] The mouse was anesthetized by intraperitoneal injection of Avertin (1.25% 2,2,2,-tribromoethanol, 20 ml/kg body weight), body length and weight were measured, and then the mouse was placed in a prone position on the platform of the PIXImus.TM. Densitometer (Lunar Inc.) for a DEXA scan. Using Lunar PIXImus software, the bone mineral density (BMD) and fat composition (% fat) and total tissue mass (TTM) were determined in the regions of interest (ROI) [i.e., whole body, vertebrae, and both femurs].

[1199] Bone MicroCT Analysis:

[1200] Procedure: MicroCT was also used to get very sensitive measurements of BMD. One vertebra and 1 femur were taken from a cohort of 4 wild type and 8 homozygous mice. Measurements were taken of lumbar 5 veterbra traebecular bone volume, traebecular thickness, connectivity density and midshaft femur total bone area and cortical thickness. The .mu.CT40 scans provided detailed information on bone mass and architecture. Multiple bones were placed into sample holders and scanned automatically. Instrument software was used to select regions of interest for analysis. Trabecular bone parameters were analyzed in the fifth lumbar vertebrae (LV5) at 16 micrometer resolution and cortical bone parameters were analyzed in the femur midshaft at a resolution of 20 micrometers.

[1201] Results:

DEXA: The male (-/-) mice exhibited increased mean volumetric bone mineral density and total body bone mineral density when compared with the values for their gender-matched (+/+) littermates and the historical means. Micro CT: The male (-/-) mice exhibited increased mean femoral mid-shaft cross-sectional area when compared with that of their gender-matched (+/+) littermates and the historical mean.

[1202] The male (-/-) mice exhibited increased bone mineral content, and total body and femoral bone mineral density when compared with their gender-matched (+/+) littermates. These results indicate that the knockout mutant phenotype may be associated with such bone abnormalities as osteopetrosis. Osteopetrosis is a condition characterized by abnormal thickening and hardening of bone and abnormal fragility of the bones. As such, PRO332 polypeptides or agonists thereof may be beneficial for the treatment of osteopetrosis. A phenotype associated with an increased bone mineral content, and total body and femoral bone mineral density suggests that agents which mimic these effects (e.g. antagonists of PRO332 polypeptides) would be useful in bone healing.

[1203] 66.9. Generation and Analysis of Mice Comprising DNA38649 (UNQ301) Gene Disruptions

[1204] In these knockout experiments, the gene encoding PRO342 polypeptides (designated as DNA38649) (UNQ301) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: NM.sub.--023059 ACCESSION:NM.sub.--023059 NID:12746439 Mus musculus Mus musculus single Ig IL-1 receptor related protein (Sigirr-pending); protein reference: Q9JLZ8 ACCESSION:Q9JLZ8 NID: Mus musculus (Mouse). TOLL/INTERLEUKIN-1 RECEPTOR 8; the human gene sequence reference: NM.sub.--021805 ACCESSION:NM.sub.--021805 NID:11141876 Homo sapiens Homo sapiens single Ig IL-1R-related molecule (SIGIRR); the human protein sequence corresponds to reference: Q9H733 ACCESSION:Q9H733 NID: Homo sapiens (Human). cDNA: FLJ21446 FIS, CLONE COL04458.

[1205] The mouse gene of interest is AI256711 (expressed sequence AI256711), ortholog of human SIGIRR (single Ig IL-1R-related molecule). Aliases include TIR8, single Ig IL-1R-related protein, and single Ig IL-1 receptor related protein.

[1206] SIGIRR is a type I plasma membrane protein that functions as a "non-signaling" or "decoy" receptor. The protein consists of an extracellular immunoglobulin domain, a transmembrane segment, and an intracellular toll/interleukin-1 receptor (TIR) domain. Upon stimulation, proinflammatory interleukin-1 receptor (IL-1R) and toll-like receptors (TLRs) recruit SIGIRR, which then sequesters downstream signaling molecules interleukin-1 receptor-associated kinase (IRAK) and TNF receptor-associated factor 6 (TRAF6), inhibiting signal transduction. SIGIRR is involved in negatively modulating innate immune responses. The protein is expressed in many tissues and cells, including dendritic cells and epithelial cells in kidney, colon, and other mucosal tissues, and is down-regulated in response to lipopolysaccharides (LPS). Thus, SIGIRR blocks innate immune reactions in non-stimulated cells, presumably preventing detrimental effects, such as chronic inflammation and sepsis (Thomassen et al, Cytokine 11(6):389-99 (1999); Polentarutti et al, Eur Cytokine Netw 14(4):211-8 (2003); Wald et al, Nat Immunol 4(9):920-7 (2003); Mantovani et al, J Leukoc Biol 75(5):738-42 (2004); O'Neill, Nat Immunol 4(9):823-4 (2003); Garlanda et al, Proc Natl Acad Sci USA 101(10):3522-6 (2004)).

[1207] Wald and colleagues [Nat Immunol 4(9):920-7 (2003)], as well as Garlanda and colleagues [Proc Natl Acad Sci USA 101(10):3522-6 (2004)], investigated the physiological role of SIGIRR using knockout mice. They showed that inflammation in response to IL-1 or LPS and intestinal inflammation susceptibility was greater in SIGIRR-deficient mice than in wild-type mice. These authors concluded that SIGIRR is essential for modulating innate immune responses and may be important for regulating inflammation in the gastrointestinal tract.

[1208] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00077 wt het hom Total Observed 16 18 20 54 Expected 13.5 27 13.5 54

Chi-Sq.=0.73 Significance=0.69419664 (hom/n)-=0.26 Avg. Litter Size=8

Mutation Information

[1209] Mutation Type: Homologous Recombination (standard) Description: Coding exons 1 through 9 were targeted (NCBI accession NM.sub.--023059.1). 1. Wild-type Expression Panel: Expression of the target gene was detected in embryonic stem (ES) cells and in all 13 adult tissue samples tested by RT-PCR, except bone and adipose. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[1210] 66.9.1. Phenotypic Analysis (for Disrupted Gene: DNA38649 (UNQ301)

[1211] (a) Overall Phenotypic Summary:

[1212] Mutation of the gene encoding the ortholog of human single Ig IL-1R-related molecule (SIGIRR) resulted in a decreased mean percentage of CD4 cells in the peripheral blood as well as a decreased mean serum IgA level. The homozygous mice also showed a decreased pain response (decreased sensitivity to heat-induced pain). In addition, the mutant male (-/-) and (+/-) mice showed increased mean serum cholesterol and triglyceride levels. Radiology results indicated that the female (-/-) mice showed decreased bone mineral content and bone mineral density index measurements. Gene disruption was confirmed by Southern blot.

[1213] (b) Phenotypic Analysis: Cardiology

[1214] In the area of cardiovascular biology, targets were identified herein for the treatment of hypertension, atherosclerosis, heart failure, stroke, various coronary artery diseases, dyslipidemias such as high cholesterol (hypercholesterolemia) and elevated serum triglycerides (hypertriglyceridemia), diabetes and/or obesity. The phenotypic tests included the measurement of serum cholesterol and triglycerides.

[1215] In the area of metabolism, targets may be identified for the treatment of diabetes. Blood chemistry phenotypic analysis includes blood glucose measurements. The COBAS Integra 400 (mfr: Roche) was used for running blood chemistry tests on the mice. In the area of metabolism, targets may be identified for the treatment of diabetes.

[1216] Blood Lipids

[1217] Procedure: A cohort of 4 wild type, 4 heterozygotes and 8 homozygotes were tested in this assay. High cholesterol levels and increased triglyceride blood levels are recognized risk factors in the development of cardiovascular disease and/or diabetes. Measuring blood lipids facilitates the finding of biological switches that regulate blood lipid levels. Inhibition of factors which elevate blood lipid levels may be useful for reducing the risk for cardiovascular disease. In these blood chemistry tests, measurements were recorded using the COBAS Integra 400 (mfr: Roche).

[1218] Results:

Blood Chemistry: The male (-/-) and (+/-) mice exhibited increased mean serum cholesterol and triglyceride levels [cholesterol >2 SD in (-/-) males; >2 SD in (+/-) males; triglycerides >1-2 SD in (-/-) males] when compared with their gender-matched (+/+) littermates and the historical means.

[1219] As summarized above, the (-/-) mice exhibited notably increased mean serum cholesterol and triglyceride levels when compared with their gender-matched (+/+) littermates and the historical means. Thus, mutant mice deficient in the PRO342 gene can serve as a model for cardiovascular disease. PRO342 polypeptides or its encoding gene would be useful in regulating blood lipids such as cholesterol and triglycerides. Thus, PRO342 polypeptides or agonists thereof would be useful in the treatment of such cardiovascular diseases as hypertension, atherosclerosis, heart failure, stroke, various coronary diseases, hypercholesterolemia, hypertriglyceridemia, diabetes and/or obesity.

[1220] (c) Immunology Phenotypic Analysis

[1221] Immune related and inflammatory diseases are the manifestation or consequence of fairly complex, often multiple interconnected biological pathways which in normal physiology are critical to respond to insult or injury, initiate repair from insult or injury, and mount innate and acquired defense against foreign organisms. Disease or pathology occurs when these normal physiological pathways cause additional insult or injury either as directly related to the intensity of the response, as a consequence of abnormal regulation or excessive stimulation, as a reaction to self, or as a combination of these.

[1222] Though the genesis of these diseases often involves multistep pathways and often multiple different biological systems/pathways, intervention at critical points in one or more of these pathways can have an ameliorative or therapeutic effect. Therapeutic intervention can occur by either antagonism of a detrimental process/pathway or stimulation of a beneficial process/pathway.

[1223] T lymphocytes (T cells) are an important component of a mammalian immune response. T cells recognize antigens which are associated with a self-molecule encoded by genes within the major histocompatibility complex (MHC). The antigen may be displayed together with MHC molecules on the surface of antigen presenting cells, virus infected cells, cancer cells, grafts, etc. The T cell system eliminates these altered cells which pose a health threat to the host mammal. T cells include helper T cells and cytotoxic T cells. Helper T cells proliferate extensively following recognition of an antigen-MHC complex on an antigen presenting cell. Helper T cells also secrete a variety of cytokines, i.e., lymphokines, which play a central role in the activation of B cells, cytotoxic T cells and a variety of other cells which participate in the immune response.

[1224] In many immune responses, inflammatory cells infiltrate the site of injury or infection. The migrating cells may be neutrophilic, eosinophilic, monocytic or lymphocytic as can be determined by histologic examination of the affected tissues. Current Protocols in Immunology, ed. John E. Coligan, 1994, John Wiley & Sons, Inc.

[1225] Many immune related diseases are known and have been extensively studied. Such diseases include immune-mediated inflammatory diseases (such as rheumatoid arthritis, immune mediated renal disease, hepatobiliary diseases, inflammatory bowel disease (IBD), psoriasis, and asthma), non-immune-mediated inflammatory diseases, infectious diseases, immunodeficiency diseases, neoplasia, and graft rejection, etc. In the area of immunology, targets were identified for the treatment of inflammation and inflammatory disorders.

[1226] In the area of immunology, targets have been identified herein for the treatment of inflammation and inflammatory disorders. Immune related diseases, in one instance, could be treated by suppressing the immune response. Using neutralizing antibodies that inhibit molecules having immune stimulatory activity would be beneficial in the treatment of immune-mediated and inflammatory diseases. Molecules which inhibit the immune response can be utilized (proteins directly or via the use of antibody agonists) to inhibit the immune response and thus ameliorate immune related disease.

[1227] The following test was performed:

[1228] (1) Flourescence-Activated Cell-Sorting (FACS) Analysis

[1229] Procedure:

[1230] FACS analysis of immune cell composition from peripheral blood was performed including CD4, CD8 and T cell receptor to evaluate T lymphocytes, CD19 for B lymphocytes, CD45 as a leukocyte marker and pan NK for natural killer cells. The FACS analysis was carried out on 2 wild type and 6 homozygous mice and included cells derived from thymus, spleen, bone marrow and lymph node.

[1231] In these studies, analyzed cells were isolated from thymus, peripheral blood, spleen, bone marrow and lymph nodes. Flow cytometry was designed to determine the relative proportions of CD4 and CD8 positive T cells, B cells, NK cells and monocytes in the mononuclear cell population. A Becton-Dickinson FACSCalibur 3-laser FACS machine was used to assess immune status. For Phenotypic Assays and Screening, this machine records CD4+/CD8-, CD8+/CD4-, NK, B cell and monocyte numbers in addition to the CD4+/CD8+ ratio.

[1232] The mononuclear cell profile was derived by staining a single sample of lysed peripheral blood from each mouse with a panel of six lineage-specific antibodies: CD45 PerCP, anti-TCRb APC, CD4 PE, CD8 FITC, pan-NK PE, and CD19 FITC. The two FITC and PE labeled antibodies stain mutually exclusive cell types. The samples were analyzed using a Becton Dickinson FACSCalibur flow cytometer with CellQuest software.

[1233] Results:

FACS3: The (-/-) mice exhibited an altered distribution of leukocyte subsets in the peripheral blood, characterized by a decreased mean percentage of CD4 cells when compared with their (+/+) littermates, the (+/+) mice for the project run and the historical mean.

[1234] The (-/-) mice exhibited an altered distribution of leukocyte subsets in the peripheral blood, characterized by decreased mean percentages of CD4 cells in the cell population when compared with their (+/+) littermates and the historical means.

[1235] Thus, knocking out the gene which encodes PRO342 polypeptides causes a decrease in the T cell population. From these observations, PRO342 polypeptides or the gene encoding PRO342 appears to act as a regulator of T cell proliferation. Thus, PRO342 polypeptides would be beneficial in enhancing T cell proliferation.

[1236] (2) Serum Immunoglobulin Isotyping Assay:

[1237] The Serum Immunoglobulin Isotyping Assay is performed using a Cytometric Bead Array (CBA) kit. This assay is used to rapidly identify the heavy and light chain isotypes of a mouse monoclonal antibody in a single sample. The values expressed are "relative fluorescence units" and are based on the detection of kappa light chains. Any value <6 is not significant.

[1238] Results:

[1239] The (-/-) mice exhibited a decreased mean serum IgA level when compared with that of their (+/+) littermates, the (+/+) mice for the project run, and the historical median.

[1240] These results suggest that the phenotype associated with these knockout mice is immunoglobulin deficiency in IgA. The most common inherited form of immunoglobulin deficiency is selective IgA deficiency, which is seen in about one person in 800. IgA mainly functions as an epithelial cell protector which can neutralize bacterial toxins and viruses. Although no obvious disease susceptibility is associated with selective IgA defects, they are commoner in people with chronic lung disease than in the general population. This suggests that lack of IgA may result in a predisposition to lung infections with various pathogens and is consistent with the role of IgA in defense at the body surfaces. Thus PRO342 polypeptides or agonists thereof, play an important role in protecting against as a natural immunity protection against skin infections and more importantly would prevent susceptibility to lung infections.

[1241] (d) Phenotypic Analysis: CNS/Neurology

[1242] In the area of neurology, analysis focused herein on identifying in vivo validated targets for the treatment of neurological and psychiatric disorders including depression, generalized anxiety disorders, attention deficit hyperactivity disorder, obsessive compulsive disorder, schizophrenia, cognitive disorders, hyperalgesia and sensory disorders. Neurological disorders include the category defined as "anxiety disorders" which include but are not limited to: mild to moderate anxiety, anxiety disorder due to a general medical condition, anxiety disorder not otherwise specified, generalized anxiety disorder, panic attack, panic disorder with agoraphobia, panic disorder without agoraphobia, posttraumatic stress disorder, social phobia, specific phobia, substance-induced anxiety disorder, acute alcohol withdrawal, obsessive compulsive disorder, agoraphobia, bipolar disorder I or II, bipolar disorder not otherwise specified, cyclothymic disorder, depressive disorder, major depressive disorder, mood disorder, substance-induced mood disorder. In addition, anxiety disorders may apply to personality disorders including but not limited to the following types: paranoid, antisocial, avoidant behavior, borderline personality disorders, dependent, histronic, narcissistic, obsessive-compulsive, schizoid, and schizotypal.

[1243] Procedure:

[1244] Behavioral screens were performed on a cohort of 4 wild type, 4 heterozygous and 8 homozygous mutant mice. All behavioral tests were done between 12 and 16 weeks of age unless reduced viability necessitates earlier testing.

[1245] Hot Plate Testing

[1246] Test Description: The hot plate test for nociception is carried out by placing each mouse on a small enclosed 55.degree. C. hot plate. Latency to a hindlimb response (lick, shake, or jump) is recorded, with a maximum time on the hot plate of 30 sec. Each animal is tested once.

[1247] Results:

Hot Plate: The (-/-) mice exhibited an increased latency to respond during hot plate testing when compared with their (+/+) littermates and the historical mean, suggesting decreased sensitivity to acute pain in the mutants.

[1248] (e) Bone Metabolism & Body Diagnostics: Radiology Phenotypic Analysis

[1249] In the area of bone metabolism, targets were identified herein for the treatment of arthritis, osteoporosis, osteopenia and osteopetrosis as well as identifying targets that promote bone healing. Tests included: [1250] DEXA for measurement of bone mineral density on femur and vertebra [1251] MicroCT for very high resolution and very high sensitivity measurements of bone mineral density for both trabecular and cortical bone.

[1252] Dexa Analysis--Test Description:

[1253] Procedure: A cohort of 4 wild type, 4 heterozygotes and 8 homozygotes were tested in this assay. Dual Energy X-ray Absorptiometry (DEXA) has been used successfully to identify changes in bone. Anesthetized animals were examined and bone mineral content (BMC), BMC/LBM ratios, volumetric bone mineral density (vBMD), total body BMD, femur BMD and vertebra BMD were measured.

[1254] The mouse was anesthetized by intraperitoneal injection of Avertin (1.25% 2,2,2,-tribromoethanol, 20 ml/kg body weight), body length and weight were measured, and then the mouse was placed in a prone position on the platform of the PIXImus.TM. Densitometer (Lunar Inc.) for a DEXA scan. Using Lunar PIXImus software, the bone mineral density (BMD) and fat composition (% fat) and total tissue mass (TTM) were determined in the regions of interest (ROI) [i.e., whole body, vertebrae, and both femurs].

[1255] Bone MicroCT Analysis:

[1256] Procedure: MicroCT was also used to get very sensitive measurements of BMD. One vertebra and 1 femur were taken from a cohort of 4 wild type and 8 homozygous mice. Measurements were taken of lumbar 5 veterbra traebecular bone volume, traebecular thickness, connectivity density and midshaft femur total bone area and cortical thickness. The .mu.CT40 scans provided detailed information on bone mass and architecture. Multiple bones were placed into sample holders and scanned automatically. Instrument software was used to select regions of interest for analysis. Trabecular bone parameters were analyzed in the fifth lumbar vertebrae (LV5) at 16 micrometer resolution and cortical bone parameters were analyzed in the femur midshaft at a resolution of 20 micrometers.

[1257] Results:

DEXA: The female (-/-) mice exhibited decreased mean bone mineral content, bone mineral density index, and bone mineral density in total body, femurs, and vertebrae when compared with their gender-matched (+/+) littermates and the historical means.

[1258] The (-/-) mice analyzed by DEXA and bone micro CT analysis exhibited decreased bone measurements when compared with their (+/+) littermates, suggestive of abnormal bone disorders. The (-/-) mice exhibited a negative bone phenotype with abnormal decreased bone measurements reflective of bone metabolic disorders. The negative bone phenotype indicates that PRO342 polypeptides or agonists thereof would be useful for maintaining bone homeostasis. In addition, PRO342 polypeptides would be useful in bone healing or for the treatment of arthritis or osteoporosis, whereas antagonists (or inhibitors) of PRO342 polypeptides or its encoding gene would lead to abnormal or pathological bone disorders including inflammatory diseases associated with abnormal bone metabolism including arthritis, osteoporosis and osteopenia.

[1259] 66.10. Generation and Analysis of Mice Comprising DNA47470-1130P1 (UNQ313) Gene Disruptions

[1260] In these knockout experiments, the gene encoding PRO356 polypeptides (designated as DNA47470-1130P1) (UNQ313) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: BC023373 ACCESSION:BC023373 NID:19483941 Mus musculus Mus musculus, Similar to angiopoietin-like factor, clone MGC:32448 IMAGE:5043159; protein reference: Q8R1Q3 ACCESSION:Q8R1Q3 NID: Mus musculus (Mouse). Similar to angiopoietin-like factor (Mus musculus 13 days embryo male testis cDNA, RIKEN full-length enriched library, clone:6030482D04 product:CDT6 (ANGIOPOIETIN-LIKE FACTOR) (CDT6 PROTEIN) homology; the human gene sequence reference: NM.sub.--021146 ACCESSION:NM.sub.--021146 NID:20127595 Homo sapiens Homo sapiens angiopoietin-like factor (CDT6); the human protein sequence corresponds to reference: O43827 ACCESSION:O43827 NID: Homo sapiens (Human). CDT6 (ANGIOPOIETIN-LIKE FACTOR) (CDT6 PROTEIN). The mouse gene of interest is defined as \"similar to angiopoietin-like factor, \" which is the ortholog of human CDT6 (cornea-derived transcript 6). Aliases include angiopoietin-like factor, AngX, and dJ647M16.1.

[1261] CDT6 is a secreted protein expressed in corneal stroma that likely functions as a ligand. CDT6 is structurally similar to proteins of the angiopoietin family, which bind to receptors that generally regulate angiogenesis. Ina mouse xenograft model, CDT6 inhibited tumor growth and aberrant blood vessel formation and stimulated extracellular matrix deposition. Thus, CDT6 likely prevents vascularization in the cornea and functions as a morphogen that induces a corneal phenotype. The potential of CDT6 as an anti-tumor agent, however, is questionable (Peek et al, Invest Ophthalmol Vis Sci 39(10):1782-8 (1998); Peek et al, J Biol Chem 277(1):686-93 (2002); Bouis et al, In Vivo 17(2):157-61 (2003)).

[1262] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00078 wt het hom Total Observed 19 45 14 78 Expected 19.5 39 19.5 78

Mutation Information

[1263] Mutation Type: Homologous Recombination (standard) Description: Coding exon 1 was targeted (NCBI accession BC023373). Chi-Sq.=0.21 Significance=0.9003245 (hom/n)=0.26 Avg. Litter Size=9 1. Wild-type Expression Panel: Expression of the target gene was detected in embryonic stem (ES) cells and in all 13 adult tissue samples tested by RT-PCR, except heart. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[1264] 66.10.1. Phenotypic Analysis (for Disrupted Gene: DNA47470-1130P1 (UNQ313)

[1265] (a) Overall Phenotypic Summary:

[1266] Mutation of the gene encoding the ortholog of human cornea-derived transcript 6 (CDT6) resulted in increased bone mineral density measurements in the (-/-) mice. Gene disruption was confirmed by Southern blot.

[1267] (b) Bone Metabolism & Body Diagnostics: Radiology Phenotypic Analysis

[1268] In the area of bone metabolism, targets were identified herein for the treatment of arthritis, osteoporosis, osteopenia and osteopetrosis as well as identifying targets that promote bone healing. Tests included: [1269] DEXA for measurement of bone mineral density on femur and vertebra [1270] MicroCT for very high resolution and very high sensitivity measurements of bone mineral density for both trabecular and cortical bone.

[1271] Dexa Analysis--Test Description:

[1272] Procedure: A cohort of 4 wild type, 4 heterozygotes and 8 homozygotes were tested in this assay. Dual Energy X-ray Absorptiometry (DEXA) has been used successfully to identify changes in bone. Anesthetized animals were examined and bone mineral content (BMC), BMC/LBM ratios, volumetric bone mineral density (vBMD), total body BMD, femur BMD and vertebra BMD were measured.

[1273] The mouse was anesthetized by intraperitoneal injection of Avertin (1.25% 2,2,2,-tribromoethanol, 20 ml/kg body weight), body length and weight were measured, and then the mouse was placed in a prone position on the platform of the PIXImus.TM. Densitometer (Lunar Inc.) for a DEXA scan. Using Lunar PIXImus software, the bone mineral density (BMD) and fat composition (% fat) and total tissue mass (TTM) were determined in the regions of interest (ROI) [i.e., whole body, vertebrae, and both femurs].

[1274] Bone MicroCT Analysis:

[1275] Procedure: MicroCT was also used to get very sensitive measurements of BMD. One vertebra and 1 femur were taken from a cohort of 4 wild type and 8 homozygous mice. Measurements were taken of lumbar 5 veterbra traebecular bone volume, traebecular thickness, connectivity density and midshaft femur total bone area and cortical thickness. The .mu.CT40 scans provided detailed information on bone mass and architecture. Multiple bones were placed into sample holders and scanned automatically. Instrument software was used to select regions of interest for analysis. Trabecular bone parameters were analyzed in the fifth lumbar vertebrae (LV5) at 16 micrometer resolution and cortical bone parameters were analyzed in the femur midshaft at a resolution of 20 micrometers.

[1276] Results:

DEXA: The male (-/-) mice exhibited increased mean volumetric bone mineral density in total body and femur when compared with their gender-matched (+/+) littermates and the historical means. Micro CT: The male (-/-) mice exhibited increased mean femoral mid-shaft cross-sectional area when compared with their gender-matched (+/+) littermates and the historical mean.

[1277] The male (-/-) mice exhibited increased bone mineral content, and total body and femoral mid-shaft cross-sectional area when compared with their gender-matched (+/+) littermates. These results indicate that the knockout mutant phenotype may be associated with such bone abnormalities as osteopetrosis. Osteopetrosis is a condition characterized by abnormal thickening and hardening of bone and abnormal fragility of the bones. As such, PRO356 polypeptides or agonists thereof would be beneficial for the treatment of osteopetrosis. A phenotype associated with an increased bone mineral content, and total body and femoral bone mineral density suggests that agents which mimic these effects (e.g. antagonists of PRO356 polypeptides) would be useful in bone healing.

[1278] 66.11. Generation and Analysis of Mice Comprising DNA44189-1322 (UNQ341) Gene Disruptions

[1279] In these knockout experiments, the gene encoding PRO540 polypeptides (designated as DNA44189-1322) (UNQ341) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: NM.sub.--133792 Mus musculus lysophospholipase 3 (Lypla3); protein reference: Q8VEB4 ACCESSION:Q8VEB4 NID: Mus musculus (Mouse). Similar to LCAT-like lysophospholipase (Lysosomal phospholipase A2); the human gene sequence reference: NM.sub.--012320 ACCESSION:NM.sub.--012320 NID: gi 20302150 ref NM.sub.--012320.2 Homo sapiens lysophospholipase 3 (lysosomal phospholipase A2) (LYPLA3); the human protein sequence corresponds to reference: Q8NCC3 ACCESSION:Q8NCC3 NID: Homo sapiens (Human). Hypothetical protein FLJ90347.

[1280] The mouse gene of interest is Lypla3 (lysophospholipase 3), ortholog of human LYPLA3 (lysophospholipase 3 [lysosomal phospholipase A2]). Aliases include ACS, LLPL, LPLA2, lysosomal phospholipase A2, DKFZp564A0122, 1-O-acylceramide synthase, and LCAT-like lysophospholipase.

[1281] LYPLA3 is a likely lysosomal enzyme that functions as an acyltransferase, catalyzing the transfer of acyl groups at the sn-2 position in phospholipids to the C-1 hydroxyl group of ceramide, forming 1-O-acylceramide. In the absence of ceramide, the enzyme can also function as a phospholipase, forming lysophospholipid and free fatty acid from phospholipids. The enzyme may also have weak lysophospholipase activity and has been detected in plasma. LYPLA3 is calcium-independent, is optimally active at acidic pH, and is expressed in a wide variety of tissues (Taniyama et al, Biochem Biophys Res Commun 257(1):50-6 (1999); Hiraoka et al, J Biol Chem 277(12):10090-9 (2002)). LYPLA3 may play a role in lung surfactant catabolism by alveolar macrophages (Abe et al, J Biol Chem 279(41):42605-11 (2004)).

[1282] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00079 wt het hom Total Observed 23 33 19 75 Expected 18.75 37.5 18.75 75

Chi-Sq.=1.53 Significance=0.46533394 (hom/n)=0.26 Avg. Litter Size=9

Mutation Information

[1283] Mutation Type: Homologous Recombination (standard) Description: Coding exon 1 was targeted (NCBI accession NM.sub.--133792.2). 1. Wild-type Expression Panel: Expression of the target gene was detected in embryonic stem (ES) cells and in all 13 adult tissue samples tested by RT-PCR. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[1284] 66.11.1. Phenotypic Analysis (for Disrupted Gene: DNA44189-1322 (UNQ341)

[1285] (a) Overall Phenotypic Summary:

[1286] Mutation of the gene encoding the ortholog of human lysophospholipase 3 (lysosomal phospholipase A2) (LYPLA3) resulted in decreased bone mineral density measurements in the male (-/-) mice. The knockout mice also exhibited an impaired glucose tolerance. Gene disruption was confirmed by Southern blot.

[1287] (b) Bone Metabolism & Body Diagnostics: Radiology Phenotypic Analysis

[1288] In the area of bone metabolism, targets were identified herein for the treatment of arthritis, osteoporosis, osteopenia and osteopetrosis as well as identifying targets that promote bone healing. Tests included: [1289] DEXA for measurement of bone mineral density on femur and vertebra [1290] MicroCT for very high resolution and very high sensitivity measurements of bone mineral density for both trabecular and cortical bone.

[1291] Dexa Analysis--Test Description:

[1292] Procedure: A cohort of 4 wild type, 4 heterozygotes and 8 homozygotes were tested in this assay. Dual Energy X-ray Absorptiometry (DEXA) has been used successfully to identify changes in bone. Anesthetized animals were examined and bone mineral content (BMC), BMC/LBM ratios, volumetric bone mineral density (vBMD), total body BMD, femur BMD and vertebra BMD were measured.

[1293] The mouse was anesthetized by intraperitoneal injection of Avertin (1.25% 2,2,2,-tribromoethanol, 20 nil/kg body weight), body length and weight were measured, and then the mouse was placed in a prone position on the platform of the PIXImus.TM. Densitometer (Lunar Inc.) for a DEXA scan. Using Lunar PIXImus software, the bone mineral density (BMD) and fat composition (% fat) and total tissue mass (TTM) were determined in the regions of interest (ROI) [i.e., whole body, vertebrae, and both femurs].

[1294] Bone MicroCT Analysis:

[1295] Procedure: MicroCT was also used to get very sensitive measurements of BMD. One vertebra and 1 femur were taken from a cohort of 4 wild type and 8 homozygous mice. Measurements were taken of lumbar 5 veterbra traebecular bone volume, traebecular thickness, connectivity density and midshaft femur total bone area and cortical thickness. The .mu.CT40 scans provided detailed information on bone mass and architecture. Multiple bones were placed into sample holders and scanned automatically. Instrument software was used to select regions of interest for analysis. Trabecular bone parameters were analyzed in the fifth lumbar vertebrae (LV5) at 16 micrometer resolution and cortical bone parameters were analyzed in the femur midshaft at a resolution of 20 micrometers.

[1296] Results:

DEXA: The male (-/-) mice exhibited decreased mean bone mineral content and bone mineral density in total body femur and vertebrae when compared with the values for their gender-matched (+/+) littermates and the historical means. However, difference in vertebrae bone mineral density is .about.1 SD below the median. Micro CT: The male (-/-) mice exhibited decreased mean femoral mid-shaft cross-sectional area when compared with that of their gender-matched (+/+) littermates and the historical mean.

[1297] The (-/-) mice analyzed by DEXA and bone micro CT analysis exhibited decreased bone measurements when compared with their (+/+) littermates, suggestive of abnormal bone disorders. The (-/-) mice exhibited a negative bone phenotype with abnormal decreased bone measurements reflective of bone metabolic disorders. The negative bone phenotype indicates that PRO540 polypeptides or agonists thereof would be useful for maintaining bone homeostasis. In addition, PRO540 polypeptides would be useful in bone healing or for the treatment of arthritis or osteoporosis, whereas antagonists (or inhibitors) of PRO540 polypeptides or its encoding gene would lead to abnormal or pathological bone disorders including inflammatory diseases associated with abnormal bone metabolism including arthritis, osteoporosis and osteopenia.

[1298] (c) Phenotypic Analysis: Metabolism--Blood Chemistry/Glucose Tolerance

[1299] In the area of metabolism, targets may be identified for the treatment of diabetes. Blood chemistry phenotypic analysis includes blood glucose measurements. The COBAS Integra 400 (mfr: Roche) was used for running blood chemistry tests on the mice. In the area of metabolism, targets may be identified for the treatment of diabetes. Blood chemistry phenotypic analysis includes glucose tolerance tests to measure insulin sensitivity and changes in glucose metabolism. Abnormal glucose tolerance test results may indicate but may not be limited to the following disorders or conditions: Diabetes Type 1 and Type 2, Syndrome X, various cardiovascular diseases and/or obesity.

[1300] Procedure: A cohort of 2 wild type and 4 homozygote mice were used in this assay. The glucose tolerance test is the standard for defining impaired glucose homeostasis in mammals. Glucose tolerance tests were performed using a Lifescan glucometer. Animals were injected IP at 2 g/kg with D-glucose delivered as a 20% solution and blood glucose levels were measured at 0, 30, 60 and 90 minutes after injection.

[1301] Results:

[1302] Blood Glucose Levels/Glucose Tolerance Test:

[1303] The male (-/-) mice exhibited impaired glucose tolerance when placed on a high fat diet compared with their gender-matched (+/+) littermates and the historical means.

[1304] These studies indicated that (-/-) mice exhibit a decreased or impaired glucose tolerance in the presence of normal fasting glucose at all 3 intervals tested when compared with their gender-matched (+/+) littermates and the historical means. Thus, knockout mutant mice exhibited the phenotypic pattern of an impaired glucose homeostasis, and therefore PRO540 polypeptides (or agonists thereof) or its encoding gene would be useful in the treatment of conditions associated with an impaired glucose homeostasis and/or various cardiovascular diseases, including diabetes.

[1305] 66.12. Generation and Analysis of Mice Comprising DNA49152-1324 (UNQ354) Gene Disruptions

[1306] In these knockout experiments, the gene encoding PRO618 polypeptides (designated as DNA49152-1324) (UNQ354) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: BC029645 ACCESSION:BC029645 NID:20987285 Mus musculus Mus musculus transmembrane serine protease 6, mRNA (cDNA clone MGC:25857 IMAGE:4195486); protein reference: Q9DBI0 ACCESSION:Q9DBI0 NID: Mus musculus (Mouse). 1300008A22RIK PROTEIN; the human gene sequence reference: NM.sub.--153609 Homo sapiens transmembrane protease, serine 6 (TMPRSS6); the human protein sequence corresponds to reference: Q8IU80 ACCESSION:Q8IU80 NID: Homo sapiens (Human). Type II transmembrane serine protease 6.

[1307] The mouse gene of interest is Tmprss6 (transmembrane serine protease 6), ortholog of human TMPRSS6. Aliases include 1300008A22Rik, matriptase-2, type II transmembrane serine protease 6, FLJ30744, and membrane-bound mosaic serine proteinase.

[1308] TMPRSS6 is a type II plasma membrane protein expressed primarily in liver that functions as a trypsin-like serine protease, catalyzing the hydrolysis of extracellular matrix proteins. TMPRSS6 likely plays a role in extracellular matrix remodeling in liver. TMPRSS6 is elevated in invasive ductal cell carcinoma, suggesting that TMPRSS6 may also play a role in metastasis (Hooper et al, Biochem J 373(Pt 3):689-702 (2003); Overall et al, Biol Chem 385(6):493-504 (2004); Velasco et al, J Biol Chem 277(40):37637-46 (2002)).

[1309] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00080 wt het hom Total Observed 26 41 14 81 Expected 20.25 40.5 20.25 81

Chi-Sq.=2.05 Significance=0.35879648 (hom/n)=0.21 Avg. Litter Size=8

Mutation Information

[1310] Mutation Type: Homologous Recombination (standard) Description: Coding exons 1 through 3 were targeted (NCBI accession NM.sub.--027902.1). 1. Wild-type Expression Panel: Expression of the target gene was detected in all 13 adult tissue samples tested by RT-PCR, except thymus, spleen, lung, skeletal muscle, bone, and adipose. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[1311] 66.12.1. Phenotypic Analysis (for Disrupted Gene: DNA49152-1324 (UNQ354)

[1312] (a) Overall Phenotypic Summary:

[1313] Mutation of the gene encoding the ortholog of human transmembrane serine protease 6 (TMPRSS6) resulted in the homozygous mutant mice exhibiting signs of growth retardation, including decreased body weight and length, total tissue mass, and lean body mass and decreased bone mineral content and density measurements. The mutant (-/-) mice also showed signs of anemia and an increased mean platelet count. Circadian testing revealed no circadian rhythm (or hypoactivity). In addition, the mutants exhibited alopecia, hypochromasia and anisocytosis characterized by abnormal erythrocytes suggestive of a defect in RBCs or hemoglobin. Gene disruption was confirmed by Southern blot.

[1314] (b) Pathology

Gross Observations: The (-/-) mice exhibited alopecia and epidermal hyperkeratosis. Microscopic: The (-/-) mice exhibited hypochromasia and anisocytosis, characterized by abnormal erythrocytes that contained less than normal amount of hemoglobin and by less than expected levels of erythropoiesis in the bone marrow and spleen, suggestive of a defect in red blood cell or hemoglobin production. In addition, the (-/-) mutants exhibited diffuse alopecia and epidermal hyperkeratosis. Gene Expression LacZ activity was not detected in the panel of tissues by immunohistochemical analysis.

[1315] (c) Immunology Phenotypic Analysis

[1316] Immune related and inflammatory diseases are the manifestation or consequence of fairly complex, often multiple interconnected biological pathways which in normal physiology are critical to respond to insult or injury, initiate repair from insult or injury, and mount innate and acquired defense against foreign organisms. Disease or pathology occurs when these normal physiological pathways cause additional insult or injury either as directly related to the intensity of the response, as a consequence of abnormal regulation or excessive stimulation, as a reaction to self, or as a combination of these.

[1317] Though the genesis of these diseases often involves multistep pathways and often multiple different biological systems/pathways, intervention at critical points in one or more of these pathways can have an ameliorative or therapeutic effect. Therapeutic intervention can occur by either antagonism of a detrimental process/pathway or stimulation of a beneficial process/pathway.

[1318] T lymphocytes (T cells) are an important component of a mammalian immune response. T cells recognize antigens which are associated with a self-molecule encoded by genes within the major histocompatibility complex

[1319] (MHC). The antigen may be displayed together with MHC molecules on the surface of antigen presenting cells, virus infected cells, cancer cells, grafts, etc. The T cell system eliminates these altered cells which pose a health threat to the host mammal. T cells include helper T cells and cytotoxic T cells. Helper T cells proliferate extensively following recognition of an antigen-MHC complex on an antigen presenting cell. Helper T cells also secrete a variety of cytokines, i.e., lymphokines, which play a central role in the activation of B cells, cytotoxic T cells and a variety of other cells which participate in the immune response.

[1320] In many immune responses, inflammatory cells infiltrate the site of injury or infection. The migrating cells may be neutrophilic, eosinophilic, monocytic or lymphocytic as can be determined by histologic examination of the affected tissues. Current Protocols in Immunology, ed. John E. Coligan, 1994, John Wiley & Sons, Inc.

[1321] Many immune related diseases are known and have been extensively studied. Such diseases include immune-mediated inflammatory diseases (such as rheumatoid arthritis, immune mediated renal disease, hepatobiliary diseases, inflammatory bowel disease (IBD), psoriasis, and asthma), non-immune-mediated inflammatory diseases, infectious diseases, immunodeficiency diseases, neoplasia, and graft rejection, etc. In the area of immunology, targets were identified for the treatment of inflammation and inflammatory disorders.

[1322] In the area of immunology, targets have been identified herein for the treatment of inflammation and inflammatory disorders. Immune related diseases, in one instance, could be treated by suppressing the immune response. Using neutralizing antibodies that inhibit molecules having immune stimulatory activity would be beneficial in the treatment of immune-mediated and inflammatory diseases. Molecules which inhibit the immune response can be utilized (proteins directly or via the use of antibody agonists) to inhibit the immune response and thus ameliorate immune related disease.

[1323] The following test was performed:

[1324] Hematology Analysis:

[1325] Test Description Blood tests are carried out by Abbott's Cell-Dyn 3500R, an automated hematology analyzer. Some of its features include a five-part WBC differential. `Patient` reports can cover over 22 parameters in all.

[1326] Results:

Hematology: The (-/-) mice exhibited decreased mean hemoglobin and hematocrit levels and an increased mean red blood cell count when compared with the levels in their (+/+) littermates and the historical means. In addition, the mean corpuscular volume and mean corpuscular hemoglobin were decreased in the (-/-) mice whereas the red cell distribution width was increased, indicating that the size of the red blood cells was variable in the mutants. The (-/-) mice also exhibited an increased mean platelet count.

[1327] These results are related to a phenotype associated with anemia. Thus, PRO618 polypeptides, agonists thereof or the encoding gene for PRO618 polypeptides must be essential for normal red blood cell production and as such would be useful in the treatment of blood disorders associated with anemia or a low hematocrit.

[1328] In addition, the (-/-) mice exhibited an increased mean platelet count when compared with their (+/+) littermates and the historical mean. Thus, mutant mice deficient in the DNA49152-1324 gene resulted in a phenotype related to coagulation disorders.

[1329] (d) Phenotypic Analysis: CNS/Neurology

[1330] In the area of neurology, analysis focused herein on identifying in vivo validated targets for the treatment of neurological and psychiatric disorders including depression, generalized anxiety disorders, attention deficit hyperactivity disorder, obsessive compulsive disorder, schizophrenia, cognitive disorders, hyperalgesia and sensory disorders. Neurological disorders include the category defined as "anxiety disorders" which include but are not limited to: mild to moderate anxiety, anxiety disorder due to a general medical condition, anxiety disorder not otherwise specified, generalized anxiety disorder, panic attack, panic disorder with agoraphobia, panic disorder without agoraphobia, posttraumatic stress disorder, social phobia, specific phobia, substance-induced anxiety disorder, acute alcohol withdrawal, obsessive compulsive disorder, agoraphobia, bipolar disorder I or II, bipolar disorder not otherwise specified, cyclothymic disorder, depressive disorder, major depressive disorder, mood disorder, substance-induced mood disorder. In addition, anxiety disorders may apply to personality disorders including but not limited to the following types: paranoid, antisocial, avoidant behavior, borderline personality disorders, dependent, histronic, narcissistic, obsessive-compulsive, schizoid, and schizotypal.

[1331] Procedure:

[1332] Behavioral screens were performed on a cohort of 4 wild type, 4 heterozygous and 8 homozygous mutant mice. All behavioral tests were done between 12 and 16 weeks of age unless reduced viability necessitates earlier testing.

[1333] (1) Circadian Test Description:

[1334] Female mice are individually housed at 4 pm on the first day of testing in 48.2 cm.times.26.5 cm home cages and administered food and water ad libitum. Animals are exposed to a 12-hour light/dark cycle with lights turning on at 7 am and turning off at 7 pm. The system software records the number of beam interruptions caused by the animal's movements, with beam breaks automatically divided into ambulations. Activity is recorded in 60, one-hour intervals during the three-day test. Data generated are displayed by median activity levels recorded for each hour (circadian rhythm) and median total activity during each light/dark cycle (locomotor activity) over the three-day testing period.

[1335] Results:

Circadian: The female (-/-) mice exhibited hypoactivity with no circadian rhythm and hypoactivity during the 1-hour and 12-hour habituation periods and all light and dark periods suggesting an abnormal sleep/wake cycle during the last 24 hours of testing when compared with the levels measured in their gender-matched (+/+) littermates and the historical means. These results demonstrate an abnormal circadian rhythm. Home-cage activity testing is also suggestive of decreased activity or hypoactivity which is indicative of a decreased anxiety-like response in the mutants. Thus, knockout mice demonstrated a phenotype consistent with depression, generalized anxiety disorders, cognitive disorders, hyperalgesia and sensory disorders and/or bipolar disorders. Thus, PRO618 polypeptides and agonists thereof would be useful for the treatment or amelioration of the symptoms associated with depressive disorders.

[1336] (2) Functional Observational Battery (FOB) Test

[1337] The FOB is a series of situations applied to the animal to determine gross sensory and motor deficits. A subset of tests from the Irwin neurological screen that evaluates gross neurological function is used. In general, short-duration, tactile, olfactory, and visual stimuli are applied to the animal to determine their ability to detect and respond normally. These simple tests take approximately 10 minutes and the mouse is returned to its home cage at the end of testing.

[1338] Results:

[1339] All 8 of the (-/-) mice exhibited thinning fur and/or bald patches.

[1340] (e) Bone Metabolism & Body Diagnostics

[1341] (1) Tissue Mass & Lean Body Mass Measurements--Dexa

[1342] Dexa Analysis--Test Description:

[1343] Procedure: A cohort of 4 wild type, 4 heterozygotes and 8 homozygotes were tested in this assay. Dual Energy X-ray Absorptiometry (DEXA) has been used successfully to identify changes in total tissue mass (TTM).

[1344] The mouse was anesthetized by intraperitoneal injection of Avertin (1.25% 2,2,2,-tribromoethanol, 20 ml/kg body weight), body length and weight were measured, and then the mouse was placed in a prone position on the platform of the PIXImus.TM. Densitometer (Lunar Inc.) for a DEXA scan. Using Lunar PIXImus software, the bone mineral density (BMD) and fat composition (% fat) and total tissue mass (TTM) were determined in the regions of interest (ROI, i.e., whole body, vertebrae, and both femurs).

[1345] Body Measurements (Body Length & Weight):

[1346] Body Measurements: A measurement of body length and weight was performed at approximately 16 weeks of age.

[1347] Results:

[1348] The male (-/-) mice exhibited decreased mean body weight and mean body length when compared with their gender-matched (+/+) littermates and the historical mean.

Obvious General Appearance: The (-/-) mice exhibited alopecia in the dorsal and ventral regions of the thorax and abdomen. The tails of all of the (-/-) mice and some of the (+/-) mice appeared shorter with lateral curvature or slight kinks.

[1349] (2) B one Metabolism: Radiology Phenotypic Analysis

[1350] In the area of bone metabolism, targets were identified herein for the treatment of arthritis, osteoporosis, osteopenia and osteopetrosis as well as identifying targets that promote bone healing. Tests included: [1351] DEXA for measurement of bone mineral density on femur and vertebra

[1352] Dexa Analysis--Test Description:

[1353] Procedure: A cohort of 4 wild type, 4 heterozygotes and 8 homozygotes were tested in this assay. Dual Energy X-ray Absorptiometry (DEXA) has been used successfully to identify changes in bone. Anesthetized animals were examined and bone mineral content (BMC), BMC/LBM ratios, volumetric bone mineral density (vBMD), total body BMD, femur BMD and vertebra BMD were measured.

[1354] The mouse was anesthetized by intraperitoneal injection of Avertin (1.25% 2,2,2,-tribromoethanol, 20 ml/kg body weight), body length and weight were measured, and then the mouse was placed in a prone position on the platform of the PIXImus.TM. Densitometer (Lunar Inc.) for a DEXA scan. Using Lunar PIXImus software, the bone mineral density (BMD) and fat composition (% fat) and total tissue mass (TTM) were determined in the regions of interest (ROI) [i.e., whole body, vertebrae, and both femurs].

[1355] Results:

DEXA: Both the male and female (-/-) mice exhibited decreased lean body mass, and bone mineral content and density measurements when compared with those of their gender-matched (+/+) littermates and the historical means. Male knockouts also showed decreased mean total tissue mass (TTM).

[1356] Mutant (-/-) mice deficient in the gene encoding PRO618 polypeptides show a phenotype consistent with growth retardation and tissue wasting diseases marked by decreased mean total mass, lean body mass. These results are consistent with the observation of decreased mean body weight and mean body length reported above. In addition, the mutant (-/-) mice exhibited decreased bone mineral content and density measurements suggestive of osteoporosis. Thus, antagonists or inhibitors of PRO618 polypeptides or its encoding gene would mimic these abnormal metabolic related effects. On the other hand, PRO618 polypeptides or agonists thereof would be useful in the prevention and/or treatment of such metabolic disorders related to growth or diseases such as cachexia or other tissue wasting diseases as well as useful in the treatment of bone disorders associated with bone loss.

[1357] 66.13. Generation and Analysis of Mice Comprising DNA52185-1370 (UNQ481) Gene Disruptions

[1358] In these knockout experiments, the gene encoding PRO944 polypeptides (designated as DNA52185-1370) (UNQ481) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: NM.sub.--016674 Mus musculus claudin 1 (Cldn1); protein reference: O88551 ACCESSION:O88551 NID: Mus musculus (Mouse). Claudin-1; the human gene sequence reference: NM.sub.--021101 ACCESSION:NM.sub.--021101 NID: gi21536297 ref NM.sub.--021101.3 Homo sapiens claudin 1 (CLDN1); the human protein sequence corresponds to reference: O95832 ACCESSION:Q95832 NID: Homo sapiens (Human). Claudin-1 (Senescence-associated epithelial membrane protein).

[1359] The mouse gene of interest is Cldn1 (claudin 1), ortholog of human CLDN1. Aliases include CLD1, SEMP1, and senescence-associated epithelial membrane protein 1.

[1360] CLDN1 is an integral plasma membrane protein that functions as a component of tight junctions, cell adhesion molecules that form a barrier between cells to limit paracellular transport of solutes and water. The extracellular segments of CLDN1 interact adhesively with claudins on adjacent cells and co-polymerize laterally, forming tight junction strands. CLDN1 is expressed in liver, airway epithelium, pancreas, placenta, adrenals, prostate and ovary. CLDN1 likely plays an important role in maintenance and regulation of cell polarity and permeability (Furuse et al, J Cell Biol 141(7):1539-50 (1998); Swisshelm et al, Gene 226(2):285-95 (1999); Heiskala et al, Traffic 2(2):93-8 (2001); Furuse et al, J Cell Biol 156(6):1099-111 (2002); Coyne et al, Am J Physiol Lung Cell Mol Physiol 285(5):L1166-78 (2003); Sasaki et al, Proc Natl Acad Sci USA 100(7):3971-6 (2003)).

[1361] Furuse and colleagues (2002) investigated the physiological role of CLDN1 using knockout mice. CLDN1 homozygous null mice died within 1 day after birth. Although tight junctions were clearly evident in the epidermis of CLDN1 homozygous null mice, 600-dalton tracer dye diffused through epidermal tight junctions of the CLDN1 homozygous null mice but not through those of the wild-type mice. Furuse and colleagues concluded that CLDN1 is required for barrier function in mammalian skin.

[1362] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00081 wt het hom Total Observed 18 40 2 60 Expected 15.0 30 15.0 60

Chi-Sq.=12.72 Significance=0.0017293665 (hom/n)=0.12 Avg. Litter Size=9 Mutation Type Homologous Recombination (standard) Coding exon 1 was targeted (NCBI accession NM.sub.--016674.2). 1. Wild-type Expression Panel: Expression of the target gene was detected in embryonic stem (ES) cells and in all 13 adult tissue samples tested by RT-PCR, except bone, heart, and adipose. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[1363] 66.13.1. Phenotypic Analysis for Disrupted Gene: DNA52185-1370 UNQ481)

[1364] (a) Overall Phenotypic Summary:

[1365] Mutation of the gene encoding the ortholog of human claudin 1 (CLDN1) resulted in lethality of (-/-) mutants. The (-/-) pups were dead at the time of genotyping. Gene disruption was confirmed by Southern blot.

[1366] (b) Pathology

Microscopic: At 12.5 days, there were 41 embryos observed: 9 (-/-) embryos, 20 (+/-) embryos, 8 (+/+) embryos, 2 resorption moles, 1 to-be-determined, and 1 inconclusive. No developmental abnormalities were detected in the 12.5 day mutant embryos by histologic examination. Gene Expression LacZ activity was not detected in the panel of tissues by immunohistochemical analysis.

[1367] Discussion Related to Embryonic Developmental Abnormality of Lethality:

[1368] Embryonic lethality in knockout mice usually results from various serious developmental problems including but not limited to neuro-degenerative diseases, angiogenic disorders, inflammatory diseases, or where the gene/protein has an important role in basic cell signaling processes in many cell types. In addition, embryonic lethal mice are useful as potential cancer models. Likewise, the corresponding heterozygous (+/-) mutant animals are particularly useful when they exhibit a phenotype and/or a pathology report which reveals highly informative clues as to the function of the knocked-out gene. For instance, EPO knockout animals were embryonic lethals, but the pathology reports on the embryos showed a profound lack of RBCs.

[1369] 66.14. Generation and Analysis of Mice Comprising DNA58855-1422 (UNQ518) Gene Disruptions

[1370] In these knockout experiments, the gene encoding PRO994 polypeptides (designated as DNA58855-1422) (UNQ518) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: NM.sub.--025453 ACCESSION:NM.sub.--025453 NID: gi 13384857 ref NM.sub.--025453.1 Mus musculus RIKEN cDNA 1810018L02 gene (1810018L02Rik); protein reference: Q9CQY8 ACCESSION:Q9CQY8 NID: Mus musculus (Mouse). 1810018L02Rik protein; the human gene sequence reference: NM.sub.--024795 ACCESSION:NM.sub.--024795 NID: gi 13376165 ref NM.sub.--024795.1 Homo sapiens hypothetical protein FLJ22800 (FLJ22800); the human protein sequence corresponds to reference: Q9H5X9 ACCESSION:Q9H5X9 NID: Homo sapiens (Human). Hypothetical protein FLJ22800.

[1371] The mouse gene of interest is RIKEN cDNA 1810018L02 gene, ortholog of human hypothetical protein FLJ22800.

[1372] Hypothetical protein FLJ22800 is a putative integral plasma membrane protein, consisting of a signal peptide and four transmembrane domains contained within an L6 membrane protein domain (Pfam accession PF05805). The function of this hypothetical protein is unknown; however, other L6 membrane family members have been implicated in cancer (Wright et al, Protein Sci 9(8):1594-600 (2000)).

[1373] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00082 wt het hom Total Observed 16 41 23 80 Expected 20 40 20 80

Chi-Sq.=1.62 Significance=0.44485807 (hom/n)=0.25 Avg. Litter Size=9

Mutation Information

[1374] Mutation Type Homologous Recombination (standard) Description: Coding exon 1 was targeted (NCBI accession NM.sub.--025453.1). 1. Wild-type Expression Panel: Panel: Expression of the target gene was detected in all 13 adult tissue samples tested by RT-PCR, except skeletal muscle and bone. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[1375] 66.14.1. Phenotypic Analysis (for Disrupted Gene: DNA58855-1422 (UNQ518)

[1376] (a) Overall Phenotypic Summary:

[1377] Mutation of the gene encoding the ortholog of a human hypothetical protein (FLJ22800) resulted in a decreased anxiety-related response in (-/-) mice. UNQ518 is expressed at higher levels in the pancreas and small intestine compared with other tissues. The (-/-) mice also exhibited enhanced motor coordination. Gene disruption was confirmed by Southern blot.

[1378] (b) Phenotypic Analysis: CNS/Neurology

[1379] In the area of neurology, analysis focused herein on identifying in vivo validated targets for the treatment of neurological and psychiatric disorders including depression, generalized anxiety disorders, attention deficit hyperactivity disorder, obsessive compulsive disorder, schizophrenia, cognitive disorders, hyperalgesia and sensory disorders. Neurological disorders include the category defined as "anxiety disorders" which include but are not limited to: mild to moderate anxiety, anxiety disorder due to a general medical condition, anxiety disorder not otherwise specified, generalized anxiety disorder, panic attack, panic disorder with agoraphobia, panic disorder without agoraphobia, posttraumatic stress disorder, social phobia, specific phobia, substance-induced anxiety disorder, acute alcohol withdrawal, obsessive compulsive disorder, agoraphobia, bipolar disorder I or II, bipolar disorder not otherwise specified, cyclothymic disorder, depressive disorder, major depressive disorder, mood disorder, substance-induced mood disorder. In addition, anxiety disorders may apply to personality disorders including but not limited to the following types: paranoid, antisocial, avoidant behavior, borderline personality disorders, dependent, histronic, narcissistic, obsessive-compulsive, schizoid, and schizotypal.

[1380] Procedure:

[1381] Behavioral screens were performed on a cohort of 4 wild type, 4 heterozygous and 8 homozygous mutant mice. All behavioral tests were done between 12 and 16 weeks of age unless reduced viability necessitates earlier testing. These tests included open field to measure anxiety, activity levels and exploration.

[1382] Open Field Test:

[1383] Several targets of known drugs have exhibited phenotypes in the open field test. These include knockouts of the seratonin transporter, the dopamine transporter (Giros et al., Nature. 1996 Feb. 15; 379(6566):606-12), and the GABA receptor (Homanics et al., Proc Natl Acad Sci USA. 1997 Apr. 15; 94(8):4143-8). An automated open-field assay was customized to address changes related to affective state and exploratory patterns related to learning. First, the field (40.times.40 cm) was selected to be relatively large for a mouse, thus designed to pick up changes in locomotor activity associated with exploration. In addition, there were 4 holes in the floor to allow for nose-poking, an activity specifically related to exploration. Several factors were also designed to heighten the affective state associated with this test. The open-field test is the first experimental procedure in which the mice are tested, and the measurements that were taken were the subjects' first experience with the chamber. In addition, the open-field was brightly lit. All these factors will heighten the natural anxiety associated with novel and open spaces. The pattern and extent of exploratory activity, and especially the center-to-total distance traveled ratio, may then be able to discern changes related to susceptibility to anxiety or depression. A large arena (40 cm.times.40 cm, VersaMax animal activity monitoring system from AccuScan Instruments) with infrared beams at three different levels was used to record rearing, hole poke, and locomotor activity. The animal was placed in the center and its activity was measured for 20 minutes. Data from this test was analyzed in five, 4-minute intervals. The total distance traveled (cm), vertical movement number (rearing), number of hole pokes, and the center to total distance ratio were recorded.

[1384] The propensity for mice to exhibit normal habituation responses to a novel environment is assessed by determining the overall change in their horizontal locomotor activity across the 5 time intervals. This calculated slope of the change in activity over time is determined using normalized, rather than absolute, total distance traveled. The slope is determined from the regression line through the normalized activity at each of the 5 time intervals. Normal habituation is represented by a negative slope value.

[1385] Results:

[1386] The (-/-) mice exhibited an increased median sum time-in-center during open field testing when compared with their gender-matched (+/+) littermates and the historical mean, suggesting a decreased anxiety-like response in the mutants.

[1387] A notable difference was observed during open field activity testing. The male (-/-) mice exhibited an increased median sum time in the center area when compared with their gender-matched (+/+) littermates, which is indicative of a decreased anxiety-like response in the mutants. Thus, knockout mice demonstrated a phenotype consistent with depression, generalized anxiety disorders, cognitive disorders, hyperalgesia and sensory disorders and/or bipolar disorders. Thus, PRO994 polypeptides and agonists thereof would be useful for the treatment or amelioration of the symptoms associated with depressive disorders.

[1388] Circadian Test Description:

[1389] Female mice are individually housed at 4 pm on the first day of testing in 48.2 cm.times.26.5 cm home cages and administered food and water ad libitum. Animals are exposed to a 12-hour light/dark cycle with lights turning on at 7 am and turning off at 7 pm. The system software records the number of beam interruptions caused by the animal's movements, with beam breaks automatically divided into ambulations. Activity is recorded in 60, one-hour intervals during the three-day test. Data generated are displayed by median activity levels recorded for each hour (circadian rhythm) and median total activity during each light/dark cycle (locomotor activity) over the three-day testing period.

[1390] Results:

Circadian: The female (-/-) mice exhibited decreased ambulatory activity during the 12-hour habituation period and all light and dark periods suggesting an abnormal sleep/wake cycle during the last 24 hours of testing when compared with the levels measured in their gender-matched (+/+) littermates and the historical means. These results demonstrate an abnormal circadian rhythm. Home-cage activity testing is also suggestive of decreased activity or hypoactivity which is indicative of a decreased anxiety-like response in the mutants. Thus, knockout mice demonstrated a phenotype consistent with depression, generalized anxiety disorders, cognitive disorders, hyperalgesia and sensory disorders and/or bipolar disorders. Thus, PRO994 polypeptides and agonists thereof would be useful for the treatment or amelioration of the symptoms associated with depressive disorders.

[1391] Inverted Screen Testing:

[1392] Behavioral screens were performed on a cohort of 4 wild type, 4 heterozygous and 8 homozygous mutant mice. All behavioral tests were done between 12 and 16 weeks of age unless reduced viability necessitates earlier testing. These tests included open field to measure anxiety, activity levels and exploration.

[1393] Inverted Screen Test Data:

[1394] The Inverted Screen is used to measure motor strength/coordination. Untrained mice were placed individually on top of a square (7.5 cm.times.7.5 cm) wire screen which was mounted horizontally on a metal rod. The rod was then rotated 180 degrees so that the mice were on the bottom of the screens. The following behavioral responses were recorded over a 1 min testing session: fell off, did not climb, and climbed up.

[1395] Results:

TABLE-US-00083 Genotype Ratio Fell Down % Ratio Climbed up % +/+ (n = 8) 0/8 0 4/8 50 -/- (n = 8) 0/8 0 8/8 100 wt population Fell Down 3.62% Climbed up 60.04%

A motor strength deficit is apparent when there is a 50% point difference between (-/-) or (+/-) mice and (+/+) mice for the fell down response. 0/8 or 1/8 (-/-) or (+/-) mice not climbing indicates impaired motor coordination. 7/8 or 8/8(-/-) or (+/-) mice climbing up indicates enhanced motor coordination.

[1396] The Inverted Screen Test is designed to measure basic sensory & motor observations:

[1397] Among the 8 (-/-) mice analyzed, all 8 (-/-) mice climbed up the screen whereas 4/8 (+/+) mice climbed up, suggesting an enhanced motor coordination in the mutants.

[1398] 66.15. Generation and Analysis of Mice Comprising DNA56050-1455 (UNQ536) Gene Disruptions

[1399] In these knockout experiments, the gene encoding PRO1079 polypeptides (designated as DNA56050-1455) (UNQ536) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: NM.sub.--029537 ACCESSION:NM.sub.--029537 NID: gi 22095006 ref NM.sub.--029537.1 Mus musculus RIKEN cDNA 6530411B15 gene (6530411B15Rik); protein reference: Q91X86 ACCESSION:Q91X86 NID: Mus musculus (Mouse). Unknown (Protein for MGC:19304); the human gene sequence reference: NM.sub.--015544 ACCESSION:NM.sub.--015544 NID: gi 7661615 ref NM.sub.--015544.1 Homo sapiens DKFZP564K1964 protein (DKFZP564K1964); the human protein sequence corresponds to reference: Q9Y2Y6 ACCESSION:Q9Y2Y6 NID: Homo sapiens (Human). TADA1 protein (DKFZP564K1964 protein).

[1400] The mouse gene of interest is RIKEN cDNA 6530411B15 gene, ortholog of human DKFZP564K1964 protein. Aliases include TADA1 protein, ETVV536, and UNQ536.

[1401] DKFZP564K1964 protein is a putative secreted protein, consisting of a weakly predicted signal peptide and no other conserved domain.

[1402] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00084 wt het hom Total Observed 11 31 2 44 Expected 11 22 11 44

Chi-Sq.=13.06 Significance=0.0014590055 (hom/n)=0.09 Avg. Litter Size=7

Mutation Information

[1403] Mutation Type: Homologous Recombination (standard) Description: Coding exons 1 and 2 were targeted (NCBI accession NM.sub.--029537.1). 1. Wild-type Expression Panel: Expression of the target gene was detected in embryonic stem (ES) cells and in all 13 adult tissue samples tested by RT-PCR. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis. Reduced viability of (-/-) mice was observed. Seven of the (-/-) mice identified were submitted as embryonic samples.

[1404] 66.15.1. Phenotypic Analysis (for Disrupted Gene: DNA56050-1455 (UNQ536)

[1405] (a) Overall Phenotypic Summary:

[1406] Mutation of the gene encoding the ortholog of a human putative secreted protein resulted in greatly reduced viability of (-/-) mutants. Seven of the (-/-) mice identified were submitted as embryonic samples. Of the 2 surviving mutants, the male died shortly after blood pressure analysis, while the female underwent the majority of Level 1 testing. The homozygous mutants exhibited numerous immunological abnormalities including anemia. Open field testing results indicated hyperactivity in the mutant (-/-) mice. The single male (-/-) mouse exhibited decreased total tissue mass and lean body mass but the female (-/-) knockout showed increased total tissue mass, fat mass (g) and % total body fat. One mouse exhibited retinal hemorrhage. Disruption of the target gene was confirmed by Southern hybridization analysis.

[1407] (b) Pathology

Microscopic: At day 12.5, there were 39 embryos observed: 7 (-/-) embryos, 9 (+/-) embryos, 9 (+/+) embryos, 4 resorption moles, and 10 inconclusive. The (-/-) embryos were generally smaller than their (+/+) littermates but no other developmental abnormalities were detected in the day 12.5 embryos. Gene Expression LacZ activity was not detected in the panel of tissues by immunohistochemical analysis.

[1408] (c) Phenotypic Analysis: CNS/Neurology

[1409] In the area of neurology, analysis focused herein on identifying in vivo validated targets for the treatment of neurological and psychiatric disorders including depression, generalized anxiety disorders, attention deficit hyperactivity disorder, obsessive compulsive disorder, schizophrenia, cognitive disorders, hyperalgesia and sensory disorders. Neurological disorders include the category defined as "anxiety disorders" which include but are not limited to: mild to moderate anxiety, anxiety disorder due to a general medical condition, anxiety disorder not otherwise specified, generalized anxiety disorder, panic attack, panic disorder with agoraphobia, panic disorder without agoraphobia, posttraumatic stress disorder, social phobia, specific phobia, substance-induced anxiety disorder, acute alcohol withdrawal, obsessive compulsive disorder, agoraphobia, bipolar disorder I or II, bipolar disorder not otherwise specified, cyclothymic disorder, depressive disorder, major depressive disorder, mood disorder, substance-induced mood disorder. In addition, anxiety disorders may apply to personality disorders including but not limited to the following types: paranoid, antisocial, avoidant behavior, borderline personality disorders, dependent, histronic, narcissistic, obsessive-compulsive, schizoid, and schizotypal.

[1410] Procedure:

[1411] Behavioral screens were performed on a cohort of 4 wild type, 4 heterozygous and 2 homozygous mutant mice. All behavioral tests were done between 12 and 16 weeks of age unless reduced viability necessitates earlier testing. These tests included open field to measure anxiety, activity levels and exploration.

[1412] Open Field Test:

[1413] Several targets of known drugs have exhibited phenotypes in the open field test. These include knockouts of the seratonin transporter, the dopamine transporter (Giros et al., Nature. 1996 Feb. 15; 379(6566):606-12), and the GABA receptor (Homanics et al., Proc Natl Acad Sci USA. 1997 Apr. 15; 94(8):4143-8). An automated open-field assay was customized to address changes related to affective state and exploratory patterns related to learning. First, the field (40.times.40 cm) was selected to be relatively large for a mouse, thus designed to pick up changes in locomotor activity associated with exploration. In addition, there were 4 holes in the floor to allow for nose-poking, an activity specifically related to exploration. Several factors were also designed to heighten the affective state associated with this test. The open-field test is the first experimental procedure in which the mice are tested, and the measurements that were taken were the subjects' first experience with the chamber. In addition, the open-field was brightly lit. All these factors will heighten the natural anxiety associated with novel and open spaces. The pattern and extent of exploratory activity, and especially the center-to-total distance traveled ratio, may then be able to discern changes related to susceptibility to anxiety or depression. A large arena (40 cm.times.40 cm, VersaMax animal activity monitoring system from AccuScan Instruments) with infrared beams at three different levels was used to record rearing, hole poke, and locomotor activity. The animal was placed in the center and its activity was measured for 20 minutes. Data from this test was analyzed in five, 4-minute intervals. The total distance traveled (cm), vertical movement number (rearing), number of hole pokes, and the center to total distance ratio were recorded.

[1414] The propensity for mice to exhibit normal habituation responses to a novel environment is assessed by determining the overall change in their horizontal locomotor activity across the 5 time intervals. This calculated slope of the change in activity over time is determined using normalized, rather than absolute, total distance traveled. The slope is determined from the regression line through the normalized activity at each of the 5 time intervals. Normal habituation is represented by a negative slope value.

[1415] Results:

Anxiety: The (-/-) mice exhibited increased sum total distance traveled during open field testing when compared with their gender-matched (+/+) littermates and the historical mean, suggesting hyperactivity or an increased anxiety-like response in the mutants.

[1416] In summary, the open field testing revealed a phenotype associated with increased anxiety which could be associated with mild to moderate anxiety, anxiety due to a general medical condition, and/or bipolar disorders; hyperactivity; sensory disorders; obsessive-compulsive disorders, schizophrenia or a paranoid personality. Thus, PRO1079 polypeptides or agonists thereof would be useful in the treatment of such neurological disorders.

[1417] (d) Immunology Phenotypic Analysis

[1418] Immune related and inflammatory diseases are the manifestation or consequence of fairly complex, often multiple interconnected biological pathways which in normal physiology are critical to respond to insult or injury, initiate repair from insult or injury, and mount innate and acquired defense against foreign organisms. Disease or pathology occurs when these normal physiological pathways cause additional insult or injury either as directly related to the intensity of the response, as a consequence of abnormal regulation or excessive stimulation, as a reaction to self, or as a combination of these.

[1419] Though the genesis of these diseases often involves multistep pathways and often multiple different biological systems/pathways, intervention at critical points in one or more of these pathways can have an ameliorative or therapeutic effect. Therapeutic intervention can occur by either antagonism of a detrimental process/pathway or stimulation of a beneficial process/pathway.

[1420] T lymphocytes (T cells) are an important component of a mammalian immune response. T cells recognize antigens which are associated with a self-molecule encoded by genes within the major histocompatibility complex (MHC). The antigen may be displayed together with MHC molecules on the surface of antigen presenting cells, virus infected cells, cancer cells, grafts, etc. The T cell system eliminates these altered cells which pose a health threat to the host mammal. T cells include helper T cells and cytotoxic T cells. Helper T cells proliferate extensively following recognition of an antigen-MHC complex on an antigen presenting cell. Helper T cells also secrete a variety of cytokines, i.e., lymphokines, which play a central role in the activation of B cells, cytotoxic T cells and a variety of other cells which participate in the immune response.

[1421] In many immune responses, inflammatory cells infiltrate the site of injury or infection. The migrating cells may be neutrophilic, eosinophilic, monocytic or lymphocytic as can be determined by histologic examination of the affected tissues. Current Protocols in Immunology, ed. John E. Coligan, 1994, John Wiley & Sons, Inc.

[1422] Many immune related diseases are known and have been extensively studied. Such diseases include immune-mediated inflammatory diseases (such as rheumatoid arthritis, immune mediated renal disease, hepatobiliary diseases, inflammatory bowel disease (IBD), psoriasis, and asthma), non-immune-mediated inflammatory diseases, infectious diseases, immunodeficiency diseases, neoplasia, and graft rejection, etc. In the area of immunology, targets were identified for the treatment of inflammation and inflammatory disorders.

[1423] In the area of immunology, targets have been identified herein for the treatment of inflammation and inflammatory disorders. Immune related diseases, in one instance, could be treated by suppressing the immune response. Using neutralizing antibodies that inhibit molecules having immune stimulatory activity would be beneficial in the treatment of immune-mediated and inflammatory diseases. Molecules which inhibit the immune response can be utilized (proteins directly or via the use of antibody agonists) to inhibit the immune response and thus ameliorate immune related disease.

[1424] The following tests were performed:

[1425] (1) Hematology Analysis:

[1426] Test Description Blood tests are carried out by Abbott's Cell-Dyn 3500R, an automated hematology analyzer. Some of its features include a five-part WBC differential. `Patient` reports can cover over 22 parameters in all.

[1427] Results:

Hematology: The female (-/-) mouse available for analysis was anemic, exhibiting a decreased red blood cell count, hemoglobin concentration, and hematocrit with an increase in mean corpuscular volume and red blood cell distribution width when compared with their (+/+) littermates and the historical means.

[1428] These results are related to a phenotype associated with anemia. Thus, PRO1079 polypeptides, agonists thereof or the encoding gene for PRO1079 polypeptides must be essential for normal red blood cell production and as such would be useful in the treatment of blood disorders associated with anemia or a low hematocrit.

[1429] (2) Flourescence-Activated Cell-Sorting (FACS) Analysis

[1430] Procedure:

[1431] FACS analysis of immune cell composition from peripheral blood was performed including CD4, CD8 and T cell receptor to evaluate T lymphocytes, CD19 for B lymphocytes, CD45 as a leukocyte marker and pan NK for natural killer cells. The FACS analysis was carried out on 2 wild type and 1 homozygous mice and included cells derived from thymus, spleen, bone marrow and lymph node.

[1432] In these studies, analyzed cells were isolated from thymus, peripheral blood, spleen, bone marrow and lymph nodes. Flow cytometry was designed to determine the relative proportions of CD4 and CD8 positive T cells, B cells, NK cells and monocytes in the mononuclear cell population. A Becton-Dickinson FACSCalibur 3-laser FACS machine was used to assess immune status. For Phenotypic Assays and Screening, this machine records CD4+/CD8-, CD8+/CD4-, NK, B cell and monocyte numbers in addition to the CD4+/CD8+ ratio.

[1433] The mononuclear cell profile was derived by staining a single sample of lysed peripheral blood from each mouse with a panel of six lineage-specific antibodies: CD45 PerCP, anti-TCRb APC, CD4 PE, CD8 FITC, pan-NK PE, and CD19 FITC. The two FITC and PE labeled antibodies stain mutually exclusive cell types. The samples were analyzed using a Becton Dickinson FACSCalibur flow cytometer with CellQuest software.

[1434] Results:

FACS3: The single female (-/-) mouse analyzed exhibited an altered distribution of leukocyte subsets in the peripheral blood, characterized by an increased percentage of natural killer cells when compared with its (+/+) littermates and the historical mean.

[1435] FACS results indicate that the homozygous mutant mice have an increased mean percentage of natural killer cells. Thus, PRO1079 polypeptides or agonists thereof function as negative regulators of NK cell production. Natural killer cells are the first line of defense to viral infection since these cells have been implicated in viral immunity and in defense against tumors. Natural killer cells or NK cells act as effectors in antibody-dependent cell-mediated cytotoxicity and have been identified by their ability to kill certain lymphoid tumor cell lines in vitro without the need for prior immunization or activation. Thus, antagonists (inhibitors) of PRO1079 polypeptides would be useful in the production of NK cells which are important for antibody dependent cell-mediated cytotoxicity.

[1436] (3) Ovalbumin Challenge

[1437] Procedure: This assay was carried out on 7 wild types and 2 homozygotes. Chicken ovalbumin (OVA) is a T-cell dependent antigen, which is commonly used as a model protein for studying antigen-specific immune responses in mice. OVA is non-toxic and inert and therefore will not cause harm to the animals even if no immune response is induced. The murine immune response to OVA has been well characterized, to the extent that the immuno dominant peptides for eliciting T cell responses have been identified. Anti-OVA antibodies are detectable 8 to 10 days after immunization using enzyme-linked immunosorbent assay (ELIZA), and determination of different isotypes of antibodies gives further information on the complex processes that may lead to a deficient response in genetically engineered mice.

[1438] As noted above, this protocol assesses the ability of mice to raise an antigen-specific immune response. Animals were injected IP with 50 mg of chicken ovalbumin emulsified in Complete Feund's Adjuvant and 14 days later the serum titer of anti-ovalbumin antibodies (IgM, IgG1 and IgG2 subclasses) was measured. The amount of OVA-specific antibody in the serum sample is proportional to the Optical Density (OD) value generated by an instrument that scans a 96-well sample plate. Data was collected for a set of serial dilutions of each serum sample.

[1439] Results of this Challenge:

[1440] The (-/-) mice exhibited decreased (low/no) mean serum IgG1 and IgG2a responses when compared with their (+/+) littermates and the historical mean.

[1441] In summary, the ovalbumin challenge studies indicate that knockout mice deficient in the gene encoding PRO1079 polypeptides exhibit immunological abnormalities when compared with their wild-type littermates. In particular, the mutant mice exhibited a decreased ability to elicit an immunological response when challenged with the T-cell dependent OVA antigen. Thus, PRO1079 polypeptides or agonists thereof, would be useful for stimulating the immune system (such as T cell proliferation) and would find utility in the cases wherein this effect would be beneficial to the individual such as in the case of leukemia, and other types of cancer, and in immunocompromised patients, such as AIDS sufferers. Accordingly, inhibitors (antagonists) of PRO1079 polypeptides would be useful for inhibiting the immune response and thus would be useful candidates for suppressing harmful immune responses, e.g. in the case of graft rejection or graft-versus-host diseases.

[1442] (e) Cardiovascular Phenotypic Analysis:

[1443] In the area of cardiovascular biology, phenotypic testing was performed to identify potential targets for the treatment of cardiovascular, endothelial or angiogenic disorders. One such phenotypic test included optic fundus photography and angiography to determine the retinal arteriovenous ratio (A/V ratio) in order to flag various eye abnormalities. An abnormal A/V ratio signals such systemic diseases or disorders that may be related to the vascular disease of hypertension (and any disease that causes hypertension; e.g. atherosclerosis), diabetes or other ocular diseases corresponding to ophthalmological disorders. Such eye abnormalities may include but are not limited to the following: retinal abnormality is retinal dysplasia, various retinopathies, restenosis, retinal artery obstruction or occlusion; retinal degeneration causing secondary atrophy of the retinal vasculature, retinitis pigmentosa, macular dystrophies, Stargardt's disease, congenital stationary night blindness, choroideremia, gyrate atrophy, Leber's congenital amaurosis, retinoschisis disorders, Wagner's syndrome, Usher syndromes, Zellweger syndrome, Saldino-Mainzer syndrome, Senior-Loken syndrome, Bardet-Biedl syndrome, Alport's syndrome, Alstom's syndrome, Cockayne's syndrome, dysplaisa spondyloepiphysaria congentia, Flynn-Aird syndrome, Friedreich ataxia, Hallgren syndrome, Marshall syndrome, Albers-Schnoberg disease, Refsum's disease, Kearns-Sayre syndrome, Waardenburg's syndrome, Alagile syndrome, myotonic dystrophy, olivopontocerebellar atrophy, Pierre-Marie dunsdrome, Stickler syndrome, carotinemeia, cystinosis, Wolfram syndrome, Bassen-Kornzweig syndrome, abetalipoproteinemia, incontinentia pigmenti, Batten's disease, mucopolysaccharidoses, homocystinuria, or mannosidosis.

[1444] Procedure: A cohort of 4 wild type, 4 heterozygotes and 1 homozygote were tested in this assay. Optic fundus photography was performed on conscious animals using a Kowa Genesis small animal fundus camera modified according to Hawes and coauthors (Hawes et al., 1999 Molecular Vision 1999; 5:22). Intra-peritoneal injection of fluorescein permitted the acquisition of direct light fundus images and fluorescent angiograms for each examination. In addition to direct ophthalmological changes, this test can detect retinal changes associated with systemic diseases such as diabetes and atherosclerosis or other retinal abnormalities. Pictures were provided of the optic fundus under normal light. The angiographic pictures allowed examination of the arteries and veins of the eye. In addition an artery to vein (A/V) ratio was determined for the eye.

[1445] Ophthalmology analysis was performed on generated F2 wild type, heterozygous, and homozygous mutant progeny using the protocol described above. Specifically, the A/V ratio was measured and calculated according to the fundus images with Kowa COMIT+ software. This test takes color photographs through a dilated pupil: the images help in detecting and classifying many diseases. The artery to vein ratio (A/V) is the ratio of the artery diameter to the vein diameter (measured before the bifurcation of the vessels). Many diseases will influence the ratio, i.e., diabetes, cardiovascular disorders, papilledema, optic atrophy or other eye abnormalities such as retinal degeneration (known as retinitis pigmentosa) or retinal dysplasia, vision problems or blindness. Thus, phenotypic observations which result in an increased artery-to-vein ratio in homozygous (-/-) and heterozygous (+/-) mutant progeny compared to wildtype (+/+) littermates would be indicative of such pathological conditions.

[1446] Results:

Fundus: One (-/-) (M-99) mouse exhibited retinal hemorrhage, preventing analysis of the artery-to-vein ratio. Angiogram: One (-/-) mouse (M-99) exhibited retinal vascular leakage.

[1447] Such detected retinal changes are most commonly associated with cardiovascular systemic diseases or disorders that may be related to the vascular disease of hypertension (and any disease that causes hypertension, e.g. atherosclerosis), diabetes or other ocular diseases corresponding to ophthalmological disorders such as retinal degeneration. Thus, antagonists of PRO1079 encoding genes would lead to similar pathological retinal changes, whereas agonists may be useful as therapeutic agents in the treatment of hypertension, atherosclerosis or other opthamological disorders including retinal degeneration and diseases associated with this condition (as indicated above).

[1448] (f) Bone Metabolism & Body Diagnostics/Radiology Phenotypic Analysis

[1449] In the area of bone metabolism, targets were identified herein for the treatment of arthritis, osteoporosis, osteopenia and osteopetrosis as well as identifying targets that promote bone healing. Tests included: [1450] DEXA for measurement of bone mineral density on femur and vertebra [1451] MicroCT for very high resolution and very high sensitivity measurements of bone mineral density for both trabecular and cortical bone.

[1452] Dexa Analysis--Test Description:

[1453] Procedure: A cohort of 4 wild type, 4 heterozygotes and 1 homozygote were tested in this assay. Dual Energy X-ray Absorptiometry (DEXA) has been used successfully to identify changes in bone. Anesthetized animals were examined and bone mineral content (BMC), BMC/LBM ratios, volumetric bone mineral density (vBMD), total body BMD, femur BMD and vertebra BMD were measured.

[1454] The mouse was anesthetized by intraperitoneal injection of Avertin (1.25% 2,2,2,-tribromoethanol, 20 ml/kg body weight), body length and weight were measured, and then the mouse was placed in a prone position on the platform of the PIXImus.TM. Densitometer (Lunar Inc.) for a DEXA scan. Using Lunar PIXImus software, the bone mineral density (BMD) and fat composition (% fat) and total tissue mass (TTM) were determined in the regions of interest (ROI) [i.e., whole body, vertebrae, and both femurs].

[1455] Results:

DEXA: The single male (-/-) mouse available for analysis exhibited decreased total tissue mass and lean body mass when compared with its gender-matched (+/+) littermates and the historical means, whereas the female (-/-) mouse analyzed exhibited increased total tissue mass (TTM), total fat mass and percent total body fat (single (-/-) female mouse had 34% body fat).

[1456] The male (-/-) mice analyzed by DEXA exhibited notably decreased total tissue mass and lean body mass as well as decreased bone measurements when compared with their (+/+) littermates, suggestive of growth retardation in these mutants. These observations are consistent with the reduced viability shown in the knockout mice. This in conjunction with the observations of decreased body weight and length is indicative of growth retardation, a tissue wasting condition such as cachexia or other growth related disorders. Thus, PRO1079 polypeptides or agonists thereof would be useful in the treatment or prevention of growth disorders and/or decreased viability. It is interesting that the female (-/-) mouse showed signs of obesity with notable increased body fat.

[1457] 66.16. Generation and Analysis of Mice Comprising DNA58727-1474 (UNQ553) Gene Disruptions

[1458] In these knockout experiments, the gene encoding PROMO polypeptides (designated as DNA58727-1474) (UNQ553) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: NM.sub.--016969 ACCESSION:NM.sub.--016969 NID: gi 8393799 ref NM.sub.--016969.1 Mus musculus myeloid-associated differentiation marker (Myadm); protein reference: O35682 ACCESSION:O35682 NID: Mus musculus (Mouse). Myeloid-associated differentiation marker (Myeloid upregulated protein); the human gene sequence reference: NM.sub.--138373 Homo sapiens myeloid-associated differentiation marker (MYADM); the human protein sequence corresponds to reference: Q96S97 ACCESSION:Q96S97 NID: Homo sapiens (Human). Myeloid-associated differentiation marker (SB135).

[1459] The mouse gene of interest is Myadm (myeloid-associated differentiation marker), ortholog of human MYADM. Aliases include D7Wsu62e.

[1460] MYADM is a likely integral plasma membrane protein, consisting of eight transmembrane segments contained within two MARVEL domains. MARVEL domains are often found in lipid-associating proteins that participate in transport vesicle biogenesis (Pfam accession PF01284). MYADM is expressed in myeloid cells and is likely involved in myeloid differentiation (Pettersson et al, J Leukoc Biol 67(3):423-31 (2000); Cui et al, Mol Biol Rep 28(3):123-38 (2001)).

[1461] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00085 wt het hom Total Observed 11 33 16 60 Expected 15 30 15 60

Chi-Sq.=4.24 Significance=0.12003164 (hom/n)=0.24 Avg. Litter Size=8

Mutation Information

[1462] Mutation Type: Homologous Recombination (standard) Description: Coding exon 1 was targeted (NCBI accession NM.sub.--016969.1). 1. Wild-type Expression Panel: Expression of the target gene was detected in all 13 adult tissue samples tested by RT-PCR, except bone and adipose. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[1463] 66.16.1. Phenotypic Analysis (for Disrupted Gene: DNA58727-1474 (UNQ553)

[1464] (a) Overall Phenotypic Summary:

[1465] Mutation of the gene encoding the ortholog of human myeloid-associated differentiation marker (MYADM) resulted in increased TNF-alpha, MCP-1, and IL-6 responses to LPS challenge in (-/-) mice. In addition, mutant (-/-) mice on a high fat diet exhibited a slightly enhanced glucose tolerance. The mutant (-/-) mice exhibited a decreased or absent startle response indicating deafness. Gene disruption was confirmed by Southern blot.

[1466] (b) Immunology Phenotypic Analysis

[1467] Immune related and inflammatory diseases are the manifestation or consequence of fairly complex, often multiple interconnected biological pathways which in normal physiology are critical to respond to insult or injury, initiate repair from insult or injury, and mount innate and acquired defense against foreign organisms. Disease or pathology occurs when these normal physiological pathways cause additional insult or injury either as directly related to the intensity of the response, as a consequence of abnormal regulation or excessive stimulation, as a reaction to self, or as a combination of these.

[1468] Though the genesis of these diseases often involves multistep pathways and often multiple different biological systems/pathways, intervention at critical points in one or more of these pathways can have an ameliorative or therapeutic effect. Therapeutic intervention can occur by either antagonism of a detrimental process/pathway or stimulation of a beneficial process/pathway.

[1469] T lymphocytes (T cells) are an important component of a mammalian immune response. T cells recognize antigens which are associated with a self-molecule encoded by genes within the major histocompatibility complex (MHC). The antigen may be displayed together with MHC molecules on the surface of antigen presenting cells, virus infected cells, cancer cells, grafts, etc. The T cell system eliminates these altered cells which pose a health threat to the host mammal. T cells include helper T cells and cytotoxic T cells. Helper T cells proliferate extensively following recognition of an antigen-MHC complex on an antigen presenting cell. Helper T cells also secrete a variety of cytokines, i.e., lymphokines, which play a central role in the activation of B cells, cytotoxic T cells and a variety of other cells which participate in the immune response.

[1470] In many immune responses, inflammatory cells infiltrate the site of injury or infection. The migrating cells may be neutrophilic, eosinophilic, monocytic or lymphocytic as can be determined by histologic examination of the affected tissues. Current Protocols in Immunology, ed. John E. Coligan, 1994, John Wiley & Sons, Inc.

[1471] Many immune related diseases are known and have been extensively studied. Such diseases include immune-mediated inflammatory diseases (such as rheumatoid arthritis, immune mediated renal disease, hepatobiliary diseases, inflammatory bowel disease (IBD), psoriasis, and asthma), non-immune-mediated inflammatory diseases, infectious diseases, immunodeficiency diseases, neoplasia, and graft rejection, etc. In the area of immunology, targets were identified for the treatment of inflammation and inflammatory disorders.

[1472] In the area of immunology, targets have been identified herein for the treatment of inflammation and inflammatory disorders Immune related diseases, in one instance, could be treated by suppressing the immune response. Using neutralizing antibodies that inhibit molecules having immune stimulatory activity would be beneficial in the treatment of immune-mediated and inflammatory diseases. Molecules which inhibit the immune response can be utilized (proteins directly or via the use of antibody agonists) to inhibit the immune response and thus ameliorate immune related disease.

[1473] The following test was performed:

[1474] Acute Phase Response:

[1475] Test Description: Bacterial lipopolysaccharide (LPS) is an endotoxin, and as such is a potent inducer of an acute phase response and systemic inflammation. The Level I LPS mice were injected intraperitoneally (i.p.) with a sublethal dose of LPS in 200 .mu.L sterile saline using a 26 gauge needle. The doses were based on the average weight of the mice tested at 1 .mu.g/g body weight 3 hours after injection; a 100 ul blood sample was then taken and analyzed for the presence of TNFa, MCP-1, and IL-6 on the FACS Calibur instrument.

[1476] Results:

[1477] The (-/-) mice exhibited increased mean serum TNF-alpha, MCP-1 and IL-6 responses to LPS challenge when compared with their (+/+) littermates and the historical means.

[1478] In summary, the LPS endotoxin challenge demonstrated that knockout mice deficient in the gene encoding PRO1110 polypeptides exhibit immunological abnormalities when compared with their wild-type littermates. In particular, the mutant mice exhibited an increased ability to elicit an immunological response (TNF-alpha, MCP-1 and IL-6 production) when challenged with the LPS endotoxin indicating a pro-inflammatory response. TNF-alpha, MCP-1 and IL-6 contribute to the later stages of B cell activation. TNF-alpha is an important inflammatory mediator. In addition, TNF-alpha, MCP-1 and IL-6 play a critical role in inducing the acute phase response and systemic inflammation. TNF-alpha can substitute for the membrane-bound signal in macrophage activation (thus serving as an effector molecule). This suggests that inhibitors or antagonists to PRO1110 polypeptides would stimulate the immune system and would find utility in the cases wherein this effect would be beneficial to the individual such as in the case of leukemia, and other types of cancer, and in immunocompromised patients, such as AIDS sufferers. Accordingly, PRO1110 polypeptides or agonists thereof would be useful in inhibiting the immune response and would be useful candidates for suppressing harmful immune responses, e.g. in the case of graft rejection or graft-versus-host diseases.

[1479] (c) Phenotypic Analysis: Metabolism--Blood Chemistry/Glucose Tolerance

[1480] In the area of metabolism, targets may be identified for the treatment of diabetes. Blood chemistry phenotypic analysis includes blood glucose measurements. The COBAS Integra 400 (mfr: Roche) was used for running blood chemistry tests on the mice. In the area of metabolism, targets may be identified for the treatment of diabetes. Blood chemistry phenotypic analysis includes glucose tolerance tests to measure insulin sensitivity and changes in glucose metabolism. Abnormal glucose tolerance test results may indicate but may not be limited to the following disorders or conditions: Diabetes Type 1 and Type 2, Syndrome X, various cardiovascular diseases and/or obesity.

[1481] Procedure: A cohort of 2 wild type and 4 homozygous mice were used in this assay. The glucose tolerance test is the standard for defining impaired glucose homeostasis in mammals. Glucose tolerance tests were performed using a Lifescan glucometer. Animals were injected IP at 2 g/kg with D-glucose delivered as a 20% solution and blood glucose levels were measured at 0, 30, 60 and 90 minutes after injection.

[1482] Results:

[1483] Glucose Tolerance Test: The male mutant (-/-) mice on a high fat diet exhibited a slightly enhanced glucose tolerance when compared with their gender-matched (+/+) littermates.

[1484] In these studies the mutant (-/-) mice showed an increased or enhanced glucose tolerance in the presence of normal fasting glucose at all 3 intervals tested when compared with their gender-matched (+/+) littermates and the historical means. Thus, knockout mice exhibited a slightly increased insulin sensitivity or the opposite phenotypic pattern of an impaired glucose homeostasis, and as such antagonists (inhibitors) to PRO1110 polypeptides or its encoding gene would be useful in the treatment of an impaired glucose homeostasis.

[1485] (d) Phenotypic Analysis: CNS/Neurology

[1486] In the area of neurology, analysis focused herein on identifying in vivo validated targets for the treatment of neurological and psychiatric disorders including depression, generalized anxiety disorders, attention deficit hyperactivity disorder, obsessive compulsive disorder, schizophrenia, cognitive disorders, hyperalgesia and sensory disorders. Neurological disorders include the category defined as "anxiety disorders" which include but are not limited to: mild to moderate anxiety, anxiety disorder due to a general medical condition, anxiety disorder not otherwise specified, generalized anxiety disorder, panic attack, panic disorder with agoraphobia, panic disorder without agoraphobia, posttraumatic stress disorder, social phobia, specific phobia, substance-induced anxiety disorder, acute alcohol withdrawal, obsessive compulsive disorder, agoraphobia, bipolar disorder I or II, bipolar disorder not otherwise specified, cyclothymic disorder, depressive disorder, major depressive disorder, mood disorder, substance-induced mood disorder. In addition, anxiety disorders may apply to personality disorders including but not limited to the following types: paranoid, antisocial, avoidant behavior, borderline personality disorders, dependent, histronic, narcissistic, obsessive-compulsive, schizoid, and schizotypal.

[1487] Procedure:

[1488] Behavioral screens were performed on a cohort of 4 wild type, 4 heterozygous and 8 homozygous mutant mice. All behavioral tests were done between 12 and 16 weeks of age unless reduced viability necessitates earlier testing.

[1489] Prepulse Inhibition of the Acoustic Startle Reflex

[1490] Prepulse inhibition of the acoustic startle reflex occurs when a loud 120 decibel (dB) startle-inducing tone is preceded by a softer (prepulse) tone. The PPI paradigm consists of six different trial types (70 dB background noise, 120 dB alone, 74 dB+120 dB-pp 4, 78 dB+120 dB-pp 8, 82 dB+120 dB-pp 12, and 90 dB+120 dB-pp 20) each repeated in pseudo random order six times for a total of 36 trials. The max response to the stimulus (V max) is averaged for each trial type. Animals with a 120 dB average value equal to or below 100 are excluded from analysis. The percent that the prepulse inhibits the animal's response to the startle stimulus is calculated and graphed.

[1491] Results:

[1492] The knockout mutant (-/-) mice exhibited a decreased or absent startle response which is indicative of deafness.

66.17. Generation and Analysis of Mice Comprising DNA62377-1381-1 (UNQ561) Gene Disruptions

[1493] In these knockout experiments, the gene encoding PRO1122 polypeptides (designated as DNA62377-1381-1) (UNQ561) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: NM.sub.--145834 ACCESSION:NM.sub.--145834 NID: gi 22003879 ref NM.sub.--145834.1 Mus musculus interleukin 17C (1117c); protein reference:Q8K4C5 ACCESSION:Q8K4C5 NID: Mus musculus (Mouse). IL-17C; the human gene sequence reference: NM.sub.--013278 ACCESSION:NM.sub.--013278 NID: gi 27477078 ref NM.sub.--013278.3 Homo sapiens interleukin 17C (IL17C); the human protein sequence corresponds to reference: Q9P0M4 ACCESSION:Q9P0M4 NID: Homo sapiens (Human). Interleukin-17C precursor (IL-17C) (Cytokine CX2).

[1494] The mouse gene of interest is 1117c (interleukin 17C), ortholog of human IL17C. Aliases include IL-17C, CX2, IL-21, and cytokine CX2.

[1495] IL17C is a secreted protein that likely functions as a ligand for an interleukin-17 family receptor. Cells that express this cytokine have not been identified; however, IL17C stimulates release of tumor necrosis factor-alpha and IL-1beta from monocytic cell line THP-1. Moreover, IL17C induces neutrophilia and expression of interferon-gamma and interleukin-6 in lung airway, supporting a role for IL17C in immune function (Li et al, Proc Natl Acad Sci USA 97(2):773-8 (2000); Hurst et al, J Immunol 169(1):443-53 (2002); Moseley et al, Cytokine Growth Factor Rev 14(2):155-74 (2003)).

[1496] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level phenotypic analysis is performed on mice from this generation

TABLE-US-00086 wt het hom Total Observed 18 34 13 65 Expected 16.25 32.5 16.25 65

Chi-Sq.=2.59 Significance=0.2738979 (hom/n)=021 Avg. Litter Size=9

Mutation Information

[1497] Mutation Type Homologous Recombination (standard) Description: Coding exons 1 and 2 were targeted (NCBI accession NM.sub.--145834.1). 1. Wild-type Expression Panel: Expression of the target gene was detected in embryonic stem (ES) cells and in all 13 adult tissue samples tested by RT-PCR, except liver; skeletal muscle; bone; stomach, small intestine, and colon; and adipose. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[1498] 66.17.1. Phenotypic Analysis (for Disrupted Gene: DNA62377-1381-1 (UNQ561)

[1499] (a) Overall Phenotypic Summary:

[1500] Mutation of the gene encoding the ortholog of human interleukin 17C (IL17C) resulted in elevated mean serum levels of IgM serum immunoglobulins in the (-/-) mice. The mutant (-/-) mice also showed an increased in IL-6 response to LPS. Gene disruption was confirmed by Southern blot.

[1501] (b) Immunology Phenotypic Analysis

[1502] Immune related and inflammatory diseases are the manifestation or consequence of fairly complex, often multiple interconnected biological pathways which in normal physiology are critical to respond to insult or injury, initiate repair from insult or injury, and mount innate and acquired defense against foreign organisms. Disease or pathology occurs when these normal physiological pathways cause additional insult or injury either as directly related to the intensity of the response, as a consequence of abnormal regulation or excessive stimulation, as a reaction to self, or as a combination of these.

[1503] Though the genesis of these diseases often involves multistep pathways and often multiple different biological systems/pathways, intervention at critical points in one or more of these pathways can have an ameliorative or therapeutic effect. Therapeutic intervention can occur by either antagonism of a detrimental process/pathway or stimulation of a beneficial process/pathway.

[1504] T lymphocytes (T cells) are an important component of a mammalian immune response. T cells recognize antigens which are associated with a self-molecule encoded by genes within the major histocompatibility complex (MHC). The antigen may be displayed together with MHC molecules on the surface of antigen presenting cells, virus infected cells, cancer cells, grafts, etc. The T cell system eliminates these altered cells which pose a health threat to the host mammal. T cells include helper T cells and cytotoxic T cells. Helper T cells proliferate extensively following recognition of an antigen-MHC complex on an antigen presenting cell. Helper T cells also secrete a variety of cytokines, i.e., lymphokines, which play a central role in the activation of B cells, cytotoxic T cells and a variety of other cells which participate in the immune response.

[1505] In many immune responses, inflammatory cells infiltrate the site of injury or infection. The migrating cells may be neutrophilic, eosinophilic, monocytic or lymphocytic as can be determined by histologic examination of the affected tissues. Current Protocols in Immunology, ed. John E. Coligan, 1994, John Wiley Si Sons, Inc.

[1506] Many immune related diseases are known and have been extensively studied. Such diseases include immune-mediated inflammatory diseases (such as rheumatoid arthritis, immune mediated renal disease, hepatobiliary diseases, inflammatory bowel disease (IBD), psoriasis, and asthma), non-immune-mediated inflammatory diseases, infectious diseases, immunodeficiency diseases, neoplasia, and graft rejection, etc. In the area of immunology, targets were identified for the treatment of inflammation and inflammatory disorders.

[1507] In the area of immunology, targets have been identified herein for the treatment of inflammation and inflammatory disorders. Immune related diseases, in one instance, could be treated by suppressing the immune response. Using neutralizing antibodies that inhibit molecules having immune stimulatory activity would be beneficial in the treatment of immune-mediated and inflammatory diseases. Molecules which inhibit the immune response can be utilized (proteins directly or via the use of antibody agonists) to inhibit the immune response and thus ameliorate immune related disease.

[1508] The following test was performed:

[1509] Serum Immunoglobulin Isotyping Assay:

[1510] The Serum Immunoglobulin Isotyping Assay is performed using a Cytometric Bead Array (CBA) kit. This assay is used to rapidly identify the heavy and light chain isotypes of a mouse monoclonal antibody in a single sample. The values expressed are "relative fluorescence units" and are based on the detection of kappa light chains. Any value <6 is not significant.

[1511] Results:

[1512] The (-/-) mice exhibited an increased mean serum IgM level when compared with that of their (+/+) littermates and the historical medians.

[1513] Mutant (-/-) mice exhibited elevation of IgM serum immunoglobulins compared to their gender-matched (+/+) littermates. IgM immunoglobulins are the first to be produced in a humoral immune response for neutralization of bacterial toxins and are particularly important in activating the complement system. The observed phenotype suggests that the PRO1122 polypeptide is a negative regulator of inflammatory responses. These immunological abnormalities suggest that inhibitors (antagonists) of PRO1122 polypeptides would be important agents which could stimulate the immune system (such as T cell proliferation) and would find utility in the cases wherein this effect would be beneficial to the individual such as in the case of leukemia, and other types of cancer, and in immunocompromised patients, such as AIDS sufferers. Accordingly, PRO1122 polypeptides or agonists thereof would be useful in inhibiting the immune response and would be useful candidates for suppressing harmful immune responses, e.g. in the case of graft rejection or graft-versus-host diseases.

[1514] Acute Phase Response:

[1515] Test Description: Bacterial lipopolysaccharide (LPS) is an endotoxin, and as such is a potent inducer of an acute phase response and systemic inflammation. The Level I LPS mice were injected intraperitoneally (i.p.) with a sub-lethal dose of LPS in 200 .mu.L sterile saline using a 26 gauge needle. The doses were based on the average weight of the mice tested at 1 .mu.g/g body weight 3 hours after injection; a 100 ul blood sample was then taken and analyzed for the presence of TNFa, MCP-1, and IL-6 on the FACS Calibur instrument.

[1516] Results:

[1517] The (-/-) mice exhibited an increased mean serum IL-6 response to LPS challenge when compared with their (+/+) littermates and the historical means.

[1518] In summary, the LPS endotoxin challenge demonstrated that knockout mice deficient in the gene encoding PRO1122 polypeptides exhibit immunological abnormalities when compared with their wild-type littermates. In particular, the mutant mice exhibited an increased ability to elicit an immunological response (IL-6 production) when challenged with the LPS endotoxin indicating a pro-inflammatory response. IL-6 contributes to the later stages of B cell activation playing a critical role in inducing the acute phase response and systemic inflammation. This suggests that inhibitors or antagonists to PRO1122 polypeptides would stimulate the immune system and would find utility in the cases wherein this effect would be beneficial to the individual such as in the case of leukemia, and other types of cancer, and in immunocompromised patients, such as AIDS sufferers. Accordingly, PRO1122 polypeptides or agonists thereof would be useful in inhibiting the immune response and would be useful candidates for suppressing harmful immune responses, e.g. in the case of graft rejection or graft-versus-host diseases.

[1519] 66.18. Generation and Analysis of Mice Comprising DNA58850-1495 (UNQ576) Gene Disruptions

[1520] In these knockout experiments, the gene encoding PRO1138 polypeptides (designated as DNA58850-1495) (UNQ576) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: NM.sub.--144539 Mus musculus SLAM family member 7 (Slamf7); protein reference: Q8BHK6 ACCESSION:Q8BHK6 NID: Mus musculus (Mouse). Mus musculus adult male testis cDNA, RIKEN full-length enriched library, clone:4932702H22 product:SIMILAR TO 19A24 PROTEIN homolog (Mus musculus adult male testis cDNA, RIKEN full-length enriched library, clone:4932704K11 product:SIMILAR TO 19A24, PROTEIN homolog) (Mus musculus adult male aorta and vein cDNA, RIKEN full-length enriched library, clone:A530014C02 product:SIMILAR TO 19A24 PROTEIN homolog); the human gene sequence reference: NM.sub.--021181 Homo sapiens SLAM family member 7 (SLAMF7); the human protein sequence corresponds to reference: Q9NY08 ACCESSION:Q9NY08 NID: Homo sapiens (Human). 19A protein.

[1521] The mouse gene of interest is Slamf7 (SLAM family member 7), ortholog of human SLAMF7. Aliases include 19A, CS1, 19A24, CRACC, 4930560D03Rik, CD2-like receptor activating cytotoxic cells, novel Ly9, and novel LY9 (lymphocyte antigen 9) like protein.

[1522] SLAMF7 is a type I plasma membrane protein that functions as a homophilic receptor or cell adhesion molecule and is expressed primarily on natural killer cells, T-cells, and activated B-cells. The protein consists of two extracellular immunoglobulin-like domains, a transmembrane segment, and an 88-amino acid cytoplasmic domain. SLAMF7 likely plays a role in regulating NK cell cytolytic activity and lymphocyte adhesion (Kumaresan et al, Mol Immunol 39(1-2):1-8 (2002); Murphy et al, Biochem J 361(Pt 3):431-6 (2002); Bouchon et al, J Immunol 167(10):5517-21 (2001); Tovar et al, Immunogenetics 54(6):394-402 (2002)).

[1523] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00087 wt het hom Total Observed 22 37 16 75 Expected 18.75 37.5 18.75 75

Chi-Sq.=1.63 Significance=0.44263932 (hom/n)=0.22 Avg. Litter Size=10

Mutation Information

[1524] Mutation Type: Homologous Recombination (standard) Description: Coding exons 2 through 6 were targeted (NCBI accession NM.sub.--144539.2). 1. Wild-type Expression Panel: Expression of the target gene was detected in all 13 adult tissue samples tested by RT-PCR, except skeletal muscle and bone. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[1525] 66.18.1. Phenotypic Analysis (for Disrupted Gene: DNA58850-1495 (UNQ576)

[1526] (a) Overall Phenotypic Summary:

[1527] Mutation of the gene encoding the ortholog of human SLAM family member 7 (SLAMF7) resulted in an increase in the IL-6 response to LPS. Gene disruption was confirmed by Southern blot.

[1528] (b) Immunology Phenotypic Analysis

[1529] Immune related and inflammatory diseases are the manifestation or consequence of fairly complex, often multiple interconnected biological pathways which in normal physiology are critical to respond to insult or injury, initiate repair from insult or injury, and mount innate and acquired defense against foreign organisms. Disease or pathology occurs when these normal physiological pathways cause additional insult or injury either as directly related to the intensity of the response, as a consequence of abnormal regulation or excessive stimulation, as a reaction to self, or as a combination of these.

[1530] Though the genesis of these diseases often involves multistep pathways and often multiple different biological systems/pathways, intervention at critical points in one or more of these pathways can have an ameliorative or therapeutic effect. Therapeutic intervention can occur by either antagonism of a detrimental process/pathway or stimulation of a beneficial process/pathway.

[1531] T lymphocytes (T cells) are an important component of a mammalian immune response. T cells recognize antigens which are associated with a self-molecule encoded by genes within the major histocompatibility complex (MHC). The antigen may be displayed together with MHC molecules on the surface of antigen presenting cells, virus infected cells, cancer cells, grafts, etc. The T cell system eliminates these altered cells which pose a health threat to the host mammal. T cells include helper T cells and cytotoxic T cells. Helper T cells proliferate extensively following recognition of an antigen-MHC complex on an antigen presenting cell. Helper T cells also secrete a variety of cytokines, i.e., lymphokines, which play a central role in the activation of B cells, cytotoxic T cells and a variety of other cells which participate in the immune response.

[1532] In many immune responses, inflammatory cells infiltrate the site of injury or infection. The migrating cells may be neutrophilic, eosinophilic, monocytic or lymphocytic as can be determined by histologic examination of the affected tissues. Current Protocols in Immunology, ed. John E. Coligan, 1994, John Wiley & Sons, Inc.

[1533] Many immune related diseases are known and have been extensively studied. Such diseases include immune-mediated inflammatory diseases (such as rheumatoid arthritis, immune mediated renal disease, hepatobiliary diseases, inflammatory bowel disease (IBD), psoriasis, and asthma), non-immune-mediated inflammatory diseases, infectious diseases, immunodeficiency diseases, neoplasia, and graft rejection, etc. In the area of immunology, targets were identified for the treatment of inflammation and inflammatory disorders.

[1534] In the area of immunology, targets have been identified herein for the treatment of inflammation and inflammatory disorders. Immune related diseases, in one instance, could be treated by suppressing the immune response. Using neutralizing antibodies that inhibit molecules having immune stimulatory activity would be beneficial in the treatment of immune-mediated and inflammatory diseases. Molecules which inhibit the immune response can be utilized (proteins directly or via the use of antibody agonists) to inhibit the immune response and thus ameliorate immune related disease.

[1535] The following test was performed:

[1536] Acute Phase Response:

[1537] Test Description Bacterial lipopolysaccharide (LPS) is an endotoxin, and as such is a potent inducer of an acute phase response and systemic inflammation. The Level I LPS mice were injected intraperitoneally (i.p.) with a sub-lethal dose of LPS in 200 .mu.L sterile saline using a 26 gauge needle. The doses were based on the average weight of the mice tested at 1 .mu.g/g body weight 3 hours after injection; a 100 ul blood sample was then taken and analyzed for the presence of TNFa, MCP-1, and IL-6 on the FACS Calibur instrument.

[1538] Results:

[1539] The (-/-) mice exhibited an increased mean serum IL-6 response to LPS challenge when compared with their (+/+) littermates and the historical means.

[1540] In summary, the LPS endotoxin challenge demonstrated that knockout mice deficient in the gene encoding PRO1138 polypeptides exhibit immunological abnormalities when compared with their wild-type littermates. In particular, the mutant mice exhibited an increased ability to elicit an immunological response (IL-6 production) when challenged with the LPS endotoxin indicating a pro-inflammatory response. IL-6 contributes to the later stages of B cell activation playing a critical role in inducing the acute phase response and systemic inflammation. This suggests that inhibitors or antagonists to PRO1138 polypeptides would stimulate the immune system and would find utility in the cases wherein this effect would be beneficial to the individual such as in the case of leukemia, and other types of cancer, and in immunocompromised patients, such as AIDS sufferers. Accordingly, PRO1138 polypeptides or agonists thereof would be useful in inhibiting the immune response and would be useful candidates for suppressing harmful immune responses, e.g. in the case of graft rejection or graft-versus-host diseases.

66.19. Generation and Analysis of Mice Comprising DNA59586-1520 (UNQ604) Gene Disruptions

[1541] In these knockout experiments, the gene encoding PRO1190 polypeptides (designated as DNA59586-1520) (UNQ604) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: NM.sub.--172506 Mus musculus biregional cell adhesion molecule-related/down-regulated by oncogenes (Cdon) binding protein (Boc); protein reference: Q8CE91 ACCESSION:Q8CE91 NID: Mus musculus (Mouse). Mus musculus 10 days neonate skin cDNA, RIKEN full-length enriched library, clone:4732455C11 product:biregional cell adhesion molecule-related/down-regulated by oncogenes (Cdon) binding protein, full insert sequence; the human gene sequence reference: NM.sub.--033254 ACCESSION:NM.sub.--033254 NID: gi 15147239 ref NM.sub.--033254.1 Homo sapiens brother of CDO (BOC); the human protein sequence corresponds to reference: Q9BWV1 ACCESSION:Q9BWV1 NID: Homo sapiens (Human). BROTHER OF CDO.

[1542] The mouse gene of interest is Boc (biregional cell adhesion molecule-related/down-regulated by oncogenes (Cdon) binding protein), ortholog of human BOC (brother of CDO). Aliases include 4732455C11 and Biregional Cdon binding protein.

[1543] BOC is a type I plasma membrane protein that likely functions as a receptor subunit for cell-cell communication. The protein interacts with homolog CDON (cell adhesion molecule-related/down-regulated by oncogenes), N-cadherins, and M-cadherins in a cis fashion, forming a receptor complex at sites of cell-cell contact in myoblasts. During embryonic development, BOC is expressed in musculoskeletal and central nervous systems and in areas of proliferation and differentiation. BOC likely plays a role in muscle cell differentiation and transformation (Wegorzewska et al, Mol Carcinog 37(1):1-4 (2003); Mulieri et al, Dev Dyn 223(3):379-88 (2002); Kang et al, EMBO J 21(1-2):114-24 (2002); Kang et al, Proc Natl Acad Sci USA 100(7):3989-94 (2003)).

[1544] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00088 wt het hom Total Observed 18 30 20 68 Expected 17 34 17 68

Chi-Sq.=1.3 Significance=0.5220458 (hom/n)=0.25 Avg. Litter Size=9

Mutation Information

[1545] Mutation Type: Homologous Recombination (standard) Description: Coding exons 1 and 2 were targeted (NCBI accession NM.sub.--172506.1). 1. Wild-type Expression Panel: Expression of the target gene was detected in embryonic stem (ES) cells and in all 13 adult tissue samples tested by RT-PCR, except skeletal muscle and bone. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[1546] 66.19.1. Phenotypic Analysis (for Disrupted Gene: DNA59586-1520 (UNQ0604)

[1547] (a) Overall Phenotypic Summary:

[1548] Mutation of the gene encoding the ortholog of human brother of CDO (BOC) resulted in two knockout mice exhibiting a systemic histiocytic storage disease affecting only the macrophages in several organs. Gene disruption was confirmed by Southern blot.

[1549] (b) Pathology

Gross: Two of the (-/-) mice examined (M-138 and F-139) exhibited an enlarged liver, spleen, and mesenteric lymph nodes. Microscopic: Among the (-/-) mice analyzed, 2 (F-139 and M-138) exhibited a systemic histiocytic storage disease affecting only the macrophages in several organs. The liver, spleen, and mesenteric lymph nodes were the most affected histologically. The cytoplasm of the macrophages was markedly enlarged and contained predominantly clear vacuoles and less prominent fibrillar material. The clear vacuoles were the artifactual remnants of structures containing material dissolved during the process required to prepare histological slides. The removed material presumably contained lipid predominantly. These lesions were characteristic of a group of genetic diseases known as lipid storage diseases.

[1550] 66.20. Generation and Analysis of Mice Comprising DNA64896-1539 (UNQ642) Gene Disruptions

[1551] In these knockout experiments, the gene encoding PRO1272 polypeptides (designated as DNA64896-1539) (UNQ642) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: NM.sub.--207531 Mus musculus RIKEN cDNA E030025L21 gene (E030025L21Rik); protein reference: Q8R3W7 ACCESSION:Q8R3W7 NID: Mus musculus (Mouse). RIKEN cDNA E030025L21 gene; the human gene sequence reference: NM.sub.--176813 Homo sapiens breast cancer membrane protein 11 (BCMP11); the human protein sequence corresponds to reference: Q8TD06 ACCESSION:Q8TD06 NID: Homo sapiens (Human). Anterior gradient protein 3 (MLHS642) (Breast cancer membrane protein 11).

[1552] The mouse gene of interest is RIKEN cDNA E030025L21 gene, ortholog of human BCMP11 (breast cancer membrane protein 11). Aliases include Gm888, HAG3, hAG-3, and anterior gradient protein 3.

[1553] BCMP11 is a putative secreted protein expressed primarily in estrogen receptor-positive breast ductal carcinoma epithelial cells. The 166-amino acid protein contains a signal peptide but no other discernable conserved domain. BCMP11 is concentrated in cytoplasmic vesicles but is capable of interacting with glycosylphosphatidylinositol-anchored metastasis-associated protein C4.4A and extracellular alpha-dystroglycan (DAG-1). Moreover, BCMP11 is homologous with secreted Xenopus laevis proteins XAG-1 and XAG-2, further supporting the function of BCMP11 as a secreted extracellular protein. BCMP11 may play a role in breast tumor cell growth or metastasis (Adam et al, J Biol Chem 278(8):6482-9 (2003); Fletcher et al, Br J Cancer 88(4):579-85 (2003)).

[1554] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00089 wt het hom Total Observed 22 23 17 62 Expected 15.5 31 15.5 62

Chi-Sq.=0.79 Significance=0.67368 (hom/n)=0.26 Avg. Litter Size=8

Mutation Information

[1555] Mutation Type Homologous Recombination (standard) Description: Coding exons 3 through 7 were targeted (NCBI accession NM.sub.--207531.1). 1. Wild-type Expression Panel: Expression of the target gene was detected in brain; spinal cord; eye; lung; and stomach, small intestine, and colon among the 13 adult tissue samples tested by RT-PCR. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[1556] 66.20.1. Phenotypic Analysis (for Disrupted Gene: DNA64896-1539 (UNQ642)

[1557] (a) Overall Phenotypic Summary:

[1558] Mutation of the gene encoding the ortholog of human breast cancer membrane protein 11 (BCMP11) resulted in the homozygous mutant mice exhibiting an increased mean serum glucose levels with an impaired glucose tolerance when compared with those of their gender-matched wild-type littermates and the historical means. In addition, impaired glucose tolerance was observed in the male mutants. Glucosuria and ketonuria were also evident in the (-/-) mice. The homozygous mutant mice also exhibited decreased bone mineral content and density measurements and decreased heart rates. Neurological analysis revealed numerous abnormalities, including impaired motor coordination and shaky behavior. The (-/-) mice exhibited diffuse abiotrophy of the cerebellum granule cell layer. The male (-/-) mice also showed testicular degeneration and the female (-/-) mice exhibited ovarian and uterine hypoplasia. Disruption of the target gene was confirmed by Southern hybridization analysis.

[1559] (b) Pathology

Microscopic: The (-/-) mice exhibited diffuse abiotrophy of the cerebellum granule cell layer, characterized by a diffuse loss of granule cells and gliosis, resulting in thinning of both the granule cell layer and molecular cell layer of the cerebellum. Notably, there was sparing of Purkinje and Golgi cells and the granule cell layer of the cerebellar paraflocculus was less severely affected by gliosis and neuron loss. The male (-/-) mice exhibited small testes, testicular degeneration, and hypospermia. Evidence of degeneration in the seminiferous tubules was minimal and restricted to late stage spermatids and spermatozoa. However, almost no normal sperm were present in the epididymides or vas deferens, and degeneration and clumping of spermatozoa was a frequent finding. The female (-/-) mice exhibited ovarian and uterine hypoplasia, with the ovaries and uterus appearing juvenile. The mammary gland was represented by just a few ducts. Heart weights were increased in the (-/-) mice, but no histopathologic lesions were noted. The pancreatic islets of Langerhans in the mutants tended to be smaller than in the (+/+) controls and the distribution of alpha (glucagon) and beta (insulin) cells was altered. Normally, glucagon-producing islet cells are arranged around the periphery of the islets, but the glucagon cells in the mutants were evenly distributed throughout the islets. Gene Expression LacZ activity was not detected in the panel of tissues by immunohistochemical analysis.

[1560] (c) Cardiology--Heart Rate

Test Description: Systolic blood pressure is measured via a noninvasive tail-cuff method for four days on the Visitech BP-2000 Blood Pressure Analysis System. The blood pressure is measured ten times each day for four days. The four days are then averaged to obtain a mouse's conscious systolic blood pressure.

[1561] Results

Heart Rate: The (-/-) mice exhibited decreased mean heart rates (male (-/-)>2 SD below the mean; female (-/-)>3 SD below the mean) when compared with that of their gender-matched (+/+) littermates and the historical mean, the difference being more notable in the females.

[1562] (d) Phenotypic Analysis: Metabolism--Blood Chemistry/Glucose Tolerance

[1563] In the area of metabolism, targets may be identified for the treatment of diabetes. Blood chemistry phenotypic analysis includes blood glucose measurements. The COBAS Integra 400 (mfr: Roche) was used for running blood chemistry tests on the mice. In the area of metabolism, targets may be identified for the treatment of diabetes. Blood chemistry phenotypic analysis includes glucose tolerance tests to measure insulin sensitivity and changes in glucose metabolism. Abnormal glucose tolerance test results may indicate but may not be limited to the following disorders or conditions: Diabetes Type 1 and Type 2, Syndrome X, various cardiovascular diseases and/or obesity.

[1564] Procedure: A cohort of 2 wild type and 4 homozygous mice were used in this assay. The glucose tolerance test is the standard for defining impaired glucose homeostasis in mammals. Glucose tolerance tests were performed using a Lifescan glucometer. Animals were injected IP at 2 g/kg with D-glucose delivered as a 20% solution and blood glucose levels were measured at 0, 30, 60 and 90 minutes after injection.

[1565] Results:

[1566] Blood Glucose Levels/Glucose Tolerance Test:

[1567] Both the male and female mutant (-/-) mice exhibited notably increased mean serum glucose levels when compared with that of their gender-matched (+/+) littermates and the historical means. In addition, the (-/-) mice exhibited impaired glucose tolerance at each of the intervals tested when compared with their gender-matched (+/+) littermates and the historical means. Glucosuria and ketonuria was evident in the (-/-) mutant mice.

[1568] These studies indicated that (-/-) mice exhibit a decreased or impaired glucose tolerance in the presence of normal fasting glucose at all 3 intervals tested when compared with their gender-matched (+/+) littermates and the historical means. Thus, knockout mutant mice exhibited the phenotypic pattern of an impaired glucose homeostasis, and therefor PRO1272 polypeptides (or agonists thereof) or its encoding gene would be useful in the treatment of conditions associated with an impaired glucose homeostasis and/or various cardiovascular diseases, including diabetes.

[1569] (e) Phenotypic Analysis: CNS/Neurology

[1570] In the area of neurology, analysis focused herein on identifying in vivo validated targets for the treatment of neurological and psychiatric disorders including depression, generalized anxiety disorders, attention deficit hyperactivity disorder, obsessive compulsive disorder, schizophrenia, cognitive disorders, hyperalgesia and sensory disorders. Neurological disorders include the category defined as "anxiety disorders" which include but are not limited to: mild to moderate anxiety, anxiety disorder due to a general medical condition, anxiety disorder not otherwise specified, generalized anxiety disorder, panic attack, panic disorder with agoraphobia, panic disorder without agoraphobia, posttraumatic stress disorder, social phobia, specific phobia, substance-induced anxiety disorder, acute alcohol withdrawal, obsessive compulsive disorder, agoraphobia, bipolar disorder I or II, bipolar disorder not otherwise specified, cyclothymic disorder, depressive disorder, major depressive disorder, mood disorder, substance-induced mood disorder. In addition, anxiety disorders may apply to personality disorders including but not limited to the following types: paranoid, antisocial, avoidant behavior, borderline personality disorders, dependent, histronic, narcissistic, obsessive-compulsive, schizoid, and schizotypal.

[1571] Procedure:

[1572] Behavioral screens were performed on a cohort of 4 wild type, 4 heterozygous and 8 homozygous mutant mice. All behavioral tests were done between 12 and 16 weeks of age unless reduced viability necessitates earlier testing.

[1573] (1) Circadian Test Description:

[1574] Female mice are individually housed at 4 pm on the first day of testing in 48.2 cm.times.26.5 cm home cages and administered food and water ad libitum. Animals are exposed to a 12-hour light/dark cycle with lights turning on at 7 am and turning off at 7 pm. The system software records the number of beam interruptions caused by the animal's movements, with beam breaks automatically divided into ambulations. Activity is recorded in 60, one-hour intervals during the three-day test. Data generated are displayed by median activity levels recorded for each hour (circadian rhythm) and median total activity during each light/dark cycle (locomotor activity) over the three-day testing period.

[1575] Results:

Circadian: The (-/-) mice exhibited decreased ambulatory activity during both light phases and a decreased light-to-total activity ratio during home-cage activity testing. These results demonstrate an abnormal circadian rhythm and is suggestive of decreased activity or hypoactivity which is indicative of a decreased anxiety-like response in the mutants. Thus, knockout mice demonstrated a phenotype consistent with depression, generalized anxiety disorders, cognitive disorders, hyperalgesia and sensory disorders and/or bipolar disorders. Thus, PRO1272 polypeptides and agonists thereof would be useful for the treatment or amelioration of the symptoms associated with depressive disorders.

[1576] (2) Functional Observational Battery (FOB) Test

[1577] The FOB is a series of situations applied to the animal to determine gross sensory and motor deficits. A subset of tests from the Irwin neurological screen that evaluates gross neurological function is used. In general, short-duration, tactile, olfactory, and visual stimuli are applied to the animal to determine their ability to detect and respond normally. These simple tests take approximately 10 minutes and the mouse is returned to its home cage at the end of testing.

[1578] Results:

[1579] Among the 8 (-/-) mice analyzed, 4 exhibited shaky behavior during the 1-minute observation period. In addition, rearing was absent in the (-/-) mice.

[1580] (3) Inverted Screen Test Data:

[1581] The Inverted Screen is used to measure motor strength/coordination. Untrained mice were placed individually on top of a square (7.5 cm.times.7.5 cm) wire screen which was mounted horizontally on a metal rod. The rod was then rotated 180 degrees so that the mice were on the bottom of the screens. The following behavioral responses were recorded over a 1 min testing session: fell off, did not climb, and climbed up.

[1582] Results:

TABLE-US-00090 Genotype Ratio Fell Down % Ratio Climbed up % +/+ (n = 8) 0/8 0 6/8 75 -/- (n = 8) 1/8 13 1/8 13

WT Population Fell Down 3.62 Climbed Up 60.04

[1583] A motor strength deficit is apparent when there is a 50% point difference between (-/-) or (+/-) mice and (+/+) mice for the fell down response. 0/8 or 1/8 (-/-) or (+/-) mice not climbing indicates impaired motor coordination. 7/8 or 8/8(-/-) or (+/-) mice climbing up indicates enhanced motor coordination.

[1584] The Inverted Screen Test is designed to measure basic sensory & motor observations:

[1585] Among the 8 (-/-) mice analyzed, only one (-/-) mouse climbed up the screen whereas 6/8 (+/+) mice climbed up. These results indicate an impaired motor strength in the mutants. These results are consistent with the observations in bone-related measurements as shown below.

[1586] (f) Bone Metabolism & Body Diagnostics

[1587] (1) Tissue Mass & Lean Body Mass Measurements--Dexa

[1588] Dexa Analysis--Test Description:

[1589] Procedure: A cohort of 4 wild type, 4 heterozygotes and 8 homozygotes were tested in this assay. Dual Energy X-ray Absorptiometry (DEXA) has been used successfully to identify changes in total tissue mass (TTM).

[1590] The mouse was anesthetized by intraperitoneal injection of Avertin (1.25% 2,2,2,-tribromoethanol, 20 ml/kg body weight), body length and weight were measured, and then the mouse was placed in a prone position on the platform of the PIXImus.TM. Densitometer (Lunar Inc.) for a DEXA scan. Using Lunar PIXImus software, the bone mineral density (BMD) and fat composition (% fat) and total tissue mass (TTM) were determined in the regions of interest (ROI, i.e., whole body, vertebrae, and both femurs).

[1591] Body Measurements (Body Length & Weight):

[1592] Body Measurements: A measurement of body length and weight was performed at approximately 16 weeks of age.

[1593] Results:

[1594] The (-/-) mice exhibited decreased mean body weight when compared with their gender-matched (+/+) littermates and the historical mean.

[1595] Fertility: The male (-/-) mouse produced no pups after 60 days of breeding and 4 matings.

[1596] (2) Bone Metabolism: Radiology Phenotypic Analysis

[1597] In the area of bone metabolism, targets were identified herein for the treatment of arthritis, osteoporosis, osteopenia and osteopetrosis as well as identifying targets that promote bone healing. Tests included: [1598] DEXA for measurement of bone mineral density on femur and vertebra [1599] MicroCT for very high resolution and very high sensitivity measurements of bone mineral density for both trabecular and cortical bone.

[1600] Dexa Analysis--Test Description:

[1601] Procedure: A cohort of 4 wild type, 4 heterozygotes and 8 homozygotes were tested in this assay. Dual Energy X-ray Absorptiometry (DEXA) has been used successfully to identify changes in bone. Anesthetized animals were examined and bone mineral content (BMC), BMC/LBM ratios, volumetric bone mineral density (vBMD), total body BMD, femur BMD and vertebra BMD were measured.

[1602] The mouse was anesthetized by intraperitoneal injection of Avertin (1.25% 2,2,2,-tribromoethanol, 20 ml/kg body weight), body length and weight were measured, and then the mouse was placed in a prone position on the platform of the PIXImus.TM. Densitometer (Lunar Inc.) for a DEXA scan. Using Lunar PIXImus software, the bone mineral density (BMD) and fat composition (% fat) and total tissue mass (TTM) were determined in the regions of interest (ROI) [i.e., whole body, vertebrae, and both femurs].

[1603] Results:

DEXA: The male (-/-) mice exhibited decreased mean total tissue mass and lean body mass. Both the male and female (-/-) mice exhibited decreased mean bone mineral content, bone mineral content index, and bone mineral density in total body, femur, and vertebrae when compared with that of their gender-matched (+/+) littermates and the historical means.

[1604] Mutant (-/-) mice deficient in the gene encoding PRO1272 polypeptides show a phenotype consistent with growth retardation and/or tissue wasting diseases marked by decreased mean total mass, lean body mass. These results are consistent to the observation of decreased mean body weight reported above. In addition, the mutant (-/-) mice exhibited decreased bone mineral content and density measurements suggestive of osteoporosis. Thus, antagonists or inhibitors of PRO1272 polypeptides or its encoding gene would mimic these abnormal metabolic related effects. On the other hand, PRO1272 polypeptides or agonists thereof would be useful in the prevention and/or treatment of such metabolic disorders as growth retardation, cachexia or other tissue wasting diseases as well as useful in the treatment of bone disorders associated with bone loss.

[1605] (g) Adult Skin Cell Proliferation:

[1606] Procedure: Skin cells were isolated from 16 week old animals (2 wild type and 4 homozygotes). These were developed into primary fibroblast cultures and the fibroblast proliferation rates were measured in a strictly controlled protocol. The ability of this assay to detect hyper-proliferative and hypo-proliferative phenotypes has been demonstrated with p53 and Ku80. Proliferation was measured using Brdu incorporation.

[1607] Specifically, in these studies the skin fibroblast proliferation assay was used. An increase in the number of cells in a standardized culture was used as a measure of relative proliferative capacity. Primary fibroblasts were established from skin biopsies taken from wild type and mutant mice. Duplicate or triplicate cultures of 0.05 million cells were plated and allowed to grow for six days. At the end of the culture period, the number of cells present in the culture was determined using a electronic particle counter.

[1608] Results:

[1609] The female (-/-) mice exhibited a increased mean skin fibroblast proliferation rate when compared with their gender-matched (+/+) littermates.

[1610] Thus, homozygous mutant mice demonstrated a hyper-proliferative phenotype. As suggested by these observations, PRO1272 polypeptides or agonists thereof would be useful in decreasing abnormal cell proliferation.

[1611] 66.21. Generation and Analysis of Mice Comprising DNA64903-1553 (UNQ655) Gene Disruptions

[1612] In these knockout experiments, the gene encoding PRO1286 polypeptides (designated as DNA64903-1553) (UNQ655) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: BC029863 ACCESSION:BC029863 NID:20987635 Mus musculus Mus musculus, clone MGC:36861 IMAGE:4460168; protein reference: Q8K2T4 ACCESSION:Q8K2T4 NID: Mus musculus (Mouse). Hypothetical protein; the human gene sequence reference: AY358935 Homo sapiens clone DNA64903 DSLR655 (UNQ655); the human protein sequence corresponds to reference: Q6UW78 Protein UNQ655/PRO1286 precursor.

[1613] The mouse gene of interest encodes "protein UNQ655/PRO1286 precursor" (UNQ655), ortholog of human UNQ655.

[1614] UNQ655 is a putative secreted protein, consisting of 93 amino acids. The protein contains a signal peptide but no other discernible conserved domain.

[1615] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00091 wt het hom Total Observed 21 34 0 55 Expected 13.75 27.5 13.75 55

Chi-Sq.=38.76 Significance=3.8315395E-9 (hom/n)=0.0 Avg. Litter Size=7

Mutation Information

[1616] Mutation Type: Homologous Recombination (standard) Description: Coding exons 1 and 2 were targeted (NCBI accession BC029863.1). 1. Wild-type Expression Panel: Panel: Expression of the target gene was detected in embryonic stem (ES) cells and in all 13 adult tissue samples tested by RT-PCR, except bone. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[1617] 66.21.1. Phenotypic Analysis (for Disrupted Gene: DNA64903-1553 (UNQ655)

[1618] (a) Overall Phenotypic Summary:

[1619] Mutation of the gene encoding the ortholog of human UNQ655 resulted in lethality of (-/-) mutants. The heterozygous mice exhibited decreased mean serum IgG2a levels. Gene disruption was confirmed by Southern blot.

[1620] (b) Pathology

Microscopic: Not tested due to embryonic lethality. At 12.5 days, there were 49 embryos observed: 18 (+/-) embryos, 8 (+/+) embryos, 22 resorption moles, and 1 inconclusive. Gene Expression: LacZ activity was not detected in the panel of tissues by immunohistochemical analysis.

[1621] Discussion Related to Embryonic Developmental Abnormality of Lethality:

[1622] Embryonic lethality in knockout mice usually results from various serious developmental problems including but not limited to neuro-degenerative diseases, angiogenic disorders, inflammatory diseases, or where the gene/protein has an important role in basic cell signaling processes in many cell types. In addition, embryonic lethals are useful as potential cancer models. Likewise, the corresponding heterozygous (+/-) mutant animals are particularly useful when they exhibit a phenotype and/or a pathology report which reveals highly informative clues as to the function of the knocked-out gene. For instance, EPO knockout animals were embryonic lethals, but the pathology reports on the embryos showed a profound lack of RBCs.

[1623] (c) Immunology Phenotypic Analysis

[1624] Immune related and inflammatory diseases are the manifestation or consequence of fairly complex, often multiple interconnected biological pathways which in normal physiology are critical to respond to insult or injury, initiate repair from insult or injury, and mount innate and acquired defense against foreign organisms. Disease or pathology occurs when these normal physiological pathways cause additional insult or injury either as directly related to the intensity of the response, as a consequence of abnormal regulation or excessive stimulation, as a reaction to self, or as a combination of these.

[1625] Though the genesis of these diseases often involves multistep pathways and often multiple different biological systems/pathways, intervention at critical points in one or more of these pathways can have an ameliorative or therapeutic effect. Therapeutic intervention can occur by either antagonism of a detrimental process/pathway or stimulation of a beneficial process/pathway.

[1626] T lymphocytes (T cells) are an important component of a mammalian immune response. T cells recognize antigens which are associated with a self-molecule encoded by genes within the major histocompatibility complex (MHC). The antigen may be displayed together with MHC molecules on the surface of antigen presenting cells, virus infected cells, cancer cells, grafts, etc. The T cell system eliminates these altered cells which pose a health threat to the host mammal. T cells include helper T cells and cytotoxic T cells. Helper T cells proliferate extensively following recognition of an antigen-MHC complex on an antigen presenting cell. Helper T cells also secrete a variety of cytokines, i.e., lymphokines, which play a central role in the activation of B cells, cytotoxic T cells and a variety of other cells which participate in the immune response.

[1627] In many immune responses, inflammatory cells infiltrate the site of injury or infection. The migrating cells may be neutrophilic, eosinophilic, monocytic or lymphocytic as can be determined by histologic examination of the affected tissues. Current Protocols in Immunology, ed. John E. Coligan, 1994, John Wiley & Sons, Inc.

[1628] Many immune related diseases are known and have been extensively studied. Such diseases include immune-mediated inflammatory diseases (such as rheumatoid arthritis, immune mediated renal disease, hepatobiliary diseases, inflammatory bowel disease (IBD), psoriasis, and asthma), non-immune-mediated inflammatory diseases, infectious diseases, immunodeficiency diseases, neoplasia, and graft rejection, etc. In the area of immunology, targets were identified for the treatment of inflammation and inflammatory disorders.

[1629] In the area of immunology, targets have been identified herein for the treatment of inflammation and inflammatory disorders. Immune related diseases, in one instance, could be treated by suppressing the immune response. Using neutralizing antibodies that inhibit molecules having immune stimulatory activity would be beneficial in the treatment of immune-mediated and inflammatory diseases. Molecules which inhibit the immune response can be utilized (proteins directly or via the use of antibody agonists) to inhibit the immune response and thus ameliorate immune related disease.

[1630] The following test was performed:

[1631] Serum Immunoglobulin Isotyping Assay:

[1632] The Serum Immunoglobulin Isotyping Assay is performed using a Cytometric Bead Array (CBA) kit. This assay is used to rapidly identify the heavy and light chain isotypes of a mouse monoclonal antibody in a single sample. The values expressed are "relative fluorescence units" and are based on the detection of kappa light chains. Any value <6 is not significant.

[1633] Results:

[1634] Serum Imm. 2: The (+/-) mice exhibited a decreased mean serum IgG2a level when compared with that of their (+/+) littermates, the (+/+) mice within the project run, and the historical median.

[1635] The serum immunoglobulin isotyping assay showed decreased or reduced levels of IgG2a in the heterozygous (+/-) mice compared to their gender-matched littermate (+/+) controls.

[1636] The serum immunoglobulin isotyping assay revealed that heterozygous adults exhibited decreased serum IgG2a levels. Thus, heterozygotes showed an abnormally low serum immunoglobulins compared with the (+/+) littermates. Thus, the gene encoding PRO1286 polypeptides is essential for making immunoglobulins (or gamma globulins). Likewise, IgG2a immunoglobulins have neutralization effects and to a lesser extent are important for activation of the complement system. These immunological abnormalities suggest that PRO1286 polypeptides or agonists thereof would be useful in stimulating the immune system and would find utility in the cases wherein this effect would be beneficial to the individual such as in the case of leukemia, and other types of cancer, and in immunocompromised patients, such as AIDS sufferers. Accordingly, inhibitors (antagonists) of PRO1286 polypeptides would inhibit the immune response and would be useful candidates for suppressing harmful immune responses, e.g. in the case of graft rejection or graft-versus-host diseases.

[1637] 66.22. Generation and Analysis of Mice Comprising DNA59218-1559 (UNQ664) Gene Disruptions

[1638] In these knockout experiments, the gene encoding PRO1295 polypeptides (designated as DNA59218-1559) (UNQ664) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: XM.sub.--485054 PREDICTED: Mus musculus congenital dyserythropoietic anemia, type I (human) (Cdan1); protein reference: XP.sub.--485054 congenital dyserythropoietic anemia, type I [Mus musculus]; the human gene sequence reference: NM.sub.--138477 Homo sapiens congenital dyserythropoietic anemia, type I (CDAN1); the human protein sequence corresponds to reference: Q8IWY9 ACCESSION:Q8IWY9 NID: Homo sapiens (Human). Codanin 1 (UNQ664/PRO1295).

[1639] The mouse gene of interest is Cdan1 (congenital dyserythropoietic anemia, type I [human]), ortholog of human CDAN1. Aliases include CDA1, CDAI, CDA-I, 1500015A01Rik, codanin, and codanin 1.

[1640] CDAN1 is a ubiquitously expressed protein located in the cytoplasm that likely functions as a structural protein, connecting the nuclear membrane with microtubules. CDAN1 may be involved in preserving nuclear membrane integrity. Mutations in CDAN1 can cause congenital dyserythropoietic anemias, a rare group of inherited red blood cell disorders associated with dysplastic changes in late erythroid precursors (Dgany et al, Ana Hum Genet. 71(6):1467-74 (2002); Pielage et al, Dev Cell 5(61:841-51 (2003)).

[1641] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00092 wt het hom Total Observed 21 32 0 53 Expected 13.25 26.5 13.25 53

Chi-Sq.=47.76 Significance=4.256456E-11 (hom/n)=0.0 Avg. Litter Size=8

Mutation Information

[1642] Mutation Type Homologous Recombination (standard) Description: Coding exons 3 through 8 were targeted (NCBI accession XM.sub.--485054.1). 1. Wild-type Expression Panel: Expression of the target gene was detected in embryonic stem (ES) cells and in all 13 adult tissue samples tested by RT-PCR, except bone and adipose. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[1643] 66.22.1. Phenotypic Analysis (for Disrupted Gene: DNA59218-1559 (UNQ664)

[1644] (a) Overall Phenotypic Summary:

[1645] Mutation of the gene encoding the ortholog of human congenital dyserythropoietic anemia, type I (human) (CDAN1) resulted in lethality of (-/-) mutants. Lethality is likely due to a defect in erythropoiesis. UNQ675 is highly expressed in the CNS compared to other tissues. Gene disruption was confirmed by Southern blot.

[1646] (b) Pathology

Microscopic: Not tested due to embryonic lethality. At 12.5 days, 51 embryos were observed: 23 (+/-) embryos, (+/+) embryos, 9 resorptions, and 4 to-be-determined. Gene Expression LacZ activity was not detected in the panel of tissues by immunohistochemical analysis.

[1647] Discussion Related to Embryonic Developmental Abnormality of Lethality:

[1648] Embryonic lethality in knockout mice usually results from various serious developmental problems including but not limited to neuro-degenerative diseases, angiogenic disorders, inflammatory diseases, or where the gene/protein has an important role in basic cell signaling processes in many cell types. In addition, embryonic lethals are useful as potential cancer models. Likewise, the corresponding heterozygous (+/-) mutant animals are particularly useful when they exhibit a phenotype and/or a pathology report which reveals highly informative clues as to the function of the knocked-out gene. For instance, EPO knockout animals were embryonic lethals, but the pathology reports on the embryos showed a profound lack of RBCs.

[1649] 66.23. Generation and Analysis of Mice Comprising DNA59588-1571 (UNQ675) Gene Disruptions

[1650] In these knockout experiments, the gene encoding PRO1309 polypeptides (designated as DNA59588-1571) (UNQ675) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: NM.sub.--028880 Mus musculus leucine rich repeat transmembrane neuronal 1 (Lrrtm1); protein reference: Q8K377 ACCESSION:Q8K377 NID: Mus musculus (Mouse). Lrrtm1 protein (Mus musculus 0 day neonate eyeball cDNA, RIKEN full-length enriched library, clone:E130010021 product:hypothetical RNI-like structure containing protein, full insert sequence) (Mus musculus 0 day neonate eyeball cDNA, RIKEN full-length enriched library, clone:E130012A05 product:hypothetical RNI-like structure containing protein, full insert sequence) (Leucine-rich repeat transmembrane neuronal 1 protein); the human gene sequence reference: NM.sub.--178839 Homo sapiens leucine rich repeat transmembrane neuronal 1 (LRRTM1); the human protein sequence corresponds to reference: Q86UE6 ACCESSION:Q86UE6 NID: Homo sapiens (Human). LRRTM1 protein (DFLL675).

[1651] The mouse gene of interest is Lrrtm1 (leucine rich repeat transmembrane neuronal 1), ortholog of human LRRTM1. Aliases include 4632401D06Rik, leucine-rich repeat transmembrane neuronal 1, DFLL675, and F1132082.

[1652] LRRTM1 is a putative integral plasma membrane protein expressed primarily in the nervous system that likely functions as a cell adhesion molecule or receptor. The protein consists of a signal peptide, several leucine-rich repeats, and a transmembrane segment. LRRTM1 may play a role in development and maintenance of the nervous system (Lauren et al, Genomics 81(4):411-21 (2003)).

[1653] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00093 wt het hom Total Observed 21 46 15 82 Expected 20.5 41 20.5 82

Chi-Sq.=0.71 Significance=0.7011734 (hom/n)=0.23 Avg. Litter Size=8

Mutation Information

[1654] Mutation Type Homologous Recombination (standard) Description: Coding exon 2 was targeted (NCBI accession NM.sub.--028880.2). 1. Wild-type Expression Panel: Expression of the target gene was detected only in brain, spinal cord, eye, and adipose among the 13 adult tissue samples tested by RT-PCR. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[1655] 66.23.1. Phenotypic Analysis (for Disrupted Gene: DNA59588-1571 (UNQ675)

[1656] (a) Overall Phenotypic Summary:

[1657] Mutation of the gene encoding the ortholog of human leucine rich repeat transmembrane neuronal 1 (LRRTM1) resulted in increased body fat in (-/-) and (+/-) mice. In addition, the mutant (-/-) mice exhibited decreased median ambulatory counts during circadian rhythm testing. Gene disruption was confirmed by Southern blot.

[1658] (b) Phenotypic Analysis: CNS/Neurology

[1659] In the area of neurology, analysis focused herein on identifying in vivo validated targets for the treatment of neurological and psychiatric disorders including depression, generalized anxiety disorders, attention deficit hyperactivity disorder, obsessive compulsive disorder, schizophrenia, cognitive disorders, hyperalgesia and sensory disorders. Neurological disorders include the category defined as "anxiety disorders" which include but are not limited to: mild to moderate anxiety, anxiety disorder due to a general medical condition, anxiety disorder not otherwise specified, generalized anxiety disorder, panic attack, panic disorder with agoraphobia, panic disorder without agoraphobia, posttraumatic stress disorder, social phobia, specific phobia, substance-induced anxiety disorder, acute alcohol withdrawal, obsessive compulsive disorder, agoraphobia, bipolar disorder I or II, bipolar disorder not otherwise specified, cyclothymic disorder, depressive disorder, major depressive disorder, mood disorder, substance-induced mood disorder. In addition, anxiety disorders may apply to personality disorders including but not limited to the following types: paranoid, antisocial, avoidant behavior, borderline personality disorders, dependent, histronic, narcissistic, obsessive-compulsive, schizoid, and schizotypal.

[1660] Procedure:

[1661] Behavioral screens were performed on a cohort of 4 wild type, 4 heterozygous and 8 homozygous mutant mice. All behavioral tests were done between 12 and 16 weeks of age unless reduced viability necessitates earlier testing.

[1662] Circadian Test Description:

[1663] Female mice are individually housed at 4 pm on the first day of testing in 48.2 cm.times.26.5 cm home cages and administered food and water ad libitum. Animals are exposed to a 12-hour light/dark cycle with lights turning on at 7 am and turning off at 7 pm. The system software records the number of beam interruptions caused by the animal's movements, with beam breaks automatically divided into ambulations. Activity is recorded in 60, one-hour intervals during the three-day test. Data generated are displayed by median activity levels recorded for each hour (circadian rhythm) and median total activity during each light/dark cycle (locomotor activity) over the three-day testing period.

[1664] Results:

Circadian: The (-/-) mice exhibited decreased median ambulatory counts during both dark periods during home-cage activity testing compared with their gender-matched (+/+) littermates and the historical mean.

[1665] These results demonstrate an abnormal circadian rhythm and is suggestive of decreased activity or hypoactivity which is indicative of a decreased anxiety-like response in the mutants. Thus, knockout mice demonstrated a phenotype consistent with depression, generalized anxiety disorders, cognitive disorders, hyperalgesia and sensory disorders and/or bipolar disorders. Thus, PRO1309 polypeptides and agonists thereof would be useful for the treatment or amelioration of the symptoms associated with depressive disorders.

[1666] (c) Bone Metabolism & Radiology Phenotypic Analysis

[1667] In the area of bone metabolism, targets were identified herein for the treatment of arthritis, osteoporosis, osteopenia and osteopetrosis as well as identifying targets that promote bone healing. Tests included: [1668] DEXA for measurement of bone mineral density on femur and vertebra [1669] MicroCT for very high resolution and very high sensitivity measurements of bone mineral density for both trabecular and cortical bone.

[1670] Dexa Analysis--Test Description:

[1671] Procedure: A cohort of 4 wild type, 4 heterozygotes and 8 homozygotes were tested in this assay. Dual Energy X-ray Absorptiometry (DEXA) has been used successfully to identify changes in bone. Anesthetized animals were examined and bone mineral content (BMC), BMC/LBM ratios, volumetric bone mineral density (vBMD), total body BMD, femur BMD and vertebra BMD were measured.

[1672] The mouse was anesthetized by intraperitoneal injection of Avertin (1.25% 2,2,2,-tribromoethanol, 20 ml/kg body weight), body length and weight were measured, and then the mouse was placed in a prone position on the platform of the PIXImus.TM. Densitometer (Lunar Inc.) for a DEXA scan. Using Lunar PIXImus software, the bone mineral density (BMD) and fat composition (% fat) and total tissue mass (TTM) were determined in the regions of interest (ROI) [i.e., whole body, vertebrae, and both femurs].

[1673] Results:

DEXA: Both the male and female (+/-) and (-/-) mice exhibited increased mean percent total body fat and total fat mass when compared with their gender-matched (+/+) littermates and the historical means, the difference being more notable in the females. The female (-/-) mice also exhibited notably increased mean total tissue mass.

[1674] These studies suggest that mutant (-/-) non-human transgenic animals exhibit a negative phenotype that would be associated with obesity. Thus, PRO1309 polypeptides or agonists thereof are essential for normal growth and metabolic processes and especially would be important in the prevention and/or treatment of obesity.

[1675] 66.24. Generation and Analysis of Mice Comprising DNA60608-1577 (UNQ682) Gene Disruptions

[1676] In these knockout experiments, the gene encoding PRO1316 polypeptides (designated as DNA60608-1577) (UNQ682) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: NM.sub.--020265 Mus musculus dickkopf homolog 2 (Xenopus laevis) (Dkk2); protein reference: Q9QYZ8 Dickkopf related protein-2 precursor (Dkk-2) (Dickkopf-2) (mDkk-2) gi|6272205|emb|CAB60110.1| dickkopf-2 [Mus musculus]; the human gene sequence reference: NM.sub.--014421 Homo sapiens dickkopf homolog 2 (Xenopus laevis) (DKK2); the human protein sequence corresponds to reference: Q9UBU2 ACCESSION:Q9UBU2 NID: Homo sapiens (Human). Dickkopf related protein-2 precursor (Dkk-2) (Dickkopf-2) (hDkk-2).

[1677] The mouse gene of interest is Dkk2 (dickkopf homolog 2 [Xenopus laevis]), ortholog of human DKK2. Aliases include DKK-2, dickkopf 2, mRNA for dickkopf-2 (dkk-2 gene), dickkopf homolog 1 (Xenopus laevis), Dickkopf gene 2, and dickkopf (Xenopus laevis) homolog 2.

[1678] DKK2 is a secreted protein that functions as a ligand for coreceptors of the canonical Wnt/beta-catenin signaling pathway. In the absence of coreceptor KREMEN2 (kringle containing transmembrane protein 2), DKK2 activates Wnt signaling by binding with coreceptor LRP6 (low density lipoprotein receptor-related protein 6). However, in the presence of KREMEN2, DKK2 inhibits Wnt signaling by binding with KREMEN2 (Mao and Niehrs, Gene 302(1-2):179-83 (2003); Brott and Sokol, Mol Cell Biol 22(17):6100-10 (2002); Li et al, J Biol Chem 277(8):5977-81 (2002); Krupnik et al, Gene 238(2):301-13 (1999)). DKK2 is involved in development (Monaghan et al, Mech Dev 87(1-2):45-56 (1999); Ang et al, Gene Expr Patterns 4(3):289-95 (2004)).

[1679] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00094 wt het hom Total Observed 18 43 19 80 Expected 20 40 20 80

Chi-Sq.=3.62 Significance=0.16365415 (hom/n)=0.26 Avg. Litter Size=8

Mutation Information

[1680] Mutation Type: Homologous Recombination (standard) Description: Coding exon 1 was targeted (NCBI accession NM.sub.--020265.2). 1. Wild-type Expression Panel: Expression of the target gene was detected in embryonic stem (ES) cells and in all 13 adult tissue samples tested by RT-PCR, except spinal cord, thymus, and bone. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[1681] 66.24.1. Phenotypic Analysis (for Disrupted Gene: DNA60608-1577 (UNQ682)

[1682] (a) Overall Phenotypic Summary:

[1683] Mutation of the gene encoding the ortholog of human dickkopf homolog 2 (Xenopus laevis) (DKK2) resulted in the homozygous mutant mice exhibiting corneal epithelialization with underdeveloped eyelids and agenesis of the Harderian gland, resulting in impaired vision in the mutants. All eight of the (-/-) mice exhibited abnormalities of the eye, including 6 (-/-) mice exhibiting palpebral closure. Gene disruption was confirmed by Southern blot.

[1684] (b) Pathology

Gross: All eight (-/-) mice exhibited severe corneal epidermidalization, characterized by thickening of the corneal stroma and scarring that blocked the vision of the mutants. The eyelids of the (-/-) mice were also underdeveloped, resulting in incomplete closure of the eyelids. Some appeared to have smaller than normal eyes. Both eyelids were notably hypoplastic and the Harderian glands were not visible upon gross examination of the (-/-) mice. Microscopic: The (-/-) mice exhibited corneal epithelialization with underdeveloped eyelids and agenesis of the Harderian gland, resulting in impaired vision in the mutants. The (-/-) mice exhibited diffuse metaplasia of the cornea and sclera, characterized by diffuse fibrosis of the collageneous stroma and keratinizing hyperkeratosis of the surface epithelium with multifocal chronic-active keratitis and ulceration. Multifocally, there were sebaceous glands and hair follicles in the cornea and sclera. These changes were more severe in the male mutants than in the females. The (-/-) mice also exhibited agenesis of the Harderian gland. Although intraorbital lacrimal glands were present in some sections, the Harderian gland was uniformly absent and the eyelids were severely hypoplastic in all mutant mice. Gene Expression LacZ activity was not detected in the panel of tissues by immunohistochemical analysis.

[1685] (c) Cardiovascular Phenotypic Analysis:

[1686] In the area of cardiovascular biology, phenotypic testing was performed to identify potential targets for the treatment of cardiovascular, endothelial or angiogenic disorders. One such phenotypic test included optic fundus photography and angiography to determine the retinal arteriovenous ratio (A/V ratio) in order to flag various eye abnormalities. An abnormal A/V ratio signals such systemic diseases or disorders that may be related to the vascular disease of hypertension (and any disease that causes hypertension, e.g. atherosclerosis), diabetes or other ocular diseases corresponding to ophthalmological disorders. Such eye abnormalities may include but are not limited to the following: retinal abnormality is retinal dysplasia, various retinopathies, restenosis, retinal artery obstruction or occlusion; retinal degeneration causing secondary atrophy of the retinal vasculature, retinitis pigmentosa, macular dystrophies, Stargardt's disease, congenital stationary night blindness, choroideremia, gyrate atrophy, Leber's congenital amaurosis, retinoschisis disorders, Wagner's syndrome, Usher syndromes, Zellweger syndrome, Saldino-Mainzer syndrome, Senior-Loken syndrome, Bardet-Biedl syndrome, Alport's syndrome, Alstom's syndrome, Cockayne's syndrome, dysplaisa spondyloepiphysaria congentia, Flynn-Aird syndrome, Friedreich ataxia, Hallgren syndrome, Marshall syndrome, Albers-Schnoberg disease, Refsum's disease, Kearns-Sayre syndrome, Waardenburg's syndrome, Alagile syndrome, myotonic dystrophy, olivopontocerebellar atrophy, Pierre-Marie dunsdrome, Stickler syndrome, carotinemeia, cystinosis, Wolfram syndrome, Bassen-Kornzweig syndrome, abetalipoproteinemia, incontinentia pigmenti, Batten's disease, mucopolysaccharidoses, homocystinuria, or mannosidosis.

[1687] Procedure: A cohort of 4 wild type, 4 heterozygotes and 8 homozygotes were tested in this assay. Optic fundus photography was performed on conscious animals using a Kowa Genesis small animal fundus camera modified according to Hawes and coauthors (Hawes et al., 1999 Molecular Vision 1999; 5:22). Intra-peritoneal injection of fluorescein permitted the acquisition of direct light fundus images and fluorescent angiograms for each examination. In addition to direct ophthalmological changes, this test can detect retinal changes associated with systemic diseases such as diabetes and atherosclerosis or other retinal abnormalities. Pictures were provided of the optic fundus under normal light. The angiographic pictures allowed examination of the arteries and veins of the eye. In addition an artery to vein (A/V) ratio was determined for the eye.

[1688] Ophthalmology analysis was performed on generated F2 wild type, heterozygous, and homozygous mutant progeny using the protocol described above. Specifically, the A/V ratio was measured and calculated according to the fundus images with Kowa COMIT+ software. This test takes color photographs through a dilated pupil: the images help in detecting and classifying many diseases. The artery to vein ratio (A/V) is the ratio of the artery diameter to the vein diameter (measured before the bifurcation of the vessels). Many diseases will influence the ratio, i.e., diabetes, cardiovascular disorders, papilledema, optic atrophy or other eye abnormalities such as retinal degeneration (known as retinitis pigmentosa) or retinal dysplasia, vision problems or blindness. Thus, phenotypic observations which result in an increased artery-to-vein ratio in homozygous (-/-) and heterozygous (+/-) mutant progeny compared to wildtype (+/+) littermates would be indicative of such pathological conditions.

[1689] Results:

Fundus: All 8 (-/-) mice exhibited severe corneal epidermidalization, characterized by thickening of the corneal stroma and scarring that blocked the vision of the mutants. The eyelids of the (-/-) mice were also underdeveloped, resulting in incomplete closure of the eyelids. Therefore, the artery-to-vein ratio could not be measured in the mutants. Angiogram: Only 1 of the (-/-) mice was successfully analyzed. No notable posterior chamber anomaly was observed.

[1690] 66.25. Generation and Analysis of Mice Comprising DNA58743-1609 (UNQ719) Gene Disruptions

[1691] In these knockout experiments, the gene encoding PRO1383 polypeptides (designated as DNA58743-1609) (UNQ719) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: NM.sub.--177735 Mus musculus hypothetical protein C130036G08 (C130036G08); protein reference: Q6NXM3 ACCESSION:Q6NXM3 NID: Mus musculus (Mouse). Hypothetical protein C130036G08; the human gene sequence reference: NM.sub.--152913 ACCESSION:NM.sub.--152913 NID: gi 23097273 ref NM.sub.--152913.1 Homo sapiens hypothetical protein DKFZp761L1417 (DKFZp761L1417); the human protein sequence corresponds to reference: Q8NOW9 ACCESSION:Q8NOW9 NID: Homo sapiens (Human). Similar to QNR-71 protein (Hypothetical protein).

[1692] The mouse gene of interest is "hypothetical protein C130036G08," ortholog of human "hypothetical protein DKFZp761L1417." Aliases include C130036G08 and DKFZp761L1417.

[1693] Hypothetical protein DKFZp761L1417 is a putative type I integral plasma membrane protein, containing a signal peptide, a PKD (repeats in polycystic kidney disease 1 [PKD1] and other proteins) domain (SMART accession SM00089), and a transmembrane segment. PKD domains are likely involved in protein-protein or protein-carbohydrate interactions, suggesting that hypothetical protein DKFZp761L1417 functions as a cell adhesion molecule or signal-transducing receptor.

[1694] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00095 wt het hom Total Observed 15 44 19 78 Expected 19.5 39 19.5 78

Chi-Sq.=1.42 Significance=0.4916442 (hom/n)=0.27 Avg. Litter Size=10

Mutation Information

[1695] Mutation Type Homologous Recombination (standard) Description: Coding exons 3 through 5 were targeted (NCBI accession NM.sub.--177735.3). 1. Wild-type Expression Panel: Expression of the target gene was detected in embryonic stem (ES) cells and in all 13 adult tissue samples tested by RT-PCR, except liver, skeletal muscle, and bone. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[1696] 66.25.1. Phenotypic Analysis (for Disrupted Gene: DNA58743-1609 (UNQ719)

[1697] (a) Overall Phenotypic Summary:

[1698] Mutation of the gene encoding the ortholog of human "hypothetical protein DKFZp761L1417" resulted in the homozygous mutant mice exhibiting decreased locomotor activity or mild hypoactivity during open field testing when compared with the level for their wild-type littermates and the historical mean. UNQ719 shows high expression in the CNS compared to other tissues. Gene disruption was confirmed by Southern blot.

[1699] (b) Phenotypic Analysis: CNS/Neurology

[1700] In the area of neurology, analysis focused herein on identifying in vivo validated targets for the treatment of neurological and psychiatric disorders including depression, generalized anxiety disorders, attention deficit hyperactivity disorder, obsessive compulsive disorder, schizophrenia, cognitive disorders, hyperalgesia and sensory disorders. Neurological disorders include the category defined as "anxiety disorders" which include but are not limited to: mild to moderate anxiety, anxiety disorder due to a general medical condition, anxiety disorder not otherwise specified, generalized anxiety disorder, panic attack, panic disorder with agoraphobia, panic disorder without agoraphobia, posttraumatic stress disorder, social phobia, specific phobia, substance-induced anxiety disorder, acute alcohol withdrawal, obsessive compulsive disorder, agoraphobia, bipolar disorder I or II, bipolar disorder not otherwise specified, cyclothymic disorder, depressive disorder, major depressive disorder, mood disorder, substance-induced mood disorder. In addition, anxiety disorders may apply to personality disorders including but not limited to the following types: paranoid, antisocial, avoidant behavior, borderline personality disorders, dependent, histronic, narcissistic, obsessive-compulsive, schizoid, and schizotypal.

[1701] Procedure:

[1702] Behavioral screens were performed on a cohort of 4 wild type, 4 heterozygous and 8 homozygous mutant mice. All behavioral tests were done between 12 and 16 weeks of age unless reduced viability necessitates earlier testing. These tests included open field to measure anxiety, activity levels and exploration.

[1703] Open Field Test:

[1704] Several targets of known drugs have exhibited phenotypes in the open field test. These include knockouts of the seratonin transporter, the dopamine transporter (Giros et al., Nature. 1996 Feb. 15; 379(6566):606-12), and the GABA receptor (Homanics et al., Proc Natl Acad Sci USA. 1997 Apr. 15; 94(8):4143-8). An automated open-field assay was customized to address changes related to affective state and exploratory patterns related to learning. First, the field (40.times.40 cm) was selected to be relatively large for a mouse, thus designed to pick up changes in locomotor activity associated with exploration. In addition, there were 4 holes in the floor to allow for nose-poking, an activity specifically related to exploration. Several factors were also designed to heighten the affective state associated with this test. The open-field test is the first experimental procedure in which the mice are tested, and the measurements that were taken were the subjects' first experience with the chamber. In addition, the open-field was brightly lit. All these factors will heighten the natural anxiety associated with novel and open spaces. The pattern and extent of exploratory activity, and especially the center-to-total distance traveled ratio, may then be able to discern changes related to susceptibility to anxiety or depression. A large arena (40 cm.times.40 cm, VersaMax animal activity monitoring system from AccuScan Instruments) with infrared beams at three different levels was used to record rearing, hole poke, and locomotor activity. The animal was placed in the center and its activity was measured for 20 minutes. Data from this test was analyzed in five, 4-minute intervals. The total distance traveled (cm), vertical movement number (rearing), number of hole pokes, and the center to total distance ratio were recorded.

[1705] The propensity for mice to exhibit normal habituation responses to a novel environment is assessed by determining the overall change in their horizontal locomotor activity across the 5 time intervals. This calculated slope of the change in activity over time is determined using normalized, rather than absolute, total distance traveled. The slope is determined from the regression line through the normalized activity at each of the 5 time intervals. Normal habituation is represented by a negative slope value.

[1706] Results:

[1707] A notable difference was observed during open field activity testing. The (-/-) mice exhibited a decreased median sum total distance traveled Thus, knockout mice demonstrated a phenotype consistent with depression, cognitive disorders, hyperalgesia and sensory disorders and/or bipolar disorders. Thus, PRO1383 polypeptides and agonists thereof would be useful for the treatment or amelioration of the symptoms associated with depressive disorders.

66.26. Generation and Analysis of Mice Comprising DNA71159-1617 (UNQ721) Gene Disruptions

[1708] In these knockout experiments, the gene encoding PRO1384 polypeptides (designated as DNA71159-1617) (UNQ721) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: NM.sub.--019985 Mus musculus C-type lectin-like receptor 2 (Clec2); protein reference: Q9JL99 ACCESSION:Q9JL99 NID: Mus musculus (Mouse). C-TYPE LECTIN-LIKE RECEPTOR 2; the human gene sequence reference: NM.sub.--016509 ACCESSION:NM.sub.--016509 NID:7706060 Homo sapiens Homo sapiens C-type lectin-like receptor-2 (L0051266); the human protein sequence corresponds to reference: Q9P 126 ACCESSION:Q9P126 NID: Homo sapiens (Human). C-TYPE LECTIN-LIKE RECEPTOR-2. The mouse gene of interest is Clec2 (C-type lectin-like receptor 2), ortholog of human CLEC2. Aliases include Clec-2, mCLEC-2, 1810061113Rik, PRO1384, and QDED721.

[1709] CLEC2 is a type II integral plasma membrane protein that likely functions as a receptor. CLEC2 consists of a signal anchor and a C-type lectin domain, which binds with carbohydrate residues. CLEC2 is expressed in liver and in myeloid and natural killer cells. CLEC2 may play a role in signal transduction and immunity (Colonna et al, Eur J Immunol 30(2):697-704 (2000); Sobanov et al, Eur J Immunol 31(12):3493-503 (2001)).

[1710] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00096 wt het hom Total Observed 16 43 3 62 Expected 15.5 31 15.5 62

Chi-Sq.=10.34 Significance=0.0056845685 (hom/n)=0.12 Avg. Litter Size=8

Mutation Information

[1711] Mutation Type: Homologous Recombination (standard) Description: Coding exons 1 and 2 were targeted (NCBI accession NM.sub.--019985.2). 1. Wild-type Expression Panel: Expression of the target gene was detected in all 13 adult tissue samples tested by RT-PCR, except skeletal muscle; bone; stomach, small intestine, and colon; heart; and adipose. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[1712] 66.26.1. Phenotypic Analysis (for disrupted gene: DNA71159-1617 (UNQ721)

[1713] (a) Overall Phenotypic Summary:

[1714] Mutation of the gene encoding the ortholog of human C-type lectin-like receptor 2 (CLEC2) resulted in greatly reduced viability of (-/-) mutants. Genetic data indicate that this mutation resulted in greatly reduced viability of the homozygous mutants. Microscopic analysis revealed numerous brain defects including mild-to-moderate congestion and hemorrhage in the diencephalon and vestibulocochlear ganglion of the homozygous embryos. The 2 surviving female homozygous mutant mice exhibited signs of anemia and decreased serum cholesterol, heart rate, and blood pressure. The mutants also exhibited an increased mean percentage of CD4 cells in the peripheral blood. Disruption of the target gene was confirmed by Southern hybridization analysis.

[1715] (b) Pathology

General Observations: Reduced viability of the (-/-) mice was observed. All but 2 of the (-/-) mice were dead at the time of genotyping. Thus, high embryonic and prenatal lethality was observed. Microscopic: At 12.5 days there were 45 embryos observed: 11 (-/-) embryos, 18 (+/-) embryos, 11 (+/+) embryos, 3 resorption moles, and 2 inconclusive. The (-/-) embryos available for analysis exhibited mild-to-moderate brain (diencephalon) and vestibulocochlear ganglion congestion and hemorrhage. There were multiple foci of congestion and hemorrhage detected in the diencephalon of all 4 (-/-) embryos examined and unilaterally in the vestibulocochlear ganglion of 2/4 12.5 day (-/-) embryos. In addition, an increased number of dilated capillaries were observed in the affected areas of the developing brains. In addition, circulating blood cells were found throughout the embryos especially the fetal liver. Gene Expression: LacZ activity was not detected in the panel of tissues by immunohistochemical analysis.

[1716] (c) Cardiology--Blood Pressure/Heart Rate

Test Description Systolic blood pressure is measured via a noninvasive tail-cuff method for four days on the Visitech BP-2000 Blood Pressure Analysis System. The blood pressure is measured ten times each day for four days. The four days are then averaged to obtain a mouse's conscious systolic blood pressure.

[1717] Results

Blood Pressure: The 2 surviving (-/-) mice exhibited decreased mean systolic blood pressure when compared with that of their gender-matched (+/+) littermates and the historical mean. Heart Rate The 2 surviving (-/-) mice exhibited a decreased mean heart rate (.about.1-2 SD below the historic mean) when compared with that of their gender-matched (+/+) littermates and the historical mean.

[1718] (d) Phenotypic Analysis: Cardiology

[1719] In the area of cardiovascular biology, targets were identified herein for the treatment of hypertension, atherosclerosis, heart failure, stroke, various coronary artery diseases, dyslipidemias such as high cholesterol (hypercholesterolemia) and elevated serum triglycerides (hypertriglyceridemia), diabetes and/or obesity. The phenotypic tests included the measurement of serum cholesterol and triglycerides.

[1720] Blood Lipids

[1721] Procedure: A cohort of 4 wild type, 4 heterozygotes and 2 homozygotes were tested in this assay. High cholesterol levels and increased triglyceride blood levels are recognized risk factors in the development of cardiovascular disease and/or diabetes. Measuring blood lipids facilitates the finding of biological switches that regulate blood lipid levels. Inhibition of factors which elevate blood lipid levels may be useful for reducing the risk for cardiovascular disease. In these blood chemistry tests, measurements were recorded using the COBAS Integra 400 (mfr: Roche).

[1722] Results:

Blood Chemistry: The 2 surviving female (-/-) mice (F-104 and F-133) exhibited a decreased mean serum cholesterol level when compared with that of their gender-matched (+/+) littermates and the historical mean.

[1723] As summarized above, the (-/-) mice exhibited notably decreased mean serum cholesterol levels when compared with their gender-matched (+/+) littermates and the historical means. Thus, mutant mice deficient in the PRO1384 gene resulted in hypocholestremia which could lead to defective membrane formation and/or function.

[1724] (e) Immunology Phenotypic Analysis

[1725] Immune related and inflammatory diseases are the manifestation or consequence of fairly complex, often multiple interconnected biological pathways which in normal physiology are critical to respond to insult or injury, initiate repair from insult or injury, and mount innate and acquired defense against foreign organisms. Disease or pathology occurs when these normal physiological pathways cause additional insult or injury either as directly related to the intensity of the response, as a consequence of abnormal regulation or excessive stimulation, as a reaction to self, or as a combination of these.

[1726] Though the genesis of these diseases often involves multistep pathways and often multiple different biological systems/pathways, intervention at critical points in one or more of these pathways can have an ameliorative or therapeutic effect. Therapeutic intervention can occur by either antagonism of a detrimental process/pathway or stimulation of a beneficial process/pathway.

[1727] T lymphocytes (T cells) are an important component of a mammalian immune response. T cells recognize antigens which are associated with a self-molecule encoded by genes within the major histocompatibility complex (MHC). The antigen may be displayed together with MHC molecules on the surface of antigen presenting cells, virus infected cells, cancer cells, grafts, etc. The T cell system eliminates these altered cells which pose a health threat to the host mammal. T cells include helper T cells and cytotoxic T cells. Helper T cells proliferate extensively following recognition of an antigen-MHC complex on an antigen presenting cell. Helper T cells also secrete a variety of cytokines, i.e., lymphokines, which play a central role in the activation of B cells, cytotoxic T cells and a variety of other cells which participate in the immune response.

[1728] In many immune responses, inflammatory cells infiltrate the site of injury or infection. The migrating cells may be neutrophilic, eosinophilic, monocytic or lymphocytic as can be determined by histologic examination of the affected tissues. Current Protocols in Immunology, ed. John E. Coligan, 1994, John Wiley & Sons, Inc.

[1729] Many immune related diseases are known and have been extensively studied. Such diseases include immune-mediated inflammatory diseases (such as rheumatoid arthritis, immune mediated renal disease, hepatobiliary diseases, inflammatory bowel disease (IBD), psoriasis, and asthma), non-immune-mediated inflammatory diseases, infectious diseases, immunodeficiency diseases, neoplasia, and graft rejection, etc. In the area of immunology, targets were identified for the treatment of inflammation and inflammatory disorders.

[1730] In the area of immunology, targets have been identified herein for the treatment of inflammation and inflammatory disorders. Immune related diseases, in one instance, could be treated by suppressing the immune response. Using neutralizing antibodies that inhibit molecules having immune stimulatory activity would be beneficial in the treatment of immune-mediated and inflammatory diseases. Molecules which inhibit the immune response can be utilized (proteins directly or via the use of antibody agonists) to inhibit the immune response and thus ameliorate immune related disease.

[1731] The following tests were performed:

[1732] (1) Hematology Analysis:

[1733] Test Description Blood tests are carried out by Abbott's Cell-Dyn 3500R, an automated hematology analyzer. Some of its features include a five-part WBC differential. `Patient` reports can cover over 22 parameters in all.

[1734] Results:

Hematology: The 2 surviving (-/-) mice (F-104 and F-133) exhibited a decreased mean red blood cell count, hemoglobin concentration, and hematocrit level when compared with the levels for their (+/+) littermates and the historical means.

[1735] These results are related to a phenotype associated with anemia. Thus, PRO1384 polypeptides, agonists thereof or the encoding gene for PRO1384 polypeptides must be essential for normal red blood cell production and as such would be useful in the treatment of blood disorders associated with anemia or a low hematocrit.

[1736] (2) Flourescence-Activated Cell-Sorting (FAGS) Analysis

[1737] Procedure:

[1738] FACS analysis of immune cell composition from peripheral blood was performed including CD4, CD8 and T cell receptor to evaluate T lymphocytes, CD19 for B lymphocytes, CD45 as a leukocyte marker and pan NK for natural killer cells. The FACS analysis was carried out on 2 wild type and 2 homozygous mice and included cells derived from thymus, spleen, bone marrow and lymph node.

[1739] In these studies, analyzed cells were isolated from thymus, peripheral blood, spleen, bone marrow and lymph nodes. Flow cytometry was designed to determine the relative proportions of CD4 and CD8 positive T cells, B cells, NK cells and monocytes in the mononuclear cell population. A Becton-Dickinson FACSCalibur 3-laser FACS machine was used to assess immune status. For Phenotypic Assays and Screening, this machine records CD4+/CD8-, CD8+/CD4-, NK, B cell and monocyte numbers in addition to the CD4+/CD8+ ratio.

[1740] The mononuclear cell profile was derived by staining a single sample of lysed peripheral blood from each mouse with a panel of six lineage-specific antibodies: CD45 PerCP, anti-TCRb APC, CD4 PE, CD8 FITC, pan-NK PE, and CD19 FITC. The two FITC and PE labeled antibodies stain mutually exclusive cell types. The samples were analyzed using a Becton Dickinson FACSCalibur flow cytometer with CellQuest software.

[1741] Results:

FACS3: The (-/-) mice exhibited an altered distribution of leukocyte subsets in the peripheral blood, characterized by an increased mean percentage of CD4 cells when compared with that of their (+/+) littermates and the historical mean.

[1742] Thus, knocking out the gene which encodes PRO1384 polypeptides causes an increase in the T cell population. From these observations, PRO1384 polypeptides or the gene encoding PRO1384 appears to act as a negative regulator of T cell proliferation. Thus, antagonists (inhibitors) of PRO1384 polypeptides would mimic this phenotype and would be beneficial in enhancing T cell proliferation.

[1743] 66.27. Generation and Analysis of Mice Comprising DNA73401-1633 (UNQ737) Gene Disruptions

[1744] In these knockout experiments, the gene encoding PRO1431 polypeptides (designated as DNA73401-1633) (UNQ737) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: NM.sub.--175684 Mus musculus FCH and double SH3 domains 1 (Fchsd1); protein reference: Q6 PFY1 ACCESSION:Q6 PFY1 NID: Mus musculus (Mouse). FCH and double SH3 domains 1; the human gene sequence reference: NM.sub.--033449 Homo sapiens FCH and double SH3 domains 1 (FCHSD1); the human protein sequence corresponds to reference: Q86WN1 ACCESSION:Q86WN1 NID: Homo sapiens (Human). FLJ00007-like protein.

[1745] The mouse gene of interest is Fchsd1 (FCH and double SH3 domains 1), ortholog of human FCHSD1. Aliases include A030002D08Rik and FLJ00007.

[1746] FCHSD1 is a putative cytoplasmic protein, consisting of a Fes/CIP4 (Fes tyrosine kinase/Cdc42-interacting protein) homology domain, two SH3 (src homology-3) domains, and a proline-rich C terminus (Katoh and Katoh, Int J Mol Med 13(5):749-54 (2004)). FES-CIP4 homology domain binds with tubulin (Takahashi et al, J Biol Chem 278(49):49129-33 (2003); Laurent et al, Mol Cell Biol 24(21):9351-8(2004)). SH3 domains likely mediate processes such as increasing the local concentration proteins, determining the subcellular location of proteins, and mediating assembly of large multiprotein complexes (InterPro accession IPRO01452). Thus, FCHSD1 may function as a docking protein for processes involving cytoskeletal rearrangement.

[1747] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00097 wt het hom Total Observed 21 38 19 78 Expected 19.5 39 19.5 78

Chi-Sq.=0.9 Significance=0.63762814 (hom/n)=0.22 Avg. Litter Size=9

Mutation Information

[1748] Mutation Type: Homologous Recombination (standard) Description: Coding exons 1 through 7 were targeted (NCBI accession NM.sub.--175684.3). 1. Wild-type Expression Panel: Expression of the target gene was detected in embryonic stem (ES) cells and in all 13 adult tissue samples tested by RT-PCR, except bone. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[1749] 66.27.1. Phenotypic Analysis (for Disrupted Gene: DNA73401-1633 (UNQ737)

[1750] (a) Overall Phenotypic Summary:

[1751] Mutation of the gene encoding the ortholog of human FCH and double SH3 domains 1 (FCHSD1) resulted in the mutant (-/-) mice exhibiting elevated mean serum glucose levels. Male knockout (-/-) mice also exhibited increased fat percentages and increased fat mass (g) as well as female (-/-) mice showed a decreased femur bone mineral density and total body bone mineral density. In addition, the male (-/-) mice showed a decreased mean systolic blood pressure. Gene disruption was confirmed by Southern blot.

[1752] (b) Phenotypic Analysis: Metabolism--Blood Chemistry

[1753] In the area of metabolism, targets may be identified for the treatment of diabetes. Blood chemistry phenotypic analysis includes blood glucose measurements. The COBAS Integra 400 (mfr: Roche) was used for running blood chemistry tests on the mice. In the area of metabolism, targets may be identified for the treatment of diabetes.

[1754] Results:

Blood Chemistry: The (-/-) mice exhibited a notably increased mean serum glucose levels when compared with their gender-matched (+/+) littermates and the historical means. However, glucose tolerance testing was normal.

[1755] As summarized above, the (-/-) mice exhibited increased mean serum glucose levels suggesting abnormal glucose metabolism or a pre-diabetic condition.

[1756] (c) Cardiology--Blood Pressure/Heart Rate

Test Description Systolic blood pressure is measured via a noninvasive tail-cuff method for four days on the Visitech BP-2000 Blood Pressure Analysis System. The blood pressure is measured ten times each day for four days. The four days are then averaged to obtain a mouse's conscious systolic blood pressure.

[1757] Results

Blood Pressure: The male (-/-) mice exhibited decreased mean systolic blood pressure when compared with that of their gender-matched (+/+) littermates and the historical mean.

[1758] (d) Bone Metabolism & Radiology Phenotypic Analysis

[1759] In the area of bone metabolism, targets were identified herein for the treatment of arthritis, osteoporosis, osteopenia and osteopetrosis as well as identifying targets that promote bone healing. Tests included: [1760] DEXA for measurement of bone mineral density on femur and vertebra [1761] MicroCT for very high resolution and very high sensitivity measurements of bone mineral density for both trabecular and cortical bone.

[1762] Dexa Analysis--Test Description:

[1763] Procedure: A cohort of 4 wild type, 4 heterozygotes and 8 homozygotes were tested in this assay. Dual

[1764] Energy X-ray Absorptiometry (DEXA) has been used successfully to identify changes in bone. Anesthetized animals were examined and bone mineral content (BMC), BMC/LBM ratios, volumetric bone mineral density (vBMD), total body BMD, femur BMD and vertebra BMD were measured.

[1765] The mouse was anesthetized by intraperitoneal injection of Avertin (1.25% 2,2,2,-tribromoethanol, 20 ml/kg body weight), body length and weight were measured, and then the mouse was placed in a prone position on the platform of the PIXImus.TM. Densitometer (Lunar Inc.) for a DEXA scan. Using Lunar PIXImus software, the bone mineral density (BMD) and fat composition (% fat) and total tissue mass (TTM) were determined in the regions of interest (ROI) [i.e., whole body, vertebrae, and both femurs].

[1766] Results:

DEXA: The male (-/-) mice exhibited increased mean percent total body fat and total fat mass when compared with their gender-matched (+/+) littermates and the historical means. The female (-/-) mice exhibited decreased femur bone mineral density and total bone mineral density.

[1767] These studies suggest that mutant male (-/-) non-human transgenic animals exhibit a negative phenotype that would be associated with obesity. Thus, PRO1431 polypeptides or agonists thereof are essential for normal growth and metabolic processes and especially would be important in the prevention and/or treatment of obesity. The female knockout mice exhibited a negative bone phenotype associated with decreased bone mineral density measurements which could be due to osteoporosis. Thus, PRO1431 polypeptides or agonists thereof would be, useful in the treatment of such bone disorders that are characterized by decreased bone mineral density.

[1768] 66.28. Generation and Analysis of Mice Comprising DNA68818-2536 (UNQ739) Gene Disruptions

[1769] In these knockout experiments, the gene encoding PRO1434 polypeptides (designated as DNA68818-2536) (UNQ739) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: NM.sub.--177033 Mus musculus RIKEN cDNA A930041011 gene (A930041G11Rik); protein reference: Q8C8N3 ACCESSION:Q8C8N3 NID: Mus musculus (Mouse). Hypothetical von Willebrand factor; the human gene sequence reference: NM.sub.--198570 Homo sapiens PSST739 (UNQ739); the human protein sequence corresponds to reference: Q6UXE2 ACCESSION:Q6UXE2 NID: Homo sapiens (Human). PSST739.

[1770] The mouse gene of interest is RIKEN cDNA A930041G11 gene, ortholog of human UNQ739. Aliases include PSST739.

[1771] UNQ739 is a putative secreted protein, containing a signal peptide, and two tandem von Willebrand factor type C (VWC) domains. VWC domains are found in numerous plasma proteins as well as intracellular proteins. VWC domains likely participate in oligomerization or complex formation (Pfam accession 00093).

[1772] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00098 wt het hom Total Observed 16 34 27 86 Expected 21.5 43 21.5 86

Chi-Sq.=1.21 Significance=0.5460744 (hom/n)=0.27 Avg. Litter Size=10

Mutation Information

[1773] Mutation Type Homologous Recombination (standard) Description: The exon preceding coding exon 1 and coding exon 1 were targeted (NCBI accession AK033944.1). 1. Wild-type Expression Panel: Expression of the target gene was detected in brain, spinal cord, eye, thymus, spleen, lung, and heart among the 13 adult tissue samples tested by RT-PCR. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[1774] 66.28.1. Phenotypic Analysis (for Disrupted Gene: DNA68818-2536 (UNQ739)

[1775] (a) Overall Phenotypic Summary:

[1776] Mutation of the gene encoding the ortholog of a human putative secreted protein (UNQ739) resulted in enhanced sensorimotor gating/attention in (-/-) mice. The homozygous mutant mice exhibited enhanced sensorimotor gating/attention at 3 of 4 prepulse intensities when compared with the level for their wild-type littermates and the historical means. In addition, the (-/-) mice exhibited a trend in decreased alkaline phosphatase levels. Hematology revealed decreased mean total white blood cell count and absolute lymphocyte counts in the (-/-) mice. Disruption of the target gene was confirmed by Southern hybridization analysis.

[1777] (b) Phenotypic Analysis: CNS/Neurology

[1778] In the area of neurology, analysis focused herein on identifying in vivo validated targets for the treatment of neurological and psychiatric disorders including depression, generalized anxiety disorders, attention deficit hyperactivity disorder, obsessive compulsive disorder, schizophrenia, cognitive disorders, hyperalgesia and sensory disorders. Neurological disorders include the category defined as "anxiety disorders" which include but are not limited to: mild to moderate anxiety, anxiety disorder due to a general medical condition, anxiety disorder not otherwise specified, generalized anxiety disorder, panic attack, panic disorder with agoraphobia, panic disorder without agoraphobia, posttraumatic stress disorder, social phobia, specific phobia, substance-induced anxiety disorder, acute alcohol withdrawal, obsessive compulsive disorder, agoraphobia, bipolar disorder I or II, bipolar disorder not otherwise specified, cyclothymic disorder, depressive disorder, major depressive disorder, mood disorder, substance-induced mood disorder. In addition, anxiety disorders may apply to personality disorders including but not limited to the following types: paranoid, antisocial, avoidant behavior, borderline personality disorders, dependent, histronic, narcissistic, obsessive-compulsive, schizoid, and schizotypal.

[1779] Procedure:

[1780] Behavioral screens were performed on a cohort of 4 wild type, 4 heterozygous and 8 homozygous mutant mice. All behavioral tests were done between 12 and 16 weeks of age unless reduced viability necessitates earlier testing.

[1781] Prepulse Inhibition of the Acoustic Startle Reflex

[1782] Prepulse inhibition of the acoustic startle reflex occurs when a loud 120 decibel (dB) startle-inducing tone is preceded by a softer (prepulse) tone. The PPI paradigm consists of six different trial types (70 dB background noise, 120 dB alone, 74 dB+120 dB-pp 4, 78 dB+120 dB-pp 8, 82 dB+120 dB-pp 12, and 90 dB+120 dB-pp 20) each repeated in pseudo random order six times for a total of 36 trials. The max response to the stimulus (V max) is averaged for each trial type. Animals with a 120 dB average value equal to or below 100 are excluded from analysis. The percent that the prepulse inhibits the animal's response to the startle stimulus is calculated and graphed.

[1783] Results:

PPI: The (-/-) mice exhibited notably increased median prepulse inhibition during pp 4, pp 8, and pp 12 when compared with the levels for their (+/+) littermates and the historical means, suggesting enhanced sensorimotor gating/attention in the mutants.

[1784] (c) Immunology Phenotypic Analysis

[1785] Immune related and inflammatory diseases are the manifestation or consequence of fairly complex, often multiple interconnected biological pathways which in normal physiology are critical to respond to insult or injury, initiate repair from insult or injury, and mount innate and acquired defense against foreign organisms. Disease or pathology occurs when these normal physiological pathways cause additional insult or injury either as directly related to the intensity of the response, as a consequence of abnormal regulation or excessive stimulation, as a reaction to self, or as a combination of these.

[1786] Though the genesis of these diseases often involves multistep pathways and often multiple different biological systems/pathways, intervention at critical points in one or more of these pathways can have an ameliorative or therapeutic effect. Therapeutic intervention can occur by either antagonism of a detrimental process/pathway or stimulation of a beneficial process/pathway.

[1787] T lymphocytes (T cells) are an important component of a mammalian immune response. T cells recognize antigens which are associated with a self-molecule encoded by genes within the major histocompatibility complex (MHC). The antigen may be displayed together with MHC molecules on the surface of antigen presenting cells, virus infected cells, cancer cells, grafts, etc. The T cell system eliminates these altered cells which pose a health threat to the host mammal. T cells include helper T cells and cytotoxic T cells. Helper T cells proliferate extensively following recognition of an antigen-MHC complex on an antigen presenting cell. Helper T cells also secrete a variety of cytokines, i.e., lymphokines, which play a central role in the activation of B cells, cytotoxic T cells and a variety of other cells which participate in the immune response.

[1788] In many immune responses, inflammatory cells infiltrate the site of injury or infection. The migrating cells may be neutrophilic, eosinophilic, monocytic or lymphocytic as can be determined by histologic examination of the affected tissues. Current Protocols in Immunology, ed. John E. Coligan, 1994, John Wiley & Sons, Inc.

[1789] Many immune related diseases are known and have been extensively studied. Such diseases include immune-mediated inflammatory diseases (such as rheumatoid arthritis, immune mediated renal disease, hepatobiliary diseases, inflammatory bowel disease (IBD), psoriasis, and asthma), non-immune-mediated inflammatory diseases, infectious diseases, immunodeficiency diseases, neoplasia, and graft rejection, etc. In the area of immunology, targets were identified for the treatment of inflammation and inflammatory disorders.

[1790] In the area of immunology, targets have been identified herein for the treatment of inflammation and inflammatory disorders. Immune related diseases, in one instance, could be treated by suppressing the immune response. Using neutralizing antibodies that inhibit molecules having immune stimulatory activity would be beneficial in the treatment of immune-mediated and inflammatory diseases. Molecules which inhibit the immune response can be utilized (proteins directly or via the use of antibody agonists) to inhibit the immune response and thus ameliorate immune related disease.

[1791] The following test was performed:

[1792] (1) Hematology Analysis:

[1793] Test Description Blood tests are carried out by Abbott's Cell-Dyn 3500R, an automated hematology analyzer. Some of its features include a five-part WBC differential. `Patient` reports can cover over 22 parameters in all.

[1794] Results:

Hematology: The (-/-) mice exhibited decreased mean total white blood cell and absolute lymphocyte counts when compared with those of their (+/+) littermates and the historical means.

[1795] These results indicate that mutant (-/-) mice have immunological abnormalities compared with their wild-type littermates. The (-/-) mice showed a decreased absolute lymphocyte count indicative of abnormal adaptive immunity. Thus, PRO1434 polypeptides must be essential for maintaining a normal immunological profile especially for adaptive immunity

[1796] 66.29. Generation and Analysis of Mice Comprising DNA61185-1646 (UNQ746) Gene Disruptions

[1797] In these knockout experiments, the gene encoding PRO1475 polypeptides (designated as DNA61185-1646) (UNQ746) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: NM.sub.--026651 ACCESSION:NM.sub.--026651 NID:22267451 Mus musculus Mus musculus RIKEN cDNA 4930467B06 gene (4930467B06Rik); protein reference: Q91X88 ACCESSION:Q91X88 NID: Mus musculus (Mouse). O-mannosyl N-acetylglucosaminyltransferase; the human gene sequence reference: NM.sub.--017739 ACCESSION:NM.sub.--017739 NID:8923252 Homo sapiens Homo sapiens O-linked mannose beta-1,2-N-acetylglucosaminyltransferase (FLJ20277); the human protein sequence corresponds to reference: Q9NXF9 ACCESSION:Q9NXF9 NID: Homo sapiens (Human). CDNA FLJ20277 FIS, CLONE HEP02567.

[1798] The mouse gene of interest is RIKEN cDNA 4930467B06 gene, ortholog of human FLJ20277 (O-linked mannose beta1,2-N-acetylglucosaminyltransferase). Aliases include 0610016107Rik, O-mannosyl N-acetylglucosaminyltransferase, MEB, GnTI.2, MGAT1.2, POMGNT1, and UDP-GlcNAc.

[1799] FLJ20277 is a Golgi membrane glycosyltransferase that catalyzes the addition of N-acetylglucosamine (GlcNAc) to the alpha-linked terminal mannose (Man) of O-mannosylated proteins (Zhang e al, Biochem J 361 (Pt 1):153-62 (2002); Schacter, Biochim Biophys Acta 1573(3):292-300 (2002)). This enzyme participates in O-mannosyl glycan synthesis, which occurs primarily brain, nerve and skeletal muscle (Yoshida et al, Dev Cell 1 (5):717-24 (2001)). Mutations in FLJ20277 cause muscle-eye-brain diseases, an autosomal recessive disorder characterized by congenital muscular dystrophy, brain malformation, and ocular abnormalities (Vervoort et al, Ann Neurol 56(1):143-8 (2004); Manya et al, Biochem Biophys Res Commun 306(1):93-7 (2003); Taniguchi et al, Hum Mol Genet. 12(5):527-34 (2003)).

[1800] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00099 wt het hom Total Observed 21 39 13 73 Expected 18.25 36.5 18.25 73

Chi-Sq.=10.29 Significance=0.0058284746 (hom/n)=0.18 Avg. Litter Size=9

Mutation Information

[1801] Mutation Type Homologous Recombination (standard) Description: The exon preceding coding exon 1 and coding exons 1 through 5 were targeted (NCBI accession NM.sub.--026651.1). 1. Wild-type Expression Panel: Expression of the target gene was detected in brain and spinal cord among 13 adult tissues samples tested by RT-PCR. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[1802] 66.29.1. Phenotypic Analysis (for Disrupted Gene: DNA61185-1646 (UNQ746)

[1803] (a) Overall Phenotypic Summary:

[1804] Mutation of the gene encoding the ortholog of human O-linked mannose beta1,2-N-acetylglucosaminyltransferase (FLJ20277) resulted in developmental malformation of the brain in (-/-) mice. Retinal vessel disorganization, peripheral retinal degeneration, and microaneurysms were observed in the homozygous mutant mice upon fundus examination. Microscopic analysis confirmed the retinal abnormalities and revealed developmental malformation of the brain in the mutants. In addition, both the male and female (-/-) mice exhibited an impaired glucose tolerance when compared with their gender-matched wild-type littermates and the historical means. The (-/-) mice were smaller than their (+/+) littermates and showed decreased mean body weight and length. Radiological observations showed abnormal bone-related measurements related to osteoporosis. Several neurological abnormalities were also observed in the knockout (-/-) mice. Disruption of the target gene was confirmed by Southern hybridization analysis.

[1805] (b) Pathology

Microscopic: The (-/-) mice exhibited mild-to-moderate multifocal developmental malformation of the brain. There was widespread evidence of defective neuronal migration in the brain as shown by the retention of nests of external granular cell neurons in the cerebellum and associated fusion of cerebellar folia, the scalloped appearance of the ventral arm of the dentate gyrus of the hippocampus, the diffuse disorganization of neurons and loss of neuronal:cell layers in the cerebral cortex, and the fusion of both hemispheres in the area of the dorsal median sulcus. Frequently, mild dilatation of the lateral ventricles was also observed. The (-/-) mice also exhibited diffuse retinal atrophy, characterized by a general reduction in ganglion cell numbers, more severely at the periphery, with associated thinning of the inner and outer nuclear layers of the retina. The retinal vessels frequently lay on the surface of the retina, in direct contact with the vitreous, instead of being embedded in the ganglion cell layer as normal. In some eyes, retinoschisis is evident within the peripheral inner nuclear layer. Gene Expression: LacZ activity was not detected in the panel of tissues by immunohistochemical analysis.

[1806] (c) Cardiovascular Phenotypic Analysis:

[1807] In the area of cardiovascular biology, phenotypic testing was performed to identify potential targets for the treatment of cardiovascular, endothelial or angiogenic disorders. One such phenotypic test included optic fundus photography and angiography to determine the retinal arteriovenous ratio (A/V ratio) in order to flag various eye abnormalities. An abnormal A/V ratio signals such systemic diseases or disorders that may be related to the vascular disease of hypertension (and any disease that causes hypertension, e.g. atherosclerosis), diabetes or other ocular diseases corresponding to ophthalmological disorders. Such eye abnormalities may include but are not limited to the following: retinal abnormality is retinal dysplasia, various retinopathies, restenosis, retinal artery obstruction or occlusion; retinal degeneration causing secondary atrophy of the retinal vasculature, retinitis pigmentosa, macular dystrophies, Stargardt's disease, congenital stationary night blindness, choroideremia, gyrate atrophy, Leber's congenital amaurosis, retinoschisis disorders, Wagner's syndrome, Usher syndromes, Zellweger syndrome, Saldino-Mainzer syndrome, Senior-Loken syndrome, Bardet-Biedl syndrome, Alport's syndrome, Alstom's syndrome, Cockayne's syndrome, dysplaisa spondyloepiphysaria congentia, Flynn-Aird syndrome, Friedreich ataxia, Hallgren syndrome, Marshall syndrome, Albers-Schnoberg disease, Refsum's disease, Kearns-Sayre syndrome, Waardenburg's syndrome, Alagile syndrome, myotonic dystrophy, olivopontocerebellar atrophy, Pierre-Marie dunsdrome, Stickler syndrome, carotinemeia, cystinosis, Wolfram syndrome, Bassen-Kornzweig syndrome, abetalipoproteinemia, incontinentia pigmenti, Batten's disease, mucopolysaccharidoses, homocystinuria, or mannosidosis.

[1808] Procedure: A cohort of 4 wild type, 4 heterozygotes and 8 homozygotes were tested in this assay. Optic fundus photography was performed on conscious animals using a Kowa Genesis small animal fundus camera modified according to Hawes and coauthors (Hawes et al., 1999 Molecular Vision 1999; 5:22). Intra-peritoneal injection of fluorescein permitted the acquisition of direct light fundus images and fluorescent angiograms for each examination. In addition to direct ophthalmological changes, this test can detect retinal changes associated with systemic diseases such as diabetes and atherosclerosis or other retinal abnormalities. Pictures were provided of the optic fundus under normal light. The angiographic pictures allowed examination of the arteries and veins of the eye. In addition an artery to vein (A/V) ratio was determined for the eye.

[1809] Ophthalmology analysis was performed on generated F2 wild type, heterozygous, and homozygous mutant progeny using the protocol described above. Specifically, the A/V ratio was measured and calculated according to the fundus images with Kowa COMIT+ software. This test takes color photographs through a dilated pupil: the images help in detecting and classifying many diseases. The artery to vein ratio (A/V) is the ratio of the artery diameter to the vein diameter (measured before the bifurcation of the vessels). Many diseases will influence the ratio, i.e., diabetes, cardiovascular disorders, papilledema, optic atrophy or other eye abnormalities such as retinal degeneration (known as retinitis pigmentosa) or retinal dysplasia, vision problems or blindness. Thus, phenotypic observations which result in an increased artery-to-vein ratio in homozygous (-/-) and, heterozygous (+/-) mutant progeny compared to wild-type (+/+) littermates would be indicative of such pathological conditions.

[1810] Results:

Fundus: The (-/-) mice exhibited optic nerve fiber layer striation and aggregation, retinal vessel disorganization, and peripheral retinal degeneration. One (-/-) mouse (F-174) also exhibited bulging eyes, suggesting increased intraocular pressure. Angiogram: The (-/-) mice exhibited severe retinal vessel disorganization, microaneurysms, and retinal capillary leakage.

[1811] In summary, in this study, (-/-) mice showed opthamological abnormalities which would lead to abnormal retinal vessels and retinal degeneration when compared with their (+/+) littermates. In summary, by knocking out the gene identified as DNA61185-1646 encoding PRO1475 polypeptides, homozygous mutant progeny exhibit phenotypes which are associated with optic nerve and retinal artery abnormalities. Such detected retinal changes are most commonly associated with cardiovascular systemic diseases or disorders that may be related to the vascular disease of hypertension (and any disease that causes hypertension, e.g. atherosclerosis), diabetes or other ocular diseases corresponding to ophthalmological disorders such as retinal degeneration and even blindness. Thus, antagonists of PRO1475 encoding genes would lead to similar pathological retinal changes, whereas agonists would be useful as therapeutic agents in the treatment of hypertension, atherosclerosis or other opthamological disorders including retinal degeneration and diseases associated with this condition (as indicated above).

[1812] (d) Phenotypic Analysis: CNS/Neurology

[1813] In the area of neurology, analysis focused herein on identifying in vivo validated targets for the treatment of neurological and psychiatric disorders including depression, generalized anxiety disorders, attention deficit hyperactivity disorder, obsessive compulsive disorder, schizophrenia, cognitive disorders, hyperalgesia and sensory disorders. Neurological disorders include the category defined as "anxiety disorders" which include but are not limited to: mild to moderate anxiety, anxiety disorder due to a general medical condition, anxiety disorder not otherwise specified, generalized anxiety disorder, panic attack, panic disorder with agoraphobia, panic disorder without agoraphobia, posttraumatic stress disorder, social phobia, specific phobia, substance-induced anxiety disorder, acute alcohol withdrawal, obsessive compulsive disorder, agoraphobia, bipolar disorder I or II, bipolar disorder not otherwise specified, cyclothymic disorder, depressive disorder, major depressive disorder, mood disorder, substance-induced mood disorder. In addition, anxiety disorders may apply to personality disorders including but not limited to the following types: paranoid, antisocial, avoidant behavior, borderline personality disorders, dependent, histronic, narcissistic, obsessive-compulsive, schizoid, and schizotypal.

[1814] Procedure:

[1815] Behavioral screens were performed on a cohort of 4 wild type, 4 heterozygous and 8 homozygous mutant mice. All behavioral tests were done between 12 and 16 weeks of age unless reduced viability necessitates earlier testing.

[1816] Circadian Test Description:

[1817] Female mice are individually housed at 4 pm on the first day of testing in 48.2 cm.times.26.5 cm home cages and administered food and water ad libitum. Animals are exposed to a 12-hour light/dark cycle with lights turning on at 7 am and turning off at 7 pm. The system software records the number of beam interruptions caused by the animal's movements, with beam breaks automatically divided into ambulations. Activity is recorded in 60, one-hour intervals during the three-day test. Data generated are displayed by median activity levels recorded for each hour (circadian rhythm) and median total activity during each light/dark cycle (locomotor activity) over the three-day testing period.

[1818] Results:

Circadian: The female (-/-) mice exhibited decreased median ambulatory counts especially during the light phase when compared with the number for their gender-matched (+/+) littermates and the historical mean. These results demonstrate an abnormal circadian rhythm. Home-cage activity testing is also suggestive of decreased activity or hypoactivity which is indicative of a decreased anxiety-like response in the mutants. Thus, knockout mice demonstrated a phenotype consistent with depression, cognitive disorders, hyperalgesia and sensory disorders and/or bipolar disorders. Thus, PRO1475 polypeptides and agonists thereof would be useful for the treatment or amelioration of the symptoms associated with depressive disorders.

[1819] Inverted Screen Testing:

[1820] Behavioral screens were performed on a cohort of 4 wild type, 4 heterozygous and 8 homozygous mutant mice. All behavioral tests were done between 12 and 16 weeks of age unless reduced viability necessitates earlier testing. These tests included open field to measure anxiety, activity levels and exploration.

[1821] Inverted Screen Test Data:

[1822] The Inverted Screen is used to measure motor strength/coordination. Untrained mice were placed individually on top of a square (7.5 cm.times.7.5 cm) wire screen which was mounted horizontally on a metal rod. The rod was then rotated 180 degrees so that the mice were on the bottom of the screens. The following behavioral responses were recorded over a 1 min testing session: fell off, did not climb, and climbed up.

[1823] Results:

TABLE-US-00100 Genotype Ratio Fell Down % Ratio Climbed up % +/+ (n = 8) 1/8 12.5% 0/8 0 -/- (n = 8) 4/8 50% 0/8 0

A motor strength deficit is apparent when there is a 50% point difference between (-/-) or (+/-) mice and (+/+) mice for the fell down response. 0/8 or 1/8 (-/-) or (+/-) mice not climbing indicates impaired motor coordination. 7/8 or 8/8(-/-) or (+/-) mice climbing up indicates enhanced motor coordination.

[1824] The Inverted Screen Test is designed to measure basic sensory & motor observations:

[1825] Among the 8 (-/-) mice analyzed, all 4 (-/-) mice fell off in the screen whereas 1/8 (+/+) mice fell off suggesting an impaired motor coordination in the mutants.

[1826] (e) Phenotypic Analysis: Metabolism--Blood Chemistry/Glucose Tolerance

[1827] In the area of metabolism, targets may be identified for the treatment of diabetes. Blood chemistry phenotypic analysis includes blood glucose measurements. The COBAS Integra 400 (mfr: Roche) was used for running blood chemistry tests on the mice. In the area of metabolism, targets may be identified for the treatment of diabetes. Blood chemistry phenotypic analysis includes glucose tolerance tests to measure insulin sensitivity and changes in glucose metabolism. Abnormal glucose tolerance test results may indicate but may not be limited to the following disorders or conditions: Diabetes Type 1 and Type 2, Syndrome X, various cardiovascular diseases and/or obesity.

[1828] Procedure: A cohort of 2 wild type and 4 homozygous mice were used in this assay. The glucose tolerance test is the standard for defining impaired glucose homeostasis in mammals. Glucose tolerance tests were performed using a Lifescan glucometer. Animals were injected IP at 2 g/kg with D-glucose delivered as a 20% solution and blood glucose levels were measured at 0, 30, 60 and 90 minutes after injection.

[1829] Results:

[1830] Blood Glucose Levels/Glucose Tolerance Test:

Oral Glucose Tolerance: The (-/-) mice exhibited an impaired glucose tolerance when compared with that of their gender-matched (+/+) littermates and the historical mean.

[1831] These studies indicated that (-/-) mice exhibit a decreased or impaired glucose tolerance in the presence of normal fasting glucose at all 3 intervals tested when compared with their gender-matched (+/+) littermates and the historical means. Thus, knockout mutant mice exhibited the phenotypic pattern of an impaired glucose homeostasis, and therefor PRO1475 polypeptides (or agonists thereof) or its encoding gene would be useful in the treatment of conditions associated with an impaired glucose homeostasis and/or various cardiovascular diseases, including diabetes.

[1832] (f) Bone Metabolism & Body Diagnostics

[1833] (1) Tissue Mass & Lean Body Mass Measurements'Dexa

[1834] Dexa Analysis--Test Description:

[1835] Procedure: A cohort of 4 wild type, 4 heterozygotes and 8 homozygotes were tested in this assay. Dual Energy X-ray Absorptiometry (DEXA) has been used successfully to identify changes in total tissue mass (TTM).

[1836] The mouse was anesthetized by intraperitoneal injection of Avertin (1.25% 2,2,2,-tribromoethanol, 20 ml/kg body weight), body length and weight were measured, and then the mouse was placed in a prone position on the platform of the PIXImus.TM. Densitometer (Lunar Inc.) for a DEXA scan. Using Lunar PIXImus software, the bone mineral density (BMD) and fat composition (% fat) and total tissue mass (TTM) were determined in the regions of interest (ROI, i.e., whole body, vertebrae, and both femurs).

[1837] Body Measurements (Body Length & Weight):

[1838] Body Measurements: A measurement of body length and weight was performed at approximately 16 weeks of age.

[1839] Results:

[1840] Obvious Observations: Obvious: The (-/-) mice were smaller than their (+/+) littermates and displayed clutched hind limbs when suspended by their tails.

[1841] Weight/Length:

[1842] The (-/-) mice exhibited decreased mean body weight and mean body length when compared with their gender-matched (+/+) littermates and the historical mean.

[1843] (2) Bone Metabolism: Radiology Phenotypic Analysis

[1844] In the area of bone metabolism, targets were identified herein for the treatment of arthritis, osteoporosis, osteopenia and osteopetrosis as well as identifying targets that promote bone healing. Tests included: [1845] DEXA for measurement of bone mineral density on femur and vertebra [1846] MicroCT for very high resolution and very high sensitivity measurements of bone mineral density for both trabecular and cortical bone.

[1847] Dexa Analysis--Test Description:

[1848] Procedure: A cohort of 4 wild type, 4 heterozygotes and 8 homozygotes were tested in this assay. Dual Energy X-ray Absorptiometry (DEXA) has been used successfully to identify changes in bone. Anesthetized animals were examined and bone mineral content (BMC), BMC/LBM ratios, volumetric bone mineral density (vBMD), total body BMD, femur BMD and vertebra BMD were measured.

[1849] The mouse was anesthetized by intraperitoneal injection of Avertin (1.25% 2,2,2,-tribromoethanol, 20 ml/kg body weight), body length and weight were measured, and then the mouse was placed in a prone position on the platform of the PIXTmus.TM. Densitometer (Lunar Inc.) for a DEXA scan. Using Lunar PLXImus software, the bone mineral density (BMD) and fat composition (% fat) and total tissue mass (TTM) were determined in the regions of interest (ROI) [i.e., whole body, vertebrae, and both femurs].

[1850] Bone MicroCT Analysis:

[1851] Procedure: MicroCT was also used to get very sensitive measurements of BMD. One vertebra and 1 femur were taken from a cohort of 4 wild type and 8 homozygous mice. Measurements were taken of lumbar 5 vertebra trabecular bone volume, trabecular thickness, connectivity density and midshaft femur total bone area and cortical thickness. The .mu.CT40 scans provided detailed information on bone mass and architecture. Multiple bones were placed into sample holders and scanned automatically. Instrument software was used to select regions of interest for analysis. Trabecular bone parameters were analyzed in the fifth lumbar vertebrae (LV5) at 16 micrometer resolution and cortical bone parameters were analyzed in the femur midshaft at a resolution of 20 micrometers.

[1852] Results:

Micro CT: micro CT: The male (-/-) mice exhibited decreased mean vertebral trabecular bone volume, number, thickness, and connectivity density when compared with their gender-matched (+/+) littermates and the historical means.

[1853] Mutant (-/-) mice deficient in the gene encoding PRO1475 polypeptides show a phenotype consistent with growth retardation and/or tissue wasting diseases as well as abnormal bone metabolism. These results are consistent with the observation of smaller appearance than their (+/+) littermates as well as decreased mean body weight and mean body length reported above. In addition, the mutant (-/-) mice exhibited decreased vertebral trabecular bone mineral content and density measurements suggestive of osteoporosis. Thus, antagonists or inhibitors of PRO1475 polypeptides or its encoding gene would mimic these abnormal metabolic related effects. On the other hand, PRO1475 polypeptides or agonists thereof would be useful in the prevention and/or treatment of such metabolic disorders as growth retardation, cachexia or other tissue wasting diseases as well as useful in the treatment of bone disorders associated with bone loss.

[1854] 66.30. Generation and Analysis of Mice Comprising DNA58732-1650 (UNQ750) Gene Disruptions

[1855] In these knockout experiments, the gene encoding PRO1481 polypeptides (designated as DNA58732-1650) (UNQ750) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: NM.sub.--172979 Mus musculus RIKEN cDNA D730046L02 gene (D730046L02Rik); protein reference: Q8C6Z1 ACCESSION:Q8C6Z1 NID: Mus musculus (Mouse). Mucin 15 precursor; the human gene sequence reference: NM.sub.--145650 Homo sapiens mucin 15 (MUC15); the human protein sequence corresponds to reference: Q8N387 ACCESSION:Q8N387 NID: Homo sapiens (Human). MUC15 protein precursor.

[1856] The mouse gene of interest is RIKEN cDNA D730046L02 gene, ortholog of human MUC15 (mucin 15). Aliases include 4732460E09, PASIII, PAS3, GLYCOPROTEIN C, GLYCOPROTEIN 4, and COMPONENT II. MUC15 is a type I plasma membrane protein, consisting of a signal peptide, an extracellular, heavily glycosylated segment, a transmembrane segment, and short cytoplasmic C-terminus. A second isoform lacking the transmembrane segment may be secreted. The protein is expressed in a wide variety of tissues, including spleen, thymus, prostate, testis, ovary, small intestine, colon, peripheral blood leukocyte, bone marrow, lymph node and lung. MUC15 likely plays a role in cell adhesion to extracellular matrix (Pallesen et al, Eur J Biochem 269(11):2755-63 (2002)).

[1857] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00101 wt het hom Total Observed 19 39 23 81 Expected 20.25 40.5 20.25 81

Chi-Sq.=2.06 Significance=0.35700697 (hom/n)=0.29 Avg. Litter Size=9

Mutation Information

[1858] Mutation Type Homologous Recombination (standard) Description: Coding exon 1 was targeted (NCBI accession NM.sub.--172979.1). 1. Wild-type Expression Panel: Expression of the target gene was detected in embryonic stem (ES) cells and in all 13 adult tissue samples tested by RT-PCR, except liver, skeletal muscle, and bone. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[1859] 66.30.1. Phenotypic Analysis (for Disrupted Gene: DNA58732-1650 (UNQ750)

[1860] (a) Overall Phenotypic Summary:

[1861] Mutation of the gene encoding the ortholog of human mucin 15 (MUC15) resulted in the homozygous mutant mice exhibiting an enhanced sensorimotor gating/attention during prepulse inhibition testing when compared with their wild-type littermates and the historical means. In addition, the mutant (-/-) mice exhibited immunological abnormalities. Gene disruption was confirmed by Southern blot.

[1862] (b) Microarray Analysis

[1863] Microarray analysis reveals overexpression of UNQ750 in breast tumors compared to normal breast tissue.

[1864] (c) Phenotypic Analysis: CNS/Neurology

[1865] In the area of neurology, analysis focused herein on identifying in vivo validated targets for the treatment of neurological and psychiatric disorders including depression, generalized anxiety disorders, attention deficit hyperactivity disorder, obsessive compulsive disorder, schizophrenia, cognitive disorders, hyperalgesia and sensory disorders. Neurological disorders include the category defined as "anxiety disorders" which include but are not limited to: mild to moderate anxiety, anxiety disorder due to a general medical condition, anxiety disorder not otherwise specified, generalized anxiety disorder, panic attack, panic disorder with agoraphobia, panic disorder without agoraphobia, posttraumatic stress disorder, social phobia, specific phobia, substance-induced anxiety disorder, acute alcohol withdrawal, obsessive compulsive disorder, agoraphobia, bipolar disorder I or II, bipolar disorder not otherwise specified, cyclothymic disorder, depressive disorder, major depressive disorder, mood disorder, substance-induced mood disorder. In addition, anxiety disorders may apply to personality disorders including but not limited to the following types: paranoid, antisocial, avoidant behavior, borderline personality disorders, dependent, histronic, narcissistic, obsessive-compulsive, schizoid, and schizotypal.

[1866] Procedure:

[1867] Behavioral screens were performed on a cohort of 4 wild type, 4 heterozygous and 8 homozygous mutant mice. All behavioral tests were done between 12 and 16 weeks of age unless reduced viability necessitates earlier testing.

[1868] Prepulse Inhibition of the Acoustic Startle Reflex

[1869] Prepulse inhibition of the acoustic startle reflex occurs when a loud 120 decibel (dB) startle-inducing tone is preceded by a softer (prepulse) tone. The PPI paradigm consists of six different trial types (70 dB background noise, 120 dB alone, 74 dB+120 dB-pp 4, 78 dB+120 dB-pp 8, 82 dB+120 dB-pp 12, and 90 dB+120 dB-pp 20) each repeated in pseudo random order six times for a total of 36 trials. The max response to the stimulus (V max) is averaged for each trial type. Animals with a 120 dB average value equal to or below 100 are excluded from analysis. The percent that the prepulse inhibits the animal's response to the startle stimulus is calculated and graphed.

[1870] Results:

PPI: The (-/-) mice exhibited increased median prepulse inhibition during pp 4, pp 8, and pp 12 when compared with the levels for their (+/+) littermates and the historical means, which is an indication of an enhanced sensorimotor gating/attention in the mutants.

[1871] (d) Immunology Phenotypic Analysis

[1872] Immune related and inflammatory diseases are the manifestation or consequence of fairly complex, often multiple interconnected biological pathways which in normal physiology are critical to respond to insult or injury, initiate repair from insult or injury, and mount innate and acquired defense against foreign organisms. Disease or pathology occurs when these normal physiological pathways cause additional insult or injury either as directly related to the intensity of the response, as a consequence of abnormal regulation or excessive stimulation, as a reaction to self, or as a combination of these.

[1873] Though the genesis of these diseases often involves multistep pathways and often multiple different biological systems/pathways, intervention at critical points in one or more of these pathways can have an ameliorative or therapeutic effect. Therapeutic intervention can occur by either antagonism of a detrimental process/pathway or stimulation of a beneficial process/pathway.

[1874] T lymphocytes (T cells) are an important component of a mammalian immune response. T cells recognize antigens which are associated with a self-molecule encoded by genes within the major histocompatibility complex (MHC). The antigen may be displayed together with MHC molecules on the surface of antigen presenting cells, virus infected cells, cancer cells, grafts, etc. The T cell system eliminates these altered cells which pose a health threat to the host mammal. T cells include helper T cells and cytotoxic T cells. Helper T cells proliferate extensively following recognition of an antigen-MHC complex on an antigen presenting cell. Helper T cells also secrete a variety of cytokines, i.e., lymphokines, which play a central role in the activation of B cells, cytotoxic T cells and a variety of other cells which participate in the immune response.

[1875] In many immune responses, inflammatory cells infiltrate the site of injury or infection. The migrating cells may be neutrophilic, eosinophilic, monocytic or lymphocytic as can be determined by histologic examination of the affected tissues. Current Protocols in Immunology, ed. John E. Coligan, 1994, John Wiley & Sons, Inc.

[1876] Many immune related diseases are known and have been extensively studied. Such diseases include immune-mediated inflammatory diseases (such as rheumatoid arthritis, immune mediated renal disease, hepatobiliary diseases, inflammatory bowel disease (IBD), psoriasis, and asthma), non-immune-mediated inflammatory diseases, infectious diseases, immunodeficiency diseases, neoplasia, and graft rejection, etc. In the area of immunology, targets were identified for the treatment of inflammation and inflammatory disorders.

[1877] In the area of immunology, targets have been identified herein for the treatment of inflammation and inflammatory disorders. Immune related diseases, in one instance, could be treated by suppressing the immune response. Using neutralizing antibodies that inhibit molecules having immune stimulatory activity would be beneficial in the treatment of immune-mediated and inflammatory diseases. Molecules which inhibit the immune response can be utilized (proteins directly or via the use of antibody agonists) to inhibit the immune response and thus ameliorate immune related disease.

[1878] The following test was performed:

[1879] (1) Flourescence-Activated Cell-Sorting (FAGS) Analysis

[1880] Procedure:

[1881] FACS analysis of immune cell composition from peripheral blood was performed including CD4, CD8 and T cell receptor to evaluate T lymphocytes, CD19 for B lymphocytes, CD45 as a leukocyte marker and pan NK for natural killer cells. The FACS analysis was carried out on 2 wild type and 6 homozygous mice and included cells derived from thymus, spleen, bone marrow and lymph node.

[1882] In these studies, analyzed cells were isolated from thymus, peripheral blood, spleen, bone marrow and lymph nodes. Flow cytometry was designed to determine the relative proportions of CD4 and CD8 positive T cells, B cells, NK cells and monocytes in the mononuclear cell population. A Becton-Dickinson FACSCalibur 3-laser FACS machine was used to assess immune status. For Phenotypic Assays and Screening, this machine records CD4+/CD8-, CD8+/CD4-, NK, B cell and monocyte numbers in addition to the CD4+/CD8+ ratio.

[1883] The mononuclear cell profile was derived by staining a single sample of lysed peripheral blood from each mouse with a panel of six lineage-specific antibodies: CD45 PerCP, anti-TCRb APC, CD4 PE, CD8 FITC, pan-NK PE, and CD19 FITC. The two FITC and PE labeled antibodies stain mutually exclusive cell types. The samples were analyzed using a Becton Dickinson FACSCalibur flow cytometer with CellQuest software.

[1884] Results:

Tissue Specific FACS-Project: The (-/-) mice exhibited an increased percentage of TCRB+ and a decreased percentage of B220+ cells in Peyer's patches when compared with those of the (+/+) mice. These results are indicative of an increase in activated T cells (TCRB+CD38+).

[1885] These results indicate that the knockout mice exhibited a decrease in a subset of B cells (pre-B cells, immature and mature B cells). Thus, the mutant homozygous mice exhibited immunological abnormalities associated with decreased levels of B cell progenitor cells. In addition, the knockout mice exhibit an increase in T cells.

[1886] These results show that knockout (-/-) mice exhibit immunological abnormalities compared to their wild-type (+/+) littermates. Antagonists (inhibitors) of PRO1481 polypeptides would be expected to mimic this phenotype. PRO1481 polypeptides or agonists thereof appear to act as a negative regulator of T cell production and a positive regulator of B cell development and would be useful in the development or maturation of B cells which could then participate in fast immune responses. Antagonists (inhibitors) of PRO1481 polypeptides would be useful in stimulating the production of T cells.

[1887] 66.31. Generation and Analysis of Mice Comprising DNA68880-1676 (UNQ774) Gene Disruptions

[1888] In these knockout experiments, the gene encoding PRO1568 polypeptides (designated as DNA68880-1676) (UNQ774) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: NM.sub.--173007 Mus musculus transmembrane 4 superfamily member 12 (Tm4sf12); protein reference: Q8BKT6 ACCESSION:Q8BKT6 NID: Mus musculus (Mouse). Mus musculus 9 days embryo whole body cDNA, RIKEN full-length enriched library, clone:D030012P12 product:TETRASPAN NET-2 homolog (Tm4sf12 protein); the human gene sequence reference: NM.sub.--012338 ACCESSION:NM.sub.--012338 NID:21264567 Homo sapiens Homo sapiens transmembrane 4 superfamily member tetraspan NET-2 (NET-2); the human protein sequence corresponds to reference: O95859 ACCESSION:Q95859 NID: Homo sapiens (Human). TETRASPAN NET-2.

[1889] The mouse gene of interest is Tm4sf12 (transmembrane 4 superfamily member 12), ortholog of human TM4SF12. Aliases include 9030619E17, EST A1426782, NET-2, and tetraspan NET-2.

[1890] TM4SF12 is a putative integral plasma membrane protein and subunit of larger cell surface complexes that likely function in cell adhesion and signal transduction. TM4SF12 is a member of the tetraspanin superfamily, containing four transmembrane segments within a tetraspanin family domain. Although the physiological role of TM4SF12 is not known, tetraspanins are involved in adhesion-dependent signaling mediated by integrins, generally playing a role in processes such as cell adhesion, migration, fertilization, immunity, development, and metastasis (Serra et al, Biochim Biophys Acta 1478(1):159-63 (2000); Berditchevski, J Cell Sci 114(Pt 23):4143-51 (2001); Tarrant et al, Trends Immunol 24(11):610-7 (2003); Le Naour et al, Cancer Immunol Immunother 53(3):148-52 (2004)).

[1891] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00102 wt het hom Total Observed 20 36 25 81 Expected 20.25 40.5 20.25 81

Chi-Sq.=0.99 Significance=0.6095709 (hom/n)=0.26 Avg. Litter Size=8

Mutation Information

[1892] Mutation Type: Homologous Recombination (standard) Coding exon 1 was targeted (NCBI accession NM.sub.--173007.1). 1. Wild-type Expression Panel: Expression of the target gene was detected in all 13 adult tissue samples tested by RT-PCR, except bone. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[1893] 66.31.1. Phenotypic Analysis (for Disrupted Gene: DNA68880-1676 (UNQ774)

[1894] (a) Overall Phenotypic Summary:

[1895] Mutation of the gene encoding the ortholog of human transmembrane 4 superfamily member 12

[1896] (TM4SF12) resulted in the homozygous mutant mice exhibited numerous ophthalmological abnormalities, including retinal microaneurysms and non-homogeneous retinal backgrounds. In addition, CAT-Scan analysis revealed moderate hydronephrosis in 2 of 3 homozygous mutants and 1 of 2 heterozygous mice analyzed. Disruption of the target gene was confirmed by Southern hybridization analysis.

[1897] (b) Cardiovascular Phenotypic Analysis:

[1898] In the area of cardiovascular biology, phenotypic testing was performed to identify potential targets for the treatment of cardiovascular, endothelial or angiogenic disorders. One such phenotypic test included optic fundus photography and angiography to determine the retinal arteriovenous ratio (A/V ratio) in order to flag various eye abnormalities. An abnormal A/V ratio signals such systemic diseases or disorders that may be related to the vascular disease of hypertension (and any disease that causes hypertension, e.g. atherosclerosis), diabetes or other ocular diseases corresponding to ophthalmological disorders. Such eye abnormalities may include but are not limited to the following: retinal abnormality is retinal dysplasia, various retinopathies, restenosis, retinal artery obstruction or occlusion; retinal degeneration causing secondary atrophy of the retinal vasculature, retinitis pigmentosa, macular dystrophies, Stargardt's disease, congenital stationary night blindness, choroideremia, gyrate atrophy, Leber's congenital amaurosis, retinoschisis disorders, Wagner's syndrome, Usher syndromes, Zellweger syndrome, Saldino-Mainzer syndrome, Senior-Loken syndrome, Bardet-Biedl syndrome, Alport's syndrome, Alstom's syndrome, Cockayne's syndrome, dysplaisa spondyloepiphysaria congentia, Flynn-Aird syndrome, Friedreich ataxia, Hallgren syndrome, Marshall syndrome, Albers-Schnoberg disease, Refsum's disease, Kearns-Sayre syndrome, Waardenburg's syndrome, Alagile syndrome, myotonic dystrophy, olivopontocerebellar atrophy, Pierre-Marie dunsdrome, Stickler syndrome, carotinemeia, cystinosis, Wolfram syndrome, Bassen-Kornzweig syndrome, abetalipoproteinemia, incontinentia pigmenti, Batten's disease, mucopolysaccharidoses, homocystinuria, or mannosidosis.

[1899] Procedure: A cohort of 4 wild type, 4 heterozygotes and 8 homozygotes were tested in this assay. Optic fundus photography was performed on conscious animals using a Kowa Genesis small animal fundus camera modified according to Hawes and coauthors (Hawes et al., 1999 Molecular Vision 1999; 5:22). Intra-peritoneal injection of fluorescein permitted the acquisition of direct light fundus images and fluorescent angiograms for each examination. In addition to direct ophthalmological changes, this test can detect retinal changes associated with systemic diseases such as diabetes and atherosclerosis or other retinal abnormalities. Pictures were provided of the optic fundus under normal light. The angiographic pictures allowed examination of the arteries and veins of the eye. In addition an artery to vein (A/V) ratio was determined for the eye.

[1900] Ophthalmology analysis was performed on generated F2 wild type, heterozygous, and homozygous mutant progeny using the protocol described above. Specifically, the A/V ratio was measured and calculated according to the fundus images with Kowa COMIT+ software. This test takes color photographs through a dilated pupil: the images help in detecting and classifying many diseases. The artery to vein ratio (A/V) is the ratio of the artery diameter to the vein diameter (measured before the bifurcation of the vessels). Many diseases will influence the ratio, i.e., diabetes, cardiovascular disorders, papilledema, optic atrophy or other eye abnormalities such as retinal degeneration (known as retinitis pigmentosa) or retinal dysplasia, vision problems or blindness. Thus, phenotypic observations which result in an increased artery-to-vein ratio in homozygous (-/-) and heterozygous (+/-) mutant progeny compared to wildtype (+/+) littermates would be indicative of such pathological conditions.

[1901] Results:

Fundus: The (-/-) mice exhibited unhealthy retinal beds with non-homogeneous backgrounds. Two (-/-) mice (M-79 and M-98) also exhibited white deposits above the retinal vessels that were approximately 2-3 times larger than the optic disc. Angiogram: All 8 (-/-) mice exhibited multiple microaneurysms and leakage of the retinal capillaries bilaterally.

[1902] Such detected retinal changes are most commonly associated with cardiovascular systemic diseases or disorders that may be related to the vascular disease of hypertension (and any disease that causes hypertension, e.g. atherosclerosis), diabetes or other ocular diseases corresponding to ophthalmological disorders such as retinal degeneration. Thus, antagonists of PRO1568 encoding genes would lead to similar pathological retinal changes, whereas agonists may be useful as therapeutic agents in the treatment of hypertension, atherosclerosis or other opthamological disorders including retinal degeneration and diseases associated with this condition (as indicated above).

[1903] Subsequent studies showed a sprouting angiogenesis defect in the UNQ774 knockout retina specifically in the nerve fiber layer (NFL); inner plexiform layer (IPL); and in the outer plexiform layer (OPL) (thus a three layered organization of the retinal vasculature showed a defective angiogenesis (sprouts) when compared with the wildtype (+/+) and heterozygous (+/-) sections [wholemount isolectin staining of the retina, 10.times. confocal images].

[1904] (c) Pathology/CAT Scan

[1905] CAT-Scan Protocol:

[1906] Mice were injected with a CT contrast agent, Omnipaque 300 (Nycomed Amershan, 300 mg of iodine per ml, 0.25 ml per animal, or 2.50-3.75 g iodine/kg of body weight) intraperitoneally. After resting in the cage for .about.10 minutes, the mouse was then sedated by intraperitoneal injection of Avertin (1.25% 2,2,2,-tribromoethanol, 20 ml/kg body weight). A CAT-scan was performed using a MicroCAT scanner (ImTek, Inc.) with the anesthetized animal lying prone on the test bed. Three dimensional images were reconstructed by the Feldkamp algorithm in a cluster of workstations using an ImTek 3D RECON software.

[1907] Results:

[1908] Among the 6 mice analyzed, 1 (+/-) mouse and 2 (-/-) mice exhibited moderate hydronephosis.

[1909] 66.32. Generation and Analysis of Mice Comprising DNA73735-1681 (UNQ779) Gene Disruptions

[1910] In these knockout experiments, the gene encoding PRO1573 polypeptides (designated as DNA73735-1681) (UNQ779) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: NM.sub.--018778 Mus musculus claudin 8 (Cldn8); protein reference: Q9Z260 ACCESSION:Q9Z260 NID: Mus musculus (Mouse). Claudin-8; the human gene sequence reference: NM.sub.--199328 Homo sapiens claudin 8 (CLDN8); the human protein sequence corresponds to reference: P56748 ACCESSION:P56748 NID: Homo sapiens (Human). Claudin-8.

[1911] The mouse gene of interest is Cldn8 (claudin 8), ortholog of human CLDN8.

[1912] CLDN8 is an integral plasma membrane protein that functions as an adhesion molecule and component of tight junctions. The protein consists, of a single claudin family domain (Pfam accession PF00822), which contains 4 transmembrane segments. CLDN8 is expressed primarily in lung and kidney and is particularly concentrated at the tight junctions along the aldosterone-sensitive nephron. CLDN8 is likely to play a role in paracellular cation transport and permeability (Yu et al, J Biol Chem 278(19):17350-9 (2003); Morita et al, Proc Natl Acad Sci USA 96(2):511-6 (1999); Heiskala et al, Traffic 2(2):93-8 (2001); Li et al, Am J Physiol Renal Physiol 286(6):F1063-71 (2004)).

[1913] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00103 wt het hom Total Observed 17 47 19 83 Expected 20.75 41.5 20.75 83

Chi-Sq.=2.58 Significance=0.2752708 (hom/n)=0.21 Avg. Litter Size=9

Mutation Information

[1914] Mutation Type: Homologous Recombination (standard) Description: Coding exon 1 was targeted (NCBI accession NM.sub.--018778.2). 1. Wild-type Expression Panel: Expression of the target gene was detected in all 13 adult tissue samples tested by RT-PCR, except spleen, bone, heart, and adipose. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis. 66.32.1. Phenotypic Analysis (for disrupted gene: DNA73735-1681 (UNQ779)

[1915] (a) Overall Phenotypic Summary:

[1916] Mutation of the gene encoding the ortholog of human claudin 8 (CLDN8) resulted in a decreased startle reflex in the mutant (-/-) mice. Gene disruption was confirmed by Southern blot.

[1917] (b) Phenotypic Analysis: CNS/Neurology

[1918] In the area of neurology, analysis focused herein on identifying in vivo validated targets for the treatment of neurological and psychiatric disorders including depression, generalized anxiety disorders, attention deficit hyperactivity disorder, obsessive compulsive disorder, schizophrenia, cognitive disorders, hyperalgesia and sensory disorders. Neurological disorders include the category defined as "anxiety disorders" which include but are not limited to: mild to moderate anxiety, anxiety disorder due to a general medical condition, anxiety disorder not otherwise specified, generalized anxiety disorder, panic attack, panic disorder with agoraphobia, panic disorder without agoraphobia, posttraumatic stress disorder, social phobia, specific phobia, substance-induced anxiety disorder, acute alcohol withdrawal, obsessive compulsive disorder, agoraphobia, bipolar disorder I or II, bipolar disorder not otherwise specified, cyclothymic disorder, depressive disorder, major depressive disorder, mood disorder, substance-induced mood disorder. In addition, anxiety disorders may apply to personality disorders including but not limited to the following types: paranoid, antisocial, avoidant behavior, borderline personality disorders, dependent, histronic, narcissistic, obsessive-compulsive, schizoid, and schizotypal.

[1919] Procedure:

[1920] Behavioral screens were performed on a cohort of 4 wild type, 4 heterozygous and 8 homozygous mutant mice. All behavioral tests were done between 12 and 16 weeks of age unless reduced viability necessitates earlier testing.

[1921] Prepulse Inhibition of the Acoustic Startle Reflex

[1922] Prepulse inhibition of the acoustic startle reflex occurs when a loud 120 decibel (dB) startle-inducing tone is preceded by a softer (prepulse) tone. The PPI paradigm consists of six different trial types (70 dB background noise, 120 dB alone, 74 dB+120 dB-pp 4, 78 dB+120 dB-pp 8, 82 dB+120 dB-pp 12, and 90 dB+120 dB-pp 20) each repeated in pseudo random order six times for a total of 36 trials. The max response to the stimulus (V max) is averaged for each trial type Animals with a 120 dB average value equal to or below 100 are excluded from analysis. The percent that the prepulse inhibits the animal's response to the startle stimulus is calculated and graphed.

[1923] Results:

PPI: The (-/-) mice exhibited a decreased startle response, suggesting a hearing impairment in the mutants.

[1924] 66.33. Generation and Analysis of Mice Comprising DNA62845-1684 (UNQ782) Gene Disruptions

[1925] In these knockout experiments, the gene encoding PRO1599 polypeptides (designated as DNA62845-1684) (UNQ782) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: XM.sub.--196763 PREDICTED: Mus musculus RIKEN cDNA 2900092M14 gene (2900092M14Rik); protein reference: XP.sub.--196763 RIKEN cDNA 2900092M14 [Mus musculus]; the human gene sequence reference: NM.sub.--214710 Homo sapiens protease, serine-like 1 (PRSSL1); the human protein sequence corresponds to reference: Q6UWY2 ACCESSION:Q6UWY2 NID: Homo sapiens (Human). GLGL782.

[1926] The mouse gene of interest is Prssl1 (protease, serine-like 1), ortholog of human PRSSL1. Aliases include UNQ782, GLGL782, and 2900092M14Rik.

[1927] PRSSL1 is a putative secreted protease, consisting of a signal peptide and a trypsin-like serine protease domain (SMART accession SM00020).

[1928] Unfortunately, another mammalian locus (KLK10, kallikrein 10, GeneID: 5655) has also been referred to as PRSSL1 in the scientific literature and sequence databases. The disrupted locus described herein is not KLK10, and represents another gene altogether. No published information concerning PRSSL1 (the gene of interest for this project) could be found at the time of this writing--thus all refers to KLK10. Therefore, care is required in interpreting the scientific literature as database sequences.

[1929] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00104 wt het hom Total Observed 23 33 24 80 Expected 20 40 20 80

Chi-Sq.=1.1 Significance=0.5769498 (hom/n)=0.28 Avg. Litter Size=10

Mutation Information

[1930] Mutation Type Homologous Recombination (standard) Description: Coding exons 2 and 3 were targeted (NCBI accession XM.sub.--196763.2). 1. Wild-type Expression Panel: Expression of the target gene was detected only in spinal cord, thymus, and spleen among the 13 adult tissue samples tested by RT-PCR. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[1931] 66.33.1. Phenotypic Analysis (for disrupted gene: DNA62845-1684 (UNQ782)

[1932] (a) Overall Phenotypic Summary:

[1933] Mutation of the gene encoding the ortholog of human protease, serine-like 1 (PRSSL1) resulted in immunological abnormalities in (-/-) mice. The homozygous mutant mice exhibited decreased mean percentages of CD8 and NK cells and an increased mean percentage of B cells in the peripheral blood. In addition, the mutants exhibited increased mean serum TNF-alpha and MCP-1 responses to LPS challenge and an increased mean serum IgG2a response to ovalbumin challenge when compared with those of their wild-type littermates and the historical means. The knockout mice also showed inflammation of several tissues. In addition, the mutant (-/-) mice showed signs of obesity with increased mean total mass, percent total body fat, and total fat mass. Disruption of the target gene was confirmed by Southern hybridization analysis.

[1934] (b) Immunology Phenotypic Analysis

[1935] Immune related and inflammatory diseases are the manifestation or consequence of fairly complex, often multiple interconnected biological pathways which in normal physiology are critical to respond to insult or injury, initiate repair from insult or injury, and mount innate and acquired defense against foreign organisms. Disease or pathology occurs when these normal physiological pathways cause additional insult or injury either as directly related to the intensity of the response, as a consequence of abnormal regulation or excessive stimulation, as a reaction to self, or as a combination of these.

[1936] Though the genesis of these diseases often involves multistep pathways and often multiple different biological systems/pathways, intervention at critical points in one or more of these pathways can have an ameliorative or therapeutic effect. Therapeutic intervention can occur by either antagonism of a detrimental process/pathway or stimulation of a beneficial process/pathway.

[1937] T lymphocytes (T cells) are an important component of a mammalian immune response. T cells recognize antigens which are associated with a self-molecule encoded by genes within the major histocompatibility complex (MHC). The antigen may be displayed together with MHC molecules on the surface of antigen presenting cells, virus infected cells, cancer cells, grafts, etc. The T cell system eliminates these altered cells which pose a health threat to the host mammal. T cells include helper T cells and cytotoxic T cells. Helper T cells proliferate extensively following recognition of an antigen-MHC complex on an antigen presenting cell. Helper T cells also secrete a variety of cytokines, i.e., lymphokines, which play a central role in the activation of B cells, cytotoxic T cells and a variety of other cells which participate in the immune response.

[1938] In many immune responses, inflammatory cells infiltrate the site of injury or infection. The migrating cells may be neutrophilic, eosinophilic, monocytic or lymphocytic as can be determined by histologic examination of the affected tissues. Current Protocols in Immunology, ed. John E. Coligan, 1994, John Wiley & Sons, Inc.

[1939] Many immune related diseases are known and have been extensively studied. Such diseases include immune-mediated inflammatory diseases (such as rheumatoid arthritis, immune mediated renal disease, hepatobiliary diseases, inflammatory bowel disease (IBD), psoriasis, and asthma), non-immune-mediated inflammatory diseases, infectious diseases, immunodeficiency diseases, neoplasia, and graft rejection, etc. In the area of immunology, targets were identified for the treatment of inflammation and inflammatory disorders.

[1940] In the area of immunology, targets have been identified herein for the treatment of inflammation and inflammatory disorders. Immune related diseases, in one instance, could be treated by suppressing the immune response. Using neutralizing antibodies that inhibit molecules having immune stimulatory activity would be beneficial in the treatment of immune-mediated and inflammatory diseases. Molecules which inhibit the immune response can be utilized (proteins directly or via the use of antibody agonists) to inhibit the immune response and thus ameliorate immune related disease.

[1941] The following tests were performed:

[1942] (1) Flourescence-activated Cell-Sorting (FAGS) Analysis

[1943] Procedure:

[1944] FACS analysis of immune cell composition from peripheral blood was performed including CD4, CD8 and T cell receptor to evaluate T lymphocytes, CD19 for B lymphocytes, CD45 as a leukocyte marker and pan NK for natural killer cells. The FACS analysis was carried out on 2 wild type and 6 homozygous mice and included cells derived from thymus, spleen, bone marrow and lymph node.

[1945] In these studies, analyzed cells were isolated from thymus, peripheral blood, spleen, bone marrow and lymph nodes. Flow cytometry was designed to determine the relative proportions of CD4 and CD8 positive T cells, B cells, NK cells and monocytes in the mononuclear cell population. A Becton-Dickinson FACSCalibur 3-laser FACS machine was used to assess immune status. For Phenotypic Assays and Screening, this machine records CD4+/CD8-, CD8+/CD4-, NK, B cell and monocyte numbers in addition to the CD4+/CD8+ ratio.

[1946] The mononuclear cell profile was derived by staining a single sample of lysed peripheral blood from each mouse with a panel of six lineage-specific antibodies: CD45 PerCP, anti-TCRb APC, CD4 PE, CD8 FITC, pan-NK PE, and CD19 FITC. The two FITC and PE labeled antibodies stain mutually exclusive cell types. The samples were analyzed using a Becton Dickinson FACSCalibur flow cytometer with CellQuest software.

[1947] Results:

FACS3: The (-/-) mice exhibited an altered distribution of leukocyte subsets in the peripheral blood, characterized by decreased mean percentages of CD8 and NK cells and an increased mean percentage of B cells when compared with their (+/+) littermates and the historical means.

[1948] In summary, FACS analysis of immune cell composition indicates that knockout (-/-) mice exhibit immunological differences with respect to both B cells and cytotoxic T cells (CD8--thymocyte subset which functions as a co-receptor for MHC class 1 molecules). Inhibitors or antagonists of PRO1599 would be useful in B cell production, whereas PRO1599 polypeptides would be expected to lead to the opposite effects. On the other hand, PRO1599 polypeptides appear to function as a positive regulator of CD8 and NK cells (the FACS results indicate that the homozygous mutant mice have a decreased mean percentage of both CD8 and natural killer cells). Natural killer cells are the first line of defense to viral infection since these cells have been implicated in viral immunity and in defense against tumors. Natural kilter cells or NK cells act as effectors in antibody-dependent cell-mediated cytotoxicity and have been identified by their ability to kill certain lymphoid tumor cell lines in vitro without the need for prior immunization or activation. Thus, PRO1599 polypeptides or agonists thereof would be useful in the production of cytotoxic T cells and NK cells important for antibody dependent cell-mediated cytotoxicity.

[1949] (2) Acute Phase Response:

[1950] Test Description: Bacterial lipopolysaccharide (LPS) is an endotoxin, and as such is a potent inducer of an acute phase response and systemic inflammation. The Level I LPS mice were injected intraperitoneally (i.p.) with a sub-lethal dose of LPS in 200 .mu.L sterile saline using a 26 gauge needle. The doses were based on the average weight of the mice tested at 1 .mu.g/g body weight 3 hours after injection; a 100 ul blood sample was then taken and analyzed for the presence of TNFa, MCP-1, and IL-6 on the FACS Calibur instrument.

[1951] Results:

[1952] Acute Phase Response: The (-/-) mice exhibited increased mean serum TNF-alpha and MCP-1 responses to LPS challenge when compared with their gender-matched (+/+) littermates and the historical means.

[1953] In summary, the LPS endotoxin challenge demonstrated that knockout mice deficient in the gene encoding PRO1599 polypeptides exhibit immunological abnormalities when compared with their wild-type littermates. In particular, the mutant mice exhibited an increased ability to elicit an immunological response (TNF-alpha and MCP-1 production) when challenged with the LPS endotoxin indicating a pro-inflammatory response. TNF-alpha and MCP-1 contribute to the later stages of B cell activation. This suggests that inhibitors or antagonists to PRO1599 polypeptides would stimulate the immune system and would find utility in the cases wherein this effect would be beneficial to the individual such as in the case of leukemia, and other types of cancer, and in immunocompromised patients, such as AIDS sufferers. Accordingly, PRO1599 polypeptides or agonists thereof would be useful in inhibiting the immune response and would be useful candidates for suppressing harmful immune responses, e.g. in the case of graft rejection or graft-versus-host diseases.

[1954] (3) Ovalbumin Challenge

[1955] Procedure: This assay was carried out on 7 wild types and 8 homozygotes. Chicken ovalbumin (OVA) is a T-cell dependent antigen, which is commonly used as a model protein for studying antigen-specific immune responses in mice. OVA is non-toxic and inert and therefore will not cause harm to the animals even if no immune response is induced. The murine immune response to OVA has been well characterized, to the extent that the immunodominant peptides for eliciting T cell responses have been identified. Anti-OVA antibodies are detectable 8 to 10 days after immunization using enzyme-linked immunosorbent assay (ELIZA), and determination of different isotypes of antibodies gives further information on the complex processes that may lead to a deficient response in genetically engineered mice.

[1956] As noted above, this protocol assesses the ability of mice to raise an antigen-specific immune response. Animals were injected IP with 50 mg of chicken ovalbumin emulsified in Complete Feund's Adjuvant and 14 days later the serum titer of anti-ovalbumin antibodies (IgM, IgG1 and IgG2 subclasses) was measured. The amount of OVA-specific antibody in the serum sample is proportional to the Optical Density (OD) value generated by an instrument that scans a 96-well sample plate. Data was collected for a set of serial dilutions of each serum sample.

[1957] Results of this Challenge:

Ovalbumin: The (-/-) mice exhibited an increased mean serum IgG2a response to ovalbumin challenge when compared with that of their (+/+) littermates and the historical mean.

[1958] In summary, the ovalbumin challenge studies indicate that knockout mice deficient in the gene encoding PRO1599 polypeptides exhibit immunological abnormalities when compared with their wild-type littermates. In particular, the mutant mice exhibited an increased ability to elicit an immunological response when challenged with the T-cell dependent OVA antigen. Thus, antagonists (inhibitors) of PRO1599 polypeptides would be useful for stimulating the immune system and would find utility in the cases wherein this effect would be beneficial to the individual such as in the case of leukemia, and other types of cancer, and in immunocompromised patients, such as AIDS sufferers. Accordingly, PRO1599 polypeptides or agonists thereof, would be useful for inhibiting the immune response and thus would be useful candidates for suppressing harmful immune responses, e.g. in the case of graft rejection or graft-versus-host diseases or autoimmune disease.

[1959] (c) Bone Metabolism & Radiology Phenotypic Analysis

[1960] In the area of bone metabolism, targets were identified herein for the treatment of arthritis, osteoporosis, osteopenia and osteopetrosis as well as identifying targets that promote bone healing. Tests included: [1961] DEXA for measurement of bone mineral density on femur and vertebra [1962] MicroCT for very high resolution and very high sensitivity measurements of bone mineral density for both trabecular and cortical bone.

[1963] Dexa Analysis--Test Description:

[1964] Procedure: A cohort of 4 wild type, 4 heterozygotes and 8 homozygotes were tested in this assay. Dual Energy X-ray Absorptiometry (DEXA) has been used successfully to identify changes in bone. Anesthetized animals were examined and bone mineral content (BMC), BMC/LBM ratios, volumetric bone mineral density (vBMD), total body BMD, femur BMD and vertebra BMD were measured.

[1965] The mouse was anesthetized by intraperitoneal injection of Avertin (1.25% 2,2,2,-tribromoethanol, 20 ml/kg body weight), body length and weight were measured, and then the mouse was placed in a prone position on the platform of the PIXImus.TM. Densitometer (Lunar Inc.) for a DEXA scan. Using Lunar PIXImus software, the bone mineral density (BMD) and fat composition (% fat) and total tissue mass (TTM) were determined in the regions of interest (ROI) [i.e., whole body, vertebrae, and both femurs].

[1966] Results:

DEXA: The female (-/-) mice exhibited increased mean total tissue mass, percent total body fat, and total fat mass when compared with their gender-matched (+/+) littermates and the historical means.

[1967] These studies suggest that mutant (-/-) non-human transgenic animals exhibit a negative phenotype that would be associated with obesity. Thus, PRO1599 polypeptides or agonists thereof are essential for normal growth and metabolic processes and especially would be important in the prevention and/or treatment of lipid storage diseases and/or obesity.

[1968] 66.34. Generation and Analysis of Mice Comprising DNA71286-1687 (UNQ785) Gene Disruptions

[1969] In these knockout experiments, the gene encoding PRO1604 polypeptides (designated as DNA71286-1687) (UNQ785) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: NM.sub.--008233 ACCESSION:NM.sub.--008233 NID:6680200 Mus musculus Mus musculus hepatoma-derived growth factor, related protein 2 (Hdgfrp2); protein reference: O35540 O35540 O35540 HEPATOMA-DERIVED GROWTH FACTOR; the human gene sequence reference: NM.sub.--032631 Homo sapiens hepatoma-derived growth factor-related protein 2 (HDGF2), transcript variant 2; the human protein sequence corresponds to reference: Q9BW08 ACCESSION:Q9BW08 NID: Homo sapiens (Human). Similar to hepatoma-derived growth factor, related protein 2.

[1970] The mouse gene of interest is Hdgfrp2 (hepatoma-derived growth factor, related protein 2), ortholog of human HDGF2. Aliases include MGC2641, hepatoma-derived growth factor 2, and HRP-2.

[1971] HDGF2 is a putative nuclear protein expressed primarily in testis and skeletal muscle. The protein contains a PWWP domain and a bipartite nuclear localization signal. PWWP domains are typically found in nuclear proteins and are likely involved in protein-protein interactions. HDGF2 is structurally similar to hepatoma-derived growth factor (HDGF), a nuclear protein that stimulates DNA synthesis and cell proliferation when over-expressed in cell lines or when applied exogenously to cells. The apparent mitogenic activity of HDGF is dependent on its ability to enter the nucleus (Izumoto et al, Biochem Biophys Res Commun 238(1):26-32 (1997); Kishima et al, J Biol Chem 277(12):10315-22 (2002)).

[1972] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00105 wt het hom Total Observed 20 36 17 73 Expected 18.25 36.5 18.25 73

Chi-Sq.=7.54 Significance=0.023052063 (hom/n)=0.18 Avg. Litter Size=9

Mutation Information

[1973] Mutation Type Homologous Recombination (standard) Description: Coding exons 1 through 3 were targeted (NCBI accession NM.sub.--008233.1). 1. Wild-type Expression Panel: Expression of the target gene was detected in embryonic stem (ES) cells and in all 13 adult tissue samples tested by RT-PCR. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[1974] 66.34.1. Phenotypic Analysis (for Disrupted Gene: DNA71286-1687 (UNQ785)

[1975] (a) Overall Phenotypic Summary:

[1976] Mutation of the gene encoding the ortholog of human hepatoma-derived growth factor, related protein 2 (HDGF2) resulted in the homozygous mutant mice exhibiting increased mean serum alkaline phosphatase levels when compared with that of their wild-type littermates and the historical means. During circadian testing, the mutant (-/-) mice exhibited hyperactivity during all light and dark periods. In addition, the female mutants exhibited a decreased mean skin fibroblast proliferation rate. Male (-/-) mice exhibited decreased bone mineral content and density measurements. Disruption of the target gene was confirmed by Southern hybridization analysis.

[1977] (b) Phenotypic Analysis: Metabolism--Blood Chemistry

[1978] In the area of metabolism, targets may be identified for the treatment of metabolic disorders. Blood chemistry phenotypic analysis includes blood glucose measurements. The COBAS Integra 400 (mfr: Roche) was used for running blood chemistry tests on the mice. In addition to measuring blood glucose levels the following blood chemistry tests are also routinely performed: Alkaline Phosphatase; Alanine Amino-Transferase; Albumin; Bilirubin; Phosphorous; Creatinine; BUN=Blood Urea Nitrogen; Calcium; Uric Acid; Sodium; Potassium; and Chloride.

Results:

[1979] Both the male and female (-/-) mice exhibited increased mean serum alkaline phosphatase levels when compared with that of their gender-matched (+/+) littermates and the historical means. This result is most likely due to changes in the liver.

[1980] (c) Phenotypic Analysis: CNS/Neurology

[1981] In the area of neurology, analysis focused herein on identifying in vivo validated targets for the treatment of neurological and psychiatric disorders including depression, generalized anxiety disorders, attention deficit hyperactivity disorder, obsessive compulsive disorder, schizophrenia, cognitive disorders, hyperalgesia and sensory disorders. Neurological disorders include the category defined as "anxiety disorders" which include but are not limited to: mild to moderate anxiety, anxiety disorder due to a general medical condition, anxiety disorder not otherwise specified, generalized anxiety disorder, panic attack, panic disorder with agoraphobia, panic disorder without agoraphobia, posttraumatic stress disorder, social phobia, specific phobia, substance-induced anxiety disorder, acute alcohol withdrawal, obsessive compulsive disorder, agoraphobia, bipolar disorder I or II, bipolar disorder not otherwise specified, cyclothymic disorder, depressive disorder, major depressive disorder, mood disorder, substance-induced mood disorder. In addition, anxiety disorders may apply to personality disorders including but not limited to the following types: paranoid, antisocial, avoidant behavior, borderline personality disorders, dependent, histronic, narcissistic, obsessive-compulsive, schizoid, and schizotypal.

[1982] Procedure:

[1983] Behavioral screens were performed on a cohort of 4 wild type, 4 heterozygous and 8 homozygous mutant mice. All behavioral tests were done between 12 and 16 weeks of age unless reduced viability necessitates earlier testing.

[1984] Circadian. Test Description:

[1985] Female mice are individually housed at 4 pm on the first day of testing in 48.2 cm.times.26.5 cm home cages and administered food and water ad libitum. Animals are exposed to a 12-hour light/dark cycle with lights turning on at 7 am and turning off at 7 pm. The system software records the number of beam interruptions caused by the animal's movements, with beam breaks automatically divided into ambulations. Activity is recorded in 60, one-hour intervals during the three-day test. Data generated are displayed by median activity levels recorded for each hour (circadian rhythm) and median total activity during each light/dark cycle (locomotor activity) over the three-day testing period.

[1986] Results:

[1987] The female (-/-) mice exhibited increased ambulatory counts (hyperactivity) during the 12-hour habituation and all light and dark periods of home-cage activity testing when compared with their gender-matched (+/+) littermates and the historical mean. These results demonstrate an enhanced circadian rhythm. Home-cage activity testing is also suggestive of increased activity or hyperactivity which is consistent with generalized anxiety disorders, attention deficit hyperactivity disorder, obsessive compulsive disorder, schizophrenia, cognitive disorders, and sensory disorders.

[1988] (d) Adult Skin Cell Proliferation:

[1989] Procedure: Skin cells were isolated from 16 week old animals (2 wild type and 4 homozygotes). These were developed into primary fibroblast cultures and the fibroblast proliferation rates were measured in a strictly controlled protocol. The ability of this assay to detect hyper-proliferative and hypo-proliferative phenotypes has been demonstrated with p53 and Ku80. Proliferation was measured using Brdu incorporation.

[1990] Specifically, in these studies the skin fibroblast proliferation assay was used. An increase in the number of cells in a standardized culture was used as a measure of relative proliferative capacity. Primary fibroblasts were established from skin biopsies taken from wild type and mutant mice. Duplicate or triplicate cultures of 0.05 million cells were plated and allowed to grow for six days. At the end of the culture period, the number of cells present in the culture was determined using a electronic particle counter.

[1991] Results:

[1992] The female (-/-) mice exhibited a decreased mean skin fibroblast proliferation rate when compared with their gender-matched (+/+) littermates.

[1993] Thus, homozygous mutant mice demonstrated a hypo-proliferative phenotype. As suggested by these observations, antagonists or inhibitors of PRO1604 polypeptides would mimic this hypo-proliferative phenotype and could function as tumor suppressors and would be useful in decreasing abnormal cell proliferation.

[1994] (e) Bone Metabolism & Radiology Phenotypic Analysis

[1995] In the area of bone metabolism, targets were identified herein for the treatment of arthritis, osteoporosis, osteopenia and osteopetrosis as well as identifying targets that promote bone healing. Tests included: [1996] DEXA for measurement of bone mineral density on femur and vertebra [1997] MicroCT for very high resolution and very high sensitivity measurements of bone mineral density for both trabecular and cortical bone.

[1998] Dexa Analysis--Test Description:

[1999] Procedure: A cohort of 4 wild type, 4 heterozygotes and 8 homozygotes were tested in this assay. Dual Energy X-ray Absorptiometry (DEXA) has been used successfully to identify changes in bone. Anesthetized animals were examined and bone mineral content (BMC), BMC/LBM ratios, volumetric bone mineral density (vBMD), total body BMD, femur BMD and vertebra BMD were measured.

[2000] The mouse was anesthetized by intraperitoneal injection of Avertin (1.25% 2,2,2,-tribromoethanol, 20 ml/kg body weight), body length and weight were measured, and then the mouse was placed in a prone position on the platform of the PIXImus.TM. Densitometer (Lunar Inc.) for a DEXA scan. Using Lunar PIXImus software, the bone mineral density (BMD) and fat composition (% fat) and total tissue mass (TTM) were determined in the regions of interest (ROI) [i.e., whole body, vertebrae, and both femurs].

[2001] Bone MicroCT Analysis:

[2002] Procedure: MicroCT was also used to get very sensitive measurements of BMD. One vertebra and 1 femur were taken from a cohort of 4 wild type and 8 homozygous mice. Measurements were taken of lumbar 5 vertebra trabecular bone volume, trabecular thickness, connectivity density and midshaft femur total bone area and cortical thickness. The .mu.CT40 scans provided detailed information on bone mass and architecture. Multiple bones were placed into sample holders and scanned automatically. Instrument software was used to select regions of interest for analysis. Trabecular bone parameters were analyzed in the fifth lumbar vertebrae (LV5) at 16 micrometer resolution and cortical bone parameters were analyzed in the femur midshaft at a resolution of 20 micrometers.

[2003] Results:

DEXA: The male (-/-) mice seemed to show a trend for decreased bone mineral content and vertebrae bone mineral density as well as total body and femur bone mineral density when compared with the values for their gender-matched (+/+) littermates and the historical means. MicroCT: The male knockouts seemed to show a trend for decreased trabecular thickness and connectivity density as well as midshaft femur total area when compared with that of their gender-matched (+/+) littermates and the historical mean. Both the DEXA and MicroCT results are barely 1 SD below the median.

[2004] 66.35. Generation and Analysis of Mice Comprising DNA77648-1688 (UN 0786) Gene Disruptions

[2005] In these knockout experiments, the gene encoding PRO1605 polypeptides (designated as DNA77648-1688) (UNQ786) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: NM.sub.--175098 Mus musculus RIKEN cDNA 6330407D12 gene (6330407D12Rik); protein reference: Q8BIS8 ACCESSION:Q8BIS8 NID: Mus musculus (Mouse). Mus musculus adult male medulla oblongata cDNA, RIKEN full-length enriched library, clone:6330407D12 product:weakly similar to N-ACETYLGLUCOSAMINYLTRANSFERASE; the human gene sequence reference: NM.sub.--138771 ACCESSION:NM.sub.--138771 NID: gi 20270308 ref NM.sub.--138771.1 Homo sapiens alpha-1,3(6)-mannosylglycoprotein beta-1,6-N-acetyl-glucosaminyltransferase-like (LOC90693); the human protein sequence corresponds to reference: Q96EE4 ACCESSION:Q96EE4 NID: Homo sapiens (Human). Hypothetical protein.

[2006] The mouse gene of interest is RIKEN cDNA 6330407D12 gene, ortholog of human alpha-1,3(6)-mannosylglycoprotein beta-1,6-N-acetyl-glucosaminyltransferase-like. Aliases include EST AA675040.

[2007] The hypothetical protein of 140 amino acids, which consists of a signal peptide and no other conserved domain, is predicted to be located in the Golgi apparatus or in the extracellular space (secreted). The protein is structurally related to N-terminal segments of MGAT5 (mannosyl [alpha-1,6-]-glycoprotein beta-1,6-N-acetyl-glucosaminyltransferase) and MGAT5B (mannosyl [alpha-1,6-]-glycoprotein beta-1,6-N-acetyl-glucosaminyltransferase, isoenzyme B), glycosyltransferases of approximately 750 amino acids that catalyze glycoprotein oligosaccharide biosynthesis. MGAT5 is located in the membrane of the Golgi apparatus and is also secreted. Secreted MGAT5 is likely to release fibroblast growth factor from heparan sulfate proteoglycans by a mechanism independent of glycosylation, enabling FGF-2 to activate its receptor on target cells (Saito et al, J Biol Chem 277(19):17002-8 (2002)).

[2008] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00106 wt het hom Total Observed 14 50 26 90 Expected 22.5 45 22.5 90

Chi-Sq.=1.3 Significance=0.5220458 (hom/n)=0.27 Avg. Litter Size=9

Mutation Information

[2009] Mutation Type: Homologous Recombination (standard) Description: The first coding exon was targeted (NM.sub.--175098.2). 1. Wild-type Expression Panel: Expression of the target gene was detected in embryonic stem (ES) cells and in all 13 adult tissue samples tested by RT-PCR, except skeletal muscle and bone. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[2010] 66.35.1. Phenotypic Analysis (for Disrupted Gene: DNA77648-1688 (UNQ786)

[2011] (a) Overall Phenotypic Summary:

[2012] Mutation of the gene encoding the ortholog of human alpha-1,3(6)-mannosylglycoprotein beta-1,6-N-acetyl-glucosaminyl transferase-like resulted in the mutant (-/-) mice exhibiting increased triglyceride levels. Four of the (-/-) mice exhibited an increased intra-cytoplasmic vacuolization of glycogen in hepatocytes. Gene disruption was confirmed by Southern blot.

[2013] (b) Pathology

Microscopic: Among the 6 (-/-) mice analyzed, 4 exhibited moderately increased intra-cytoplasmic vacuolization of glycogen in hepatocytes. Gene Expression LacZ activity was not detected in the panel of tissues by immunohistochemical analysis.

[2014] (c) Phenotypic Analysis: Cardiology

[2015] In the area of cardiovascular biology, targets were identified herein for the treatment of hypertension, atherosclerosis, heart failure, stroke, various coronary artery diseases, dyslipidemias such as high cholesterol (hypercholesterolemia) and elevated serum triglycerides (hypertriglyceridemia), diabetes and/or obesity. The phenotypic tests included the measurement of serum triglycerides.

[2016] Blood Lipids

[2017] Procedure: A cohort of 4 wild type, 4 heterozygotes and 8 homozygotes were tested in this assay. High cholesterol levels and increased triglyceride blood levels are recognized risk factors in the development of cardiovascular disease and/or diabetes. Measuring blood lipids facilitates the finding of biological switches that regulate blood lipid levels. Inhibition of factors which elevate blood lipid levels may be useful for reducing the risk for cardiovascular disease. In these blood chemistry tests, measurements were recorded using the COBAS Integra 400 (mfr: Roche).

[2018] Results:

Blood Chemistry: The male (-/-) mice exhibited increased mean serum triglyceride levels when compared with their gender-matched (+/+) littermates and the historical means.

[2019] As summarized above, the (-/-) mice exhibited increased mean serum triglyceride levels when compared with their gender-matched (+/+) littermates and the historical means. Thus, mutant mice deficient in the PRO1605 gene can serve as a model for cardiovascular disease. PRO1605 polypeptides or its encoding gene would be useful in regulating blood lipids such as triglycerides. Thus, PRO1605 polypeptides or agonists thereof would be useful in the treatment of such cardiovascular diseases as hypertension, atherosclerosis, heart failure, stroke, various coronary diseases, hypercholesterolemia, hypertriglyceridemia, diabetes and/or obesity.

[2020] 66.36. Generation and Analysis of Mice Comprising DNA77301-1708 (UNQ803) Gene Disruptions

[2021] In these knockout experiments, the gene encoding PRO1693 polypeptides (designated as DNA77301-1708) (UNQ803) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: NM.sub.--178678 Mus musculus leucine rich repeat transmembrane neuronal 3 (Lrrtm3); protein reference: Q8BGJ7 ACCESSION:Q8BGJ7 NID: Mus musculus (Mouse). Mus musculus 16 days neonate cerebellum cDNA, RIKEN full-length enriched library, clone:9630003D05 product:hypothetical Leucine-rich repeat, typical subtype containing protein, full insert sequence; the human gene sequence reference: NM.sub.--178011 Homo sapiens leucine rich repeat transmembrane neuronal 3 (LRRTM3); the human protein sequence corresponds to reference: Q86VH5 ACCESSION:Q86VH5 NID: Homo sapiens (Human). Leucine-rich repeat transmembrane neuronal 3 protein (GFNV803).

[2022] The mouse gene of interest is Lrrtm3 (leucine rich repeat transmembrane neuronal 3), ortholog of human LRRTM3. Aliases include 9630044H04Rik and leucine-rich repeat transmembrane neuronal 3 protein.

[2023] LRRTM3 is a putative integral plasma membrane protein, consisting of a signal peptide, several leucine-rich repeats, a transmembrane segment, and a potential cytoplasmic C-terminal domain. The protein is expressed primarily in the nervous system of vertebrates. LRRTM3 may function as a cell adhesion molecule or signal-transducing receptor, possibly playing a role in development and maintenance of the nervous system (Lauren et al, Genomics 81(4):411-21 (2003)).

[2024] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00107 wt het hom Total Observed 24 25 15 64 Expected 16 32 16 64

Chi-Sq.=0.15 Significance=0.9277435 (hom/n)=0.25 Avg. Litter Size=9

Mutation Information

[2025] Mutation Type: Homologous Recombination (standard) Description: Coding exon 2 was targeted (NCBI accession NM.sub.--178678.2). 1. Wild-type Expression Panel: Expression of the target gene was detected only in brain, spinal cord, and eye among the 13 adult tissue samples tested by RT-PCR. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[2026] 66.36.1. Phenotypic Analysis (for Disrupted Gene: DNA77301-1708 (UNQ803)

[2027] (a) Overall Phenotypic Summary:

[2028] Mutation of the gene encoding the ortholog of human leucine rich repeat transmembrane neuronal 3 (LRRTM3) resulted in the homozygous mutant mice exhibiting an increased mean absolute neutrophil count when compared with the levels for their wild-type littermates and the historical means. Gene disruption was confirmed by Southern blot.

[2029] (b) Immunology Phenotypic Analysis

[2030] Immune related and inflammatory diseases are the manifestation or consequence of fairly complex, often multiple interconnected biological pathways which in normal physiology are critical to respond to insult or injury, initiate repair from insult or injury, and mount innate and acquired defense against foreign organisms. Disease or pathology occurs when these normal physiological pathways cause additional insult or injury either as directly related to the intensity of the response, as a consequence of abnormal regulation or excessive stimulation, as a reaction to self, or as a combination of these.

[2031] Though the genesis of these diseases often involves multistep pathways and often multiple different biological systems/pathways, intervention at critical points in one or more of these pathways can have an ameliorative or therapeutic effect. Therapeutic intervention can occur by either antagonism of a detrimental process/pathway or stimulation of a beneficial process/pathway.

[2032] T lymphocytes (T cells) are an important component of a mammalian immune response. T cells recognize antigens which are associated with a self-molecule encoded by genes within the major histocompatibility complex (MHC). The antigen may be displayed together with MHC molecules on the surface of antigen presenting cells, virus infected cells, cancer cells, grafts, etc. The T cell system eliminates these altered cells which pose a health threat to the host mammal. T cells include helper T cells and cytotoxic T cells. Helper T cells proliferate extensively following recognition of an antigen-MHC complex on an antigen presenting cell. Helper T cells also secrete a variety of cytokines, i.e., lymphokines, which play a central role in the activation of B cells, cytotoxic T cells and a variety of other cells which participate in the immune response.

[2033] In many immune responses, inflammatory cells infiltrate the site of injury or infection. The migrating cells may be neutrophilic, eosinophilic, monocytic or lymphocytic as can be determined by histologic examination of the affected tissues. Current Protocols in Immunology, ed. John E. Coligan, 1994, John Wiley & Sons, Inc.

[2034] Many immune related diseases are known and have been extensively studied. Such diseases include immune-mediated inflammatory diseases (such as rheumatoid arthritis, immune mediated renal disease, hepatobiliary diseases, inflammatory bowel disease (IBD), psoriasis, and asthma), non-immune-mediated inflammatory diseases, infectious diseases, immunodeficiency diseases, neoplasia, and graft rejection, etc. In the area of immunology, targets were identified for the treatment of inflammation and inflammatory disorders.

[2035] In the area of immunology, targets have been identified herein for the treatment of inflammation and inflammatory disorders. Immune related diseases, in one instance, could be treated by suppressing the immune response. Using neutralizing antibodies that inhibit molecules having immune stimulatory activity would be beneficial in the treatment of immune-mediated and inflammatory diseases. Molecules which inhibit the immune response can be utilized (proteins directly or via the use of antibody agonists) to inhibit the immune response and thus ameliorate immune related disease.

[2036] The following tests were performed:

[2037] Hematology Analysis:

[2038] Test Description Blood tests are carried out by Abbott's Cell-Dyn 3500R, an automated hematology analyzer. Some of its features include a five-part WBC differential. `Patient` reports can cover over 22 parameters in all.

[2039] Results:

Hematology: The (-/-) mice exhibited an increased mean absolute neutrophil count when compared with that of their (+/+) littermates and the historical mean.

[2040] These results indicate that mutant (-/-) mice exhibit immunological abnormalities compared with their wildtype littermates. In summary, the hematology results indicate that the homozygous mutant mice exhibited increased neutrophils indicating elevated levels of precursors of macrophages with increased phagocytic activity or ability to engulf or kill extracellular pathogens.

[2041] 66.37. Generation and Analysis of Mice Comprising DNA68883-1691 (UNQ826) Gene Disruptions

[2042] In these knockout experiments, the gene encoding PRO1753 polypeptides (designated as DNA68883-1691) (UNQ826) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: NM.sub.--010959 Mus musculus oncoprotein induced transcript 3 (Oit3); protein reference: Q8C9U1 ACCESSION:Q8C9U1 NID: Mus musculus (Mouse). Mus musculus 0 day neonate thymus cDNA, RIKEN full-length enriched library, clone:A430107A04 product:ALC homolog; the human gene sequence reference: NM.sub.--152635 Homo sapiens oncoprotein induced transcript 3 (OIT3); the human protein sequence corresponds to reference: Q8WWZ8 ACCESSION:Q8WWZ8 NID: Homo sapiens (Human). LZP (Hypothetical protein FLJ39116) (PPFL826).

[2043] The mouse gene of interest is Oit3 (oncoprotein induced transcript 3), ortholog of human OIT3. Aliases include LZP, EF-9, FLJ39116, and liver-specific ZP domain-containing protein.

[2044] OIT3 is a putative secreted protein expressed primarily in liver. The protein contains a signal peptide, three tandem epidermal growth factor-like domains, and a novel zona pellucida domain. Although a truncated form of the protein can be detected in blood, OIT3 is located mainly on the nuclear envelope of hepatocytes. OIT3 gene is activated by oncoprotein E2a-Pbx1 in NIH 3T3 fibroblasts but is rarely expressed in hepatocellular carcinoma, suggesting that OIT3 may be a useful negative marker for hepatocellular carcinoma. The biological role of OIT3 is not known (Fu and Kamp, Mol Cell Biol 17(3):1503-12 (1997); Xu et al, Hepatology 38(3):735-44 (2003); Xu et al, DNA Seq 15(2):81-7 (2004)).

[2045] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00108 wt het hom Total Observed 19 41 15 75 Expected 18.75 37.5 18.75 75

Chi-Sq.=5.82 Significance=0.054475725 (hom/n)=0.2 Avg. Litter Size=10

Mutation Information

[2046] Mutation Type Homologous Recombination (standard) Description: Coding exons 1 and 2 were targeted (NCBI accession NM.sub.--010959.1). 1. Wild-type Expression Panel: Expression of the target gene was detected in all 13 adult tissue samples tested by RT-PCR, except adipose. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[2047] 66.37.1. Phenotypic Analysis (for Disrupted Gene: DNA68883-1691 (UNQ826)

[2048] (a) Overall Phenotypic Summary:

[2049] Mutation of the gene encoding the ortholog of human oncoprotein induced transcript 3 (OIT3) resulted in the male homozygous mutant mice exhibiting an increased anxiety-like response during open field testing when compared with their gender-matched wild-type littermates and the historical mean. In addition, tissue specific FACS revealed an immunological alteration in the mutant (-/-) mice marked by decreased percentage of B220hiCD43-, IgM+, and IgD+. Female (-/-) mice exhibited decreased bone mineral content and bone mineral density measurements. UNQ826 shows high expression in both normal and diseased liver tissue. Disruption of the target gene was confirmed by Southern hybridization analysis.

[2050] (b) Immunology Phenotypic Analysis

[2051] Immune related and inflammatory diseases are the manifestation or consequence of fairly complex, often multiple interconnected biological pathways which in normal physiology are critical to respond to insult or injury, initiate repair from insult or injury, and mount innate and acquired defense against foreign organisms. Disease or pathology occurs when these normal physiological pathways cause additional insult or injury either as directly related to the intensity of the response, as a consequence of abnormal regulation or excessive stimulation, as a reaction to self, or as a combination of these.

[2052] Though the genesis of these diseases often involves multistep pathways and often multiple different biological systems/pathways, intervention at critical points in one or more of these pathways can have an ameliorative or therapeutic effect. Therapeutic intervention can occur by either antagonism of a detrimental process/pathway or stimulation of a beneficial process/pathway.

[2053] T lymphocytes (T cells) are an important component of a mammalian immune response. T cells recognize antigens which are associated with a self-molecule encoded by genes within the major histocompatibility complex (MHC). The antigen may be displayed together with MHC molecules on the surface of antigen presenting cells, virus infected cells, cancer cells, grafts, etc. The T cell system eliminates these altered cells which pose a health threat to the host mammal. T cells include helper T cells and cytotoxic T cells. Helper T cells proliferate extensively following recognition of an antigen-MHC complex on an antigen presenting cell. Helper T cells also secrete a variety of cytokines, i.e., lymphokines, which play a central role in the activation of B cells, cytotoxic T cells and a variety of other cells which participate in the immune response.

[2054] In many immune responses, inflammatory cells infiltrate the site of injury or infection. The migrating cells may be neutrophilic, eosinophilic, monocytic or lymphocytic as can be determined by histologic examination of the affected tissues. Current Protocols in Immunology, ed. John E. Coligan, 1994, John Wiley & Sons, Inc.

[2055] Many immune related diseases are known and have been extensively studied. Such diseases include immune-mediated inflammatory diseases (such as rheumatoid arthritis, immune mediated renal disease, hepatobiliary diseases, inflammatory bowel disease (IBD), psoriasis, and asthma), non-immune-mediated inflammatory diseases, infectious diseases, immunodeficiency diseases, neoplasia, and graft rejection, etc. In the area of immunology, targets were identified for the treatment of inflammation and inflammatory disorders.

[2056] In the area of immunology, targets have been identified herein for the treatment of inflammation and inflammatory disorders. Immune related diseases, in one instance, could be treated by suppressing the immune response. Using neutralizing antibodies that inhibit molecules having immune stimulatory activity would be beneficial in the treatment of immune-mediated and inflammatory diseases. Molecules which inhibit the immune response can be utilized (proteins directly or via the use of antibody agonists) to inhibit the immune response and thus ameliorate immune related disease.

[2057] The following test was performed:

[2058] Flourescence-Activated Cell-Sorting (FACS) Analysis/Tissue Specific FACS

[2059] Procedure:

[2060] FACS analysis of immune cell composition from peripheral blood was performed including CD4, CD8 and T cell receptor to evaluate T lymphocytes, CD19 for B lymphocytes, CD45 as a leukocyte marker and pan NK for natural killer cells. The FACS analysis was carried out on 2 wild type and 6 homozygous mice and included cells derived from thymus, spleen, bone marrow and lymph node.

[2061] In these studies, analyzed cells were isolated from thymus, peripheral blood, spleen, bone marrow and lymph nodes. Flow cytometry was designed to determine the relative proportions of CD4 and CD8 positive T cells, B, cells, NK cells and monocytes in the mononuclear cell population. A Becton-Dickinson FACSCalibur 3-laser FACS machine was used to assess immune status. For Phenotypic Assays and Screening, this machine records CD4+/CD8-, CD8+/CD4-, NK, B cell and monocyte numbers in addition to the CD4+/CD8+ ratio.

[2062] The mononuclear cell profile was derived by staining a single sample of lysed peripheral blood from each mouse with a panel of six lineage-specific antibodies: CD45 PerCP, anti-TCRb APC, CD4 PE, CD8 FITC, pan-NK PE, and CD19 FITC. The two FITC and PE labeled antibodies stain mutually exclusive cell types. The samples were analyzed using a Becton Dickinson FACSCalibur flow cytometer with CellQuest software.

[2063] Results:

Tissue Specific FACS-Project: The (-/-) mice exhibited a decreased percentage of B220hiCD43-, IgM+, and IgD+ cells in bone marrow when compared with that of their (+/+) littermates. These results are indicative of a decrease in the bone marrow of a subset of pre-B, immature and mature B cells. Thus, PRO1753 polypeptides are important in the development of B cell population in the bone marrow and would be useful in stimulating B cell production.

[2064] (c) Phenotypic Analysis: CNS/Neurology

[2065] In the area of neurology, analysis focused herein on identifying in vivo validated targets for the treatment of neurological and psychiatric disorders including depression, generalized anxiety disorders, attention deficit hyperactivity disorder, obsessive compulsive disorder, schizophrenia, cognitive disorders, hyperalgesia and sensory disorders. Neurological disorders include the category defined as "anxiety disorders" which include but are not limited to: mild to moderate anxiety, anxiety disorder due to a general medical condition, anxiety disorder not otherwise specified, generalized anxiety disorder, panic attack, panic disorder with agoraphobia, panic disorder without agoraphobia, posttraumatic stress disorder, social phobia, specific phobia, substance-induced anxiety disorder, acute alcohol withdrawal, obsessive compulsive disorder, agoraphobia, bipolar disorder I or II, bipolar disorder not otherwise specified, cyclothymic disorder, depressive disorder, major depressive disorder, mood disorder, substance-induced mood disorder. In addition, anxiety disorders may apply to personality disorders including but not limited to the following types: paranoid, antisocial, avoidant behavior, borderline personality disorders, dependent, histronic, narcissistic, obsessive-compulsive, schizoid, and schizotypal.

[2066] Procedure:

[2067] Behavioral screens were performed on a cohort of 4 wild type, 4 heterozygous and 8 homozygous mutant mice. All behavioral tests were done between 12 and 16 weeks of age unless reduced viability necessitates earlier testing. These tests included open field to measure anxiety, activity levels and exploration.

[2068] Open Field Test:

[2069] Several targets of known drugs have exhibited phenotypes in the open field test. These include knockouts of the seratonin transporter, the dopamine transporter (Giros et al., Nature. 1996 Feb. 15; 379(6566):606-12), and the GABA receptor (Homanics et al., Proc Natl Acad Sci USA. 1997 Apr. 15; 94(8):4143-8). An automated open-field assay was customized to address changes related to affective state and exploratory patterns related to learning. First, the field (40.times.40 cm) was selected to be relatively large for a mouse, thus designed to pick up changes in locomotor activity associated with exploration. In addition, there were 4 holes in the floor to allow for nose-poking, an activity specifically related to exploration. Several factors were also designed to heighten the affective state associated with this test. The open-field test is the first experimental procedure in which the mice are tested, and the measurements that were taken were the subjects' first experience with the chamber. In addition, the open-field was brightly lit. All these factors will heighten the natural anxiety associated with novel and open spaces. The pattern and extent of exploratory activity, and especially the center-to-total distance traveled ratio, may then be able to discern changes related to susceptibility to anxiety or depression. A large arena (40 cm.times.40 cm, VersaMax animal activity monitoring system from AccuScan Instruments) with infrared beams at three different levels was used to record rearing, hole poke, and locomotor activity. The animal was placed in the center and its activity was measured for 20 minutes. Data from this test was analyzed in five, 4-minute intervals. The total distance traveled (cm), vertical movement number (rearing), number of hole pokes, and the center to total distance ratio were recorded.

[2070] The propensity for mice to exhibit normal habituation responses to a novel environment is assessed by determining the overall change in their horizontal locomotor activity across the 5 time intervals. This calculated slope of the change in activity over time is determined using normalized, rather than absolute, total distance traveled. The slope is determined from the regression line through the normalized activity at each of the 5 time intervals. Normal habituation is represented by a negative slope value.

[2071] Results:

Openfield2: The male (-/-) mice exhibited decreased median sum time-in-center when compared with their gender-matched (+/+) littermates and the historical mean, suggesting an increased anxiety-like response in the mutants. In addition, whiskers were absent in 2 of 8 (+/+) wild-type mice and 6 of 8 (-/-) knockout mice. Knockout mice with absent whiskers at increased frequency is probably related to the anxiety phenotype.

[2072] In summary, the open field testing revealed a phenotype associated with increased anxiety which could be associated with mild to moderate anxiety, anxiety due to a general medical condition, and/or bipolar disorders; hyperactivity; sensory disorders; obsessive-compulsive disorders, schizophrenia or a paranoid personality. Thus, PRO1753 polypeptides or agonists thereof would be useful in the treatment of such neurological disorders.

[2073] (d) Bone Metabolism: Radiology Phenotypic Analysis

[2074] In the area of bone metabolism, targets were identified herein for the treatment of arthritis, osteoporosis, osteopenia and osteopetrosis as well as identifying targets that promote bone healing. Tests included: [2075] DEXA for measurement of bone mineral density on femur and vertebra [2076] MicroCT for very high resolution and very high sensitivity measurements of bone mineral density for both trabecular and cortical bone.

[2077] Dexa Analysis--Test Description:

[2078] Procedure: A cohort of 4 wild type, 4 heterozygotes and 8 homozygotes were tested in this assay. Dual Energy X-ray Absorptiometry (DEXA) has been used successfully to identify changes in bone. Anesthetized animals were examined and bone mineral content (BMC), BMC/LBM ratios, volumetric bone mineral density (vBMD), total body BMD, femur BMD and vertebra BMD were measured.

[2079] The mouse was anesthetized by intraperitoneal injection of Avertin (1.25% 2,2,2,-tribromoethanol, 20 ml/kg body weight), body length and weight were measured, and then the mouse was placed in a prone position on the platform of the PIXImus.TM. Densitometer (Lunar Inc.) for a DEXA scan. Using Lunar PIXImus software, the bone mineral density (BMD) and fat composition (% fat) and total tissue mass (TTM) were determined in the regions of interest (ROI) [i.e., whole body, vertebrae, and both femurs].

[2080] Results:

DEXA:

[2081] The female (-/-) mice exhibited decreased mean bone mineral content and bone mineral density in total body and vertebrae when compared with their gender-matched (+/+) littermates and the historical means.

[2082] Thus, mutant (-/-) mice deficient in the gene encoding PRO1753 polypeptides show a phenotype consistent with osteoporosis marked by decreased bone mineral content and density measurements. Thus, antagonists or inhibitors of PRO1753 polypeptides or its encoding gene would mimic these abnormal metabolic related effects. On the other hand, PRO1753 polypeptides or agonists thereof would be useful in the prevention and/or treatment of bone disorders associated with bone loss.

[2083] 66.38. Generation and Analysis of Mice Comprising DNA76396-1698 (UNQ828) Gene Disruptions

[2084] In these knockout experiments, the gene encoding PRO1755 polypeptides (designated as DNA76396-1698) (UNQ828) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: NM.sub.--175696 Mus musculus RIKEN cDNA C530028O21 gene (C530028O21Rik); protein reference: Q6P1B3 ACCESSION:Q6P1B3 NID: Mus musculus (Mouse). C530028O21Rik protein; the human gene sequence reference: NM.sub.--153685 Homo sapiens hypothetical protein DKFZp547D2210 (DKFZp547D2210); the human protein sequence corresponds to reference: Q8IYJ0 ACCESSION:Q8IYJ0 NID: Homo sapiens (Human). Hypothetical protein DKFZp547D2210.

[2085] The mouse gene of interest is RIKEN cDNA C530028O21 gene, ortholog of human hypothetical protein DKFZp547D2210. Aliases include EST AI255183 and DKFZp547D2210.

[2086] Hypothetical protein DKFZp547D2210 is a likely type I integral membrane protein, consisting of a signal peptide and a transmembrane domain. The function of this protein is not known, and its predicted cell location is ambiguous.

[2087] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00109 wt het hom Total Observed 16 33 16 65 Expected 16.25 32.5 16.25 65

Chi-Sq.=0.09 Significance=0.95599747 (hom/n)=0.26 Avg. Litter Size=8

Mutation Information

[2088] Mutation Type Homologous Recombination (standard) Description: Coding exons 1 through 4 were targeted (NCBI accession NM.sub.--175696.2). 1. Wild-type Expression Panel: Expression of the target gene was detected in embryonic stem (ES) cells and in all 13 adult tissue samples tested by RT-PCR. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[2089] 66.38.1. Phenotypic Analysis (for Disrupted Gene: DNA76396-1698 (UNQ828)

[2090] (a) Overall Phenotypic Summary:

[2091] Mutation of the gene encoding the ortholog of a human hypothetical membrane protein resulted in an the female homozygous mutant mice exhibiting an increased mean skin fibroblast proliferation rate when compared with that of their gender-matched wild-type littermates and the historical mean. In addition, the male (-/-) mice showed an impaired glucose tolerance. The (-/-) mice also exhibited decreased mean serum IgG1 levels. UNQ828 is highly expressed in the CNS compared to other normal tissues. The endothelium also shows moderately high expression. Disruption of the target gene was confirmed by Southern hybridization analysis.

[2092] (b) Phenotypic Analysis: Metabolism--Blood Chemistry/Glucose Tolerance

[2093] In the area of metabolism, targets may be identified for the treatment of diabetes. Blood chemistry phenotypic analysis includes blood glucose measurements. The COBAS Integra 400 (mfr: Roche) was used for running blood chemistry tests on the mice. In the area of metabolism, targets may be identified for the treatment of diabetes. Blood chemistry phenotypic analysis includes glucose tolerance tests to measure insulin sensitivity and changes in glucose metabolism. Abnormal glucose tolerance test results may indicate but may not be limited to the following disorders or conditions: Diabetes Type 1 and Type 2, Syndrome X, various cardiovascular diseases and/or obesity.

[2094] Procedure: A cohort of 2 wild type and 4 homozygous mice were used in this assay. The glucose tolerance test is the standard for defining impaired glucose homeostasis in mammals. Glucose tolerance tests were performed using a Lifescan glucometer. Animals were injected IP at 2 g/kg with D-glucose delivered as a 20% solution and blood glucose levels were measured at 0, 30, 60 and 90 minutes after injection.

[2095] Results:

[2096] Blood Glucose Levels/Glucose Tolerance Test:

Oral Glucose Tolerance: The male (-/-) mice exhibited a modestly impaired glucose tolerance when compared with that of their gender-matched (+/+) littermates and the historical mean.

[2097] These studies indicated that (-/-) mice exhibit a decreased or impaired glucose tolerance in the presence of normal fasting glucose at all 3 intervals tested when compared with their gender-matched (+/+) littermates and the historical means. Thus, knockout mutant mice exhibited the phenotypic pattern of an impaired glucose homeostasis, and therefor PRO1755 polypeptides (or agonists thereof) or its encoding gene would be useful in the treatment of conditions associated with an impaired glucose homeostasis and/or various cardiovascular diseases, including diabetes.

[2098] (c) Immunology Phenotypic Analysis

[2099] Immune related and inflammatory diseases are the manifestation or consequence of fairly complex, often multiple interconnected biological pathways which in normal physiology are critical to respond to insult or injury, initiate repair from insult or injury, and mount innate and acquired defense against foreign organisms. Disease or pathology occurs when these normal physiological pathways cause additional insult or injury either as directly related to the intensity of the response, as a consequence of abnormal regulation or excessive stimulation, as a reaction to self, or as a combination of these.

[2100] Though the genesis of these diseases often involves multistep pathways and often multiple different biological systems/pathways, intervention at critical points in one or more of these pathways can have an ameliorative or therapeutic effect. Therapeutic intervention can occur by either antagonism of a detrimental process/pathway or stimulation of a beneficial process/pathway.

[2101] T lymphocytes (T cells) are an important component of a mammalian immune response. T cells recognize antigens which are associated with a self-molecule encoded by genes within the major histocompatibility complex (MHC). The antigen may be displayed together with MHC molecules on the surface of antigen presenting cells, virus infected cells, cancer cells, grafts, etc. The T cell system eliminates these altered cells which pose a health threat to the host mammal. T cells include helper T cells and cytotoxic T cells. Helper T cells proliferate extensively following recognition of an antigen-MHC complex on an antigen presenting cell. Helper T cells also secrete a variety of cytokines, i.e., lymphokines, which play a central role in the activation of B cells, cytotoxic T cells and a variety of other cells which participate in the immune response.

[2102] In many immune responses, inflammatory cells infiltrate the site of injury or infection. The migrating cells may be neutrophilic, eosinophilic, monocytic or lymphocytic as can be determined by histologic examination of the affected tissues. Current Protocols in Immunology, ed. John E. Coligan, 1994, John Wiley & Sons, Inc.

[2103] Many immune related diseases are known and have been extensively studied. Such diseases include immune-mediated inflammatory diseases (such as rheumatoid arthritis, immune mediated renal disease, hepatobiliary diseases, inflammatory bowel disease (IBD), psoriasis, and asthma), non-immune-mediated inflammatory diseases, infectious diseases, immunodeficiency diseases, neoplasia, and graft rejection, etc. In the area of immunology, targets were identified for the treatment of inflammation and inflammatory disorders.

[2104] In the area of immunology, targets have been identified herein for the treatment of inflammation and inflammatory disorders. Immune related diseases, in one instance, could be treated by suppressing the immune response. Using neutralizing antibodies that inhibit molecules having immune stimulatory activity would be beneficial in the treatment of immune-mediated and inflammatory diseases. Molecules which inhibit the immune response can be utilized (proteins directly or via the use of antibody agonists) to inhibit the immune response and thus ameliorate immune related disease.

[2105] The following test was performed:

[2106] Serum Immunoglobulin Isotyping Assay:

[2107] The Serum Immunoglobulin Isotyping Assay is performed using a Cytometric Bead Array (CBA) kit. This assay is used to rapidly identify the heavy and light chain isotypes of a mouse monoclonal antibody in a single sample. The values expressed are "relative fluorescence units" and are based on the detection of kappa light chains. Any value <6 is not significant.

[2108] Results:

Serum Imm. 2: The (-/-) mice exhibited a decreased mean serum IgG1 level when compared with that of their (+/+) littermates, the (+/+) mice for the project run, and the historical median.

[2109] Thus, mutant (-/-) mice showed decreased IgG1 serum immunoglobulins compared to their gender-matched (+/+) littermates. These immunoglobulins have neutralization effects and to a lesser extent are important for activation of the complement system. The observed phenotype suggests that the PRO1755 polypeptide is a regulator of inflammatory responses. Thus, the gene encoding PRO1755 polypeptides is essential for making IgG1 immunoglobulins (or gamma globulins). These immunological abnormalities suggest that PRO1755 polypeptides may be important agents which could stimulate the immune system and would find utility in the cases wherein this effect would be beneficial to the individual such as in the case of leukemia, and other types of cancer, and in immunocompromised patients, such as AIDS sufferers. Accordingly, antagonists (inhibitors) of PRO1755 polypeptides can play a role in inhibiting the immune response and would be useful candidates for suppressing harmful immune responses, e.g. in the case of graft rejection or graft-versus-host diseases.

[2110] (d) Adult Skin Cell Proliferation:

[2111] Procedure: Skin cells were isolated from 16 week old animals (2 wild type and 4 homozygotes). These were developed into primary fibroblast cultures and the fibroblast proliferation rates were measured in a strictly controlled protocol. The ability of this assay to detect hyper-proliferative and hypo-proliferative phenotypes has been demonstrated with p53 and Ku80. Proliferation was measured using Brdu incorporation.

[2112] Specifically, in these studies the skin fibroblast proliferation assay was used. An increase in the number of cells in a standardized culture was used as a measure of relative proliferative capacity. Primary fibroblasts were established from skin biopsies taken from wild type and mutant mice. Duplicate or triplicate cultures of 0.05 million cells were plated and allowed to grow for six days. At the end of the culture period, the number of cells present in the culture was determined using a electronic particle counter.

[2113] Results:

Skin Proliferation: The female (-/-) mice exhibited an increased mean skin fibroblast proliferation rate when compared with that of their gender-matched (+/+) littermates and the historical mean. Two out of the four (-/-) mice showed significantly increased proliferation.

[2114] Thus, homozygous mutant mice demonstrated a hyper-proliferative phenotype. As suggested by these observations, PRO1755 polypeptides or agonists thereof could function as tumor suppressors and would be useful in decreasing abnormal cell proliferation.

[2115] 66.39. Generation and Analysis of Mice Comprising DNA71235-1706 (UNQ839) Gene Disruptions

[2116] In these knockout experiments, the gene encoding PRO1777 polypeptides (designated as DNA71235-1706) (UNQ839) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: NM.sub.--028710 Mus musculus RIKEN cDNA 6330406P08 gene (6330406P08Rik); protein reference: Q9D3B4 ACCESSION:Q9D3B4 NID: Mus musculus (Mouse).

6330406P08RIK PROTEIN; the human gene sequence reference: NM.sub.--014960 Homo sapiens Arylsulfatase G (KIAA1001); the human protein sequence corresponds to reference: Q96EG1 ACCESSION:Q96EG1 NID: Homo sapiens (Human). Arylsulfatase G.

[2117] The mouse gene of interest is RIKEN cDNA 6330406P08 gene, ortholog of human ARSG (Arylsulfatase G). Aliases include KIAA1001.

[2118] ARSG is an enzyme that likely catalyzes the hydrolysis of arylsulfoester bonds. The location of this enzyme is not clearly known. Bioinformatic analyses of ARSG suggest that the enzyme may be located in lysosomes or may be secreted. ARSG expressed in COST cells is located in the endoplasmic reticulum (Ferrante et al, Eur J Hum Genet. 10(12):813-8 (2002)).

[2119] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00110 wt het hom Total Observed 12 33 12 57 Expected 14.25 28.5 14.25 57

Chi-Sq.=0.01 Significance=0.99501246 (hom/n)=0.25 Avg. Litter Size=8

Mutation Information

[2120] Mutation Type: Homologous Recombination (standard) Description: Coding exon 1 was targeted (NCBI accession NM.sub.--028710.2). 1. Wild-type Expression Panel: Expression of the target gene was detected in embryonic stem (ES) cells and in all 13 adult tissue samples tested by RT-PCR, except skeletal muscle, bone, and adipose. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[2121] 66.39.1. Phenotypic Analysis (for Disrupted Gene: DNA71235-1706 (UNQ839)

[2122] (a) Overall Phenotypic Summary:

[2123] Mutation of the gene encoding the ortholog of human Arylsulfatase G (ARSG) resulted in immunological abnormalities in (-/-) mice. The homozygous mutant mice exhibited a decreased mean percentage of natural killer cells in the peripheral blood and an increased mean serum IgG3 level when compared with the levels for their wild-type littermates and the historical means. The female mutants also exhibited a decreased mean skin fibroblast proliferation rate. The male (-/-) mice also exhibited an increased mean percent total body fat mass and decreased mean bone mineral density-related measurements. Micro-CT results showed a decreased mean femoral mid-shaft cross-sectional area. The female (-/-) mice exhibited an increased median ambulatory counts during home cage testing indicating an enhanced circadian rhythm. Disruption of the target gene was confirmed by Southern hybridization analysis.

[2124] (b) Microarray Analysis

[2125] Microarray analysis shows UNQ839 being highly overexpressed in breast tumors compared to normal breast tissue.

[2126] (c) Immunology Phenotypic Analysis

[2127] Immune related and inflammatory diseases are the manifestation or consequence of fairly complex, often multiple interconnected biological pathways which in normal physiology are critical to respond to insult or injury, initiate repair from insult or injury, and mount innate and acquired defense against foreign organisms. Disease or pathology occurs when these normal physiological pathways cause additional insult or injury either as directly related to the intensity of the response, as a consequence of abnormal regulation or excessive stimulation, as a reaction to self, or as a combination of these.

[2128] Though the genesis of these diseases often involves multistep pathways and often multiple different biological systems/pathways, intervention at critical points in one or more of these pathways can have an ameliorative or therapeutic effect. Therapeutic intervention can occur by either antagonism of a detrimental process/pathway or stimulation of a beneficial process/pathway.

[2129] T lymphocytes (T cells) are an important component of a mammalian immune response. T cells recognize antigens which are associated with a self-molecule encoded by genes within the major histocompatibility complex (MHC). The antigen may be displayed together with MHC molecules on the surface of antigen presenting cells, virus infected cells, cancer cells, grafts, etc. The T cell system eliminates these altered cells which pose a health threat to the host mammal. T cells include helper T cells and cytotoxic T cells. Helper T cells proliferate extensively following recognition of an antigen-MHC complex on an antigen presenting cell. Helper T cells also secrete a variety of cytokines, i.e., lymphokines, which play a central role in the activation of B cells, cytotoxic T cells and a variety of other cells which participate in the immune response.

[2130] In many immune responses, inflammatory cells infiltrate the site of injury or infection. The migrating cells may be neutrophilic, eosinophilic, monocytic or lymphocytic as can be determined by histologic examination of the affected tissues. Current Protocols in Immunology, ed. John E. Coligan, 1994, John Wiley & Sons, Inc.

[2131] Many immune related diseases are known and have been extensively studied. Such diseases include immune-mediated inflammatory diseases (such as rheumatoid arthritis, immune mediated renal disease, hepatobiliary diseases, inflammatory bowel disease (IBD), psoriasis, and asthma), non-immune-mediated inflammatory diseases, infectious diseases, immunodeficiency diseases, neoplasia, and graft rejection, etc. In the area of immunology, targets were identified for the treatment of inflammation and inflammatory disorders.

[2132] In the area of immunology, targets have been identified herein for the treatment of inflammation and inflammatory disorders. Immune related diseases, in one instance, could be treated by suppressing the immune response. Using neutralizing antibodies that inhibit molecules having immune stimulatory activity would be beneficial in the treatment of immune-mediated and inflammatory diseases. Molecules which inhibit the immune response can be utilized (proteins directly or via the use of antibody agonists) to inhibit the immune response and thus ameliorate immune related disease.

[2133] The following tests were performed:

[2134] (1) Flourescence-Activated Cell-Sorting (FACS) Analysis

[2135] Procedure:

[2136] FACS analysis of immune cell composition from peripheral blood was performed including CD4, CD8 and T cell receptor to evaluate T lymphocytes, CD19 for B lymphocytes, CD45 as a leukocyte marker and pan NK for natural killer cells. The FACS analysis was carried out on 2 wild type and 6 homozygous mice and included cells derived from thymus, spleen, bone marrow and lymph node.

[2137] In these studies, analyzed cells were isolated from thymus, peripheral blood, spleen, bone marrow and lymph nodes. Flow cytometry was designed to determine the relative proportions of CD4 and CD8 positive T cells, B cells, NK cells and monocytes in the mononuclear cell population. A Becton-Dickinson FACSCalibur 3-laser FACS machine was used to assess immune status. For Phenotypic Assays and Screening, this machine records CD4+/CD8-, CD8+/CD4-, NK, B cell and monocyte numbers in addition to the CD4+/CD8+ ratio.

[2138] The mononuclear cell profile was derived by staining a single sample of lysed peripheral blood from each mouse with a panel of six lineage-specific antibodies: CD45 PerCP, anti-TCRb APC, CD4 PE, CD8 FITC, pan-NK PE, and CD19 FITC. The two FITC and PE labeled antibodies stain mutually exclusive cell types. The samples were analyzed using a Becton Dickinson FACSCalibur flow cytometer with CellQuest software.

Results:

[2139] FACS: The (-/-) mice exhibited an altered distribution of different leukocyte subsets, characterized by a decreased mean percentage of natural killer cells in the peripheral blood when compared with their wild-type littermates and the historical mean.

[2140] In summary, the FACS results indicate that the homozygous mutant mice have an impaired immune system, especially in view of the decreased mean percentage of natural killer cells which is an indicator of a negative phenotype associated with knocking out the DNA71235-1706 gene which encodes PRO1777 polypeptides. Natural killer cells are the first line of defense to viral infection since these cells have been implicated in viral immunity and in defense against tumors. Natural killer cells or NK cells act as effectors in antibody-dependent cell-mediated cytotoxicity and have been identified by their ability to kill certain lymphoid tumor cell lines in vitro without the need for prior immunization or activation. However, their known function in host defense is in the early phases of infection with several intracellular pathogens, particularly herpes viruses. Thus, PRO1777 polypeptides and agonists thereof would be important for a healthy immune system and would be useful in stimulating the immune system particularly during viral infections.

[2141] (2) Serum Immunoglobulin Isotyping Assay:

[2142] The Serum Immunoglobulin Isotyping Assay is performed using a Cytometric Bead Array (CBA) kit. This assay is used to rapidly identify the heavy and light chain isotypes of a mouse monoclonal antibody in a single sample. The values expressed are "relative fluorescence units" and are based on the detection of kappa light chains. Any value <6 is not significant.

[2143] Results:

Serum Imm. 2: The (-/-) mice exhibited an increased mean serum IgG3 level when compared with that of their (+/+) littermates, the (+/+) mice for the project run, and the historical median.

[2144] The serum immunoglobulin isotyping assay revealed that homozygous adults exhibited increased serum IgG3 levels. Thus, homozygotes showed elevated serum immunoglobulins compared with the (+/+) littermates. IgG3 immunoglobulins have neutralization effects and to a lesser extent are important for activation of the complement system. These immunological abnormalities suggest that antagonists or inhibitors of PRO1777 polypeptides would stimulate the immune system and would find utility in the cases wherein this effect would be beneficial to the individual such as in the case of leukemia, and other types of cancer, and in immunocompromised patients, such as AIDS sufferers. Accordingly, PRO1777 polypeptides or agonists thereof would inhibit the immune response and would be useful candidates for suppressing harmful immune responses, e.g. in the case of graft rejection or graft-versus-host diseases.

[2145] (d) Adult Skin Cell Proliferation:

[2146] Procedure: Skin cells were isolated from 16 week old animals (2 wild type and 4 homozygotes). These were developed into primary fibroblast cultures and the fibroblast proliferation rates were measured in a strictly controlled protocol. The ability of this assay to detect hyper-proliferative and hypo-proliferative phenotypes has been demonstrated with p53 and Ku80. Proliferation was measured using Brdu incorporation.

[2147] Specifically, in these studies the skin fibroblast proliferation assay was used. An increase in the number of cells in a standardized culture was used as a measure of relative proliferative capacity. Primary fibroblasts were established from skin biopsies taken from wild type and mutant mice. Duplicate or triplicate cultures of 0.05 million cells were plated and allowed to grow for six days. At the end of the culture period, the number of cells present in the culture was determined using a electronic particle counter.

[2148] Results:

Skin Proliferation: The female (-/-) mice exhibited a decreased mean skin fibroblast proliferation rate when compared with that of their gender-matched (+/+) littermates and the historical mean.

[2149] Thus, homozygous mutant mice demonstrated a hypo-proliferative phenotype. As suggested by these observations, antagonists or inhibitors of PRO1777 polypeptides would mimic this hypo-proliferative phenotype and could function as tumor suppressors and would be useful in decreasing abnormal cell proliferation. These results are consistent with the microarray data showing overexpression of this gene in breast tumors.

[2150] (e) Phenotypic Analysis: CNS/Neurology

[2151] In the area of neurology, analysis focused herein on identifying in vivo validated targets for the treatment of neurological and psychiatric disorders including depression, generalized anxiety disorders, attention deficit hyperactivity disorder, obsessive compulsive disorder, schizophrenia, cognitive disorders, hyperalgesia and sensory disorders. Neurological disorders include the category defined as "anxiety disorders" which include but are not limited to: mild to moderate anxiety, anxiety disorder due to a general medical condition, anxiety disorder not otherwise specified, generalized anxiety disorder, panic attack, panic disorder with agoraphobia, panic disorder without agoraphobia, posttraumatic stress disorder, social phobia, specific phobia, substance-induced anxiety disorder, acute alcohol withdrawal, obsessive compulsive disorder, agoraphobia, bipolar disorder I or II, bipolar disorder not otherwise specified, cyclothymic disorder, depressive disorder, major depressive disorder, mood disorder, substance-induced mood disorder. In addition, anxiety disorders may apply to personality disorders including but not limited to the following types: paranoid, antisocial, avoidant behavior, borderline personality disorders, dependent, histronic, narcissistic, obsessive-compulsive, schizoid, and schizotypal.

[2152] Procedure:

[2153] Behavioral screens were performed on a cohort of 4 wild type, 4 heterozygous and 8 homozygous mutant mice. All behavioral tests were done between 12 and 16 weeks of age unless reduced viability necessitates earlier testing.

[2154] Circadian Test Description:

[2155] Female mice are individually housed at 4 pm on the first day of testing in 48.2 cm.times.26.5 cm home cages and administered food and water ad libitum. Animals are exposed to a 12-hour light/dark cycle with lights turning on at 7 am and turning off at 7 pm. The system software records the number of beam interruptions caused by the animal's movements, with beam breaks automatically divided into ambulations. Activity is recorded in 60, one-hour intervals during the three-day test. Data generated are displayed by median activity levels recorded for each hour (circadian rhythm) and median total activity during each light/dark cycle (locomotor activity) over the three-day testing period.

[2156] Results:

Circadian: The female (-/-) mice exhibited a notably increased median ambulatory counts during both dark periods when compared with the number for their gender-matched (+/+) littermates and the historical means.

[2157] These results demonstrate an enhanced circadian rhythm. Home-cage activity testing is also suggestive of increased activity or hyperactivity which is consistent with generalized anxiety disorders, attention deficit hyperactivity disorder, obsessive compulsive disorder, schizophrenia, cognitive disorders, and sensory disorders.

[2158] (f) Bone Metabolism & Radiology Phenotypic Analysis

[2159] In the area of bone metabolism, targets were identified herein for the treatment of arthritis, osteoporosis, osteopenia and osteopetrosis as well as identifying targets that promote bone healing. Tests included: [2160] DEXA for measurement of bone mineral density on femur and vertebra [2161] MicroCT for very high resolution and very high sensitivity measurements of bone mineral density for both trabecular and cortical bone.

[2162] Dexa Analysis--Test Description:

[2163] Procedure: A cohort of 4 wild type, 4 heterozygotes and 8 homozygotes were tested in this assay. Dual Energy X-ray Absorptiometry (DEXA) has been used successfully to identify changes in bone. Anesthetized animals were examined and bone mineral content (BMC), BMC/LBM ratios, volumetric bone mineral density (vBMD), total body BMD, femur BMD and vertebra BMD were measured.

[2164] The mouse was anesthetized by intraperitoneal injection of Avertin (1.25% 2,2,2,-tribromoethanol, 20 ml/kg body weight), body length and weight were measured, and then the mouse was placed in a prone position on the platform of the PIXImus.TM. Densitometer (Lunar Inc.) for a DEXA scan. Using Lunar PIXImus software, the bone mineral density (BMD) and fat composition (% fat) and total tissue mass (TTM) were determined in the regions of interest (ROI) [i.e., whole body, vertebrae, and both femurs].

[2165] Bone MicroCT Analysis:

[2166] Procedure: MicroCT was also used to get very sensitive measurements of BMD. One vertebra and 1 femur were taken from a cohort of 4 wild type and 8 homozygous mice. Measurements were taken of lumbar 5 vertebra trabecular bone volume, trabecular thickness, connectivity density and midshaft femur total bone area and cortical thickness. The .mu.CT40 scans provided detailed information on bone mass and architecture. Multiple bones were placed into sample holders and scanned automatically. Instrument software was used to select regions of interest for analysis. Trabecular bone parameters were analyzed in the fifth lumbar vertebrae (LV5) at 16 micrometer resolution and cortical bone parameters were analyzed in the femur midshaft at a resolution of 20 micrometers.

[2167] Results:

DEXA: The male (-/-) mice exhibited decreased mean bone mineral density-related measurements with decreased bone mineral content and mean bone mineral density when compared with those of their gender-matched (+/+) littermates and the historical means. Micro CT: The male (-/-) mice also exhibited decreased mean femoral mid-shaft cross-sectional area when compared with that of their gender-matched (+/+) littermates and the historical mean.

[2168] These results demonstrate that knockout mutant mice exhibit abnormal bone metabolism with decreased bone measurements similar to osteoporosis characterized by decrease in bone mass with decreased density and possibly fragility leading to bone fractures. Thus, it appears that PRO1777 polypeptides or agonists thereof would be useful in maintaining bone homeostasis. In addition, PRO1777 polypeptides or its encoding gene would be useful in bone healing or for the treatment of arthritis or osteoporosis; whereas antagonists to PRO1777 polypeptides or its encoding gene would lead to abnormal or pathological bone disorders including arthritis, osteoporosis, and osteopenia.

[2169] The male (-/-) mice also exhibited increased mean percent total body fat and total fat mass when compared with their gender-matched (+/+) littermates and the historical means.

[2170] These studies suggest that mutant (-/-) non-human transgenic animals exhibit a negative phenotype that would be associated with obesity. Pathological observations are consistent with the radiological findings. Thus, PRO1777 polypeptides or agonists thereof are essential for normal growth and metabolic processes and especially would be important in the prevention and/or treatment of lipid storage diseases and/or obesity.

[2171] 66.40. Generation and Analysis of Mice Comprising DNA77652-2505 (UNQ850) Gene Disruptions

[2172] In these knockout experiments, the gene encoding PRO1788 polypeptides (designated as DNA77652-2505) (UNQ850) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: XM.sub.--485965 PREDICTED: Mus musculus RIKEN cDNA 9530051K01 gene (9530051K01Rik); protein reference: XP.sub.--485965 similar to hypothetical protein, estradiol-induced [Mus musculus]; the human gene sequence reference: NM.sub.--015516 Homo sapiens hypothetical protein, estradiol-induced (E2IG4); the human protein sequence corresponds to reference: Q9UJX9 ACCESSION:Q9UJX9 NID: Homo sapiens (Human). E2IG4.

[2173] The mouse gene of interest is RIKEN cDNA 9530051K01 gene, ortholog of human TSK (likely ortholog of chicken tsukushi). Aliases include E2IG4.

[2174] TSK is a secreted protein, consisting of a signal peptide, a leucine-rich repeat N-terminal domain, and several leucine-rich repeats. TSK binds with bone morphogenic protein or chordin to form a ternary complex and inhibits BMP-induced Hensen's node formation during gastrulation. TSK likely plays a role in dorsalization during embryonic development (Ohta et al, Dev Cell 7(3):347-58 (2004)). TSK is also expressed in estrogen-responsive breast cancer cells and is proposed to play a role in breast tissue remodeling or epithelium-stroma interactions (Charpaentier et al, Cancer Res 60(21):5977-83 (2000)).

[2175] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00111 wt het hom Total Observed 21 42 26 89 Expected 22.25 44.5 22.25 89

Chi-Sq.=0.78 Significance=0.6770569 (hom/n)=0.27 Avg. Litter Size=10

Mutation Information

[2176] Mutation Type Homologous Recombination (standard) Coding exon 2 was targeted (NCBI accession AK035461.1). 1. Wild-type Expression Panel: Expression of the target gene was detected in embryonic stem (ES) cells and in spleen; liver; skeletal muscle; stomach, small intestine, and colon; heart; and adipose among the 13 adult tissue samples tested by RT-PCR. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[2177] 66.40.1. Phenotypic Analysis (for Disrupted Gene: DNA77652-2505 (UNQ850)

[2178] (a) Overall Phenotypic Summary:

[2179] Mutation of the gene encoding the ortholog of human likely ortholog of chicken tsukushi (TSK) resulted in the mutant (-/-) mice exhibiting increased mean serum IgM levels. Gene disruption was confirmed by Southern blot.

[2180] (b) Immunology Phenotypic Analysis

[2181] Immune related and inflammatory diseases are the manifestation or consequence of fairly complex, often multiple interconnected biological pathways which in normal physiology are critical to respond to insult or injury, initiate repair from insult or injury, and mount innate and acquired defense against foreign organisms. Disease or pathology occurs when these normal physiological pathways cause additional insult or injury either as directly related to the intensity of the response, as a consequence of abnormal regulation or excessive stimulation, as a reaction to self, or as a combination of these.

[2182] Though the genesis of these diseases often involves multistep pathways and often multiple different biological systems/pathways, intervention at critical points in one or more of these pathways can have an ameliorative or therapeutic effect. Therapeutic intervention can occur by either antagonism of a detrimental process/pathway or stimulation of a beneficial process/pathway.

[2183] T lymphocytes (T cells) are an important component of a mammalian immune response. T cells recognize antigens which are associated with a self-molecule encoded by genes within the major histocompatibility complex (MHC). The antigen may be displayed together with MHC molecules on the surface of antigen presenting cells, virus infected cells, cancer cells, grafts, etc. The T cell system eliminates these altered cells which pose a health threat to the host mammal. T cells include helper T cells and cytotoxic T cells. Helper T cells proliferate extensively following recognition of an antigen-MHC complex on an antigen presenting cell. Helper T cells also secrete a variety of cytokines, i.e., lymphokines, which play a central role in the activation of B cells, cytotoxic T cells and a variety of other cells which participate in the immune response.

[2184] In many immune responses, inflammatory cells infiltrate the site of injury or infection. The migrating cells may be neutrophilic, eosinophilic, monocytic or lymphocytic as can be determined by histologic examination of the affected tissues. Current Protocols in Immunology, ed. John E. Coligan, 1994, John Wiley & Sons, Inc.

[2185] Many immune related diseases are known and have been extensively studied. Such diseases include immune-mediated inflammatory diseases (such as rheumatoid arthritis, immune mediated renal disease, hepatobiliary diseases, inflammatory bowel disease (IBD), psoriasis, and asthma), non-immune-mediated inflammatory diseases, infectious diseases, immunodeficiency diseases, neoplasia, and graft rejection, etc. In the area of immunology, targets were identified for the treatment of inflammation and inflammatory disorders.

[2186] In the area of immunology, targets have been identified herein for the treatment of inflammation and inflammatory disorders. Immune related diseases, in one instance, could be treated by suppressing the immune response. Using neutralizing antibodies that inhibit molecules having immune stimulatory activity would be beneficial in the treatment of immune-mediated and inflammatory diseases. Molecules which inhibit the immune response can be utilized (proteins directly or via the use of antibody agonists) to inhibit the immune response and thus ameliorate immune related disease.

[2187] The following test was performed:

[2188] Serum Immunoglobulin Isotyping Assay:

[2189] The Serum Immunoglobulin Isotyping Assay is performed using a Cytometric Bead Array (CBA) kit. This assay is used to rapidly identify the heavy and light chain isotypes of a mouse monoclonal antibody in a single sample. The values expressed are "relative fluorescence units" and are based on the detection of kappa light chains. Any value <6 is not significant.

[2190] Results:

Serum Imm. 2: The (-/-) mice exhibited an increased mean serum IgM level when compared with that of their (+/+) littermates, the (+/+) mice for the project run, and the historical median.

[2191] Mutant (-/-) mice exhibited elevation of IgM serum immunoglobulins compared to their gender-matched (+/+) littermates. IgM immunoglobulins are the first to be produced in a humoral immune response for neutralization of bacterial toxins and are particularly important in activating the complement system. The observed phenotype suggests that the PRO1788 polypeptide is a negative regulator of inflammatory responses. These immunological abnormalities suggest that inhibitors (antagonists) of PRO1788 polypeptides would be important agents which could stimulate the immune system (such as T cell proliferation) and would find utility in the cases wherein this effect would be beneficial to the individual such as in the case of leukemia, and other types of cancer, and in immunocompromised patients, such as AIDS sufferers. Accordingly, PRO1788 polypeptides or agonists thereof would be useful in inhibiting the immune response and would be useful candidates for suppressing harmful immune responses, e.g. in the case of graft rejection or graft-versus-host diseases.

[2192] 66.41. Generation and Analysis of Mice Comprising DNA45409-2511 (UNQ855) Gene Disruptions

[2193] In these knockout experiments, the gene encoding PRO1864 polypeptides (designated as DNA45409-2511) (UNQ855) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: NM.sub.--024270 Mus musculus STARD3 N-terminal like (Stard3nl); protein reference: Q9DCI3 ACCESSION:Q9DCI3 NID: Mus musculus (Mouse). MLN64 N-terminal domain homolog (STARD3 N-terminal like protein); the human gene sequence reference: NM.sub.--032016 Homo sapiens STARD3 N-terminal like (STARD3NL); the human protein sequence corresponds to reference: O95772 ACCESSION:Q95772 NID: Homo sapiens (Human). H_NH1021A08.1, PROTEIN (UNKNOWN) (PROTEIN FOR MGC:14607) (SIMILAR TO STEROIDOGENIC ACUTE REGULATORY PROTEIN RELATED). The mouse gene of interest is Stard3nl (STARD3 N-terminal like), ortholog of human STARD3NL. Aliases include MENTHO, 0610035N01Rik, 6530409L22Rik, MGC3251, and MLN64 N-terminal domain homolog. STARD3NL is a ubiquitously expressed integral membrane protein located primarily on late endosomes. Bioinformatic analyses suggest that STARD3NL may also be an extracellular protein. STARD3NL consists of four transmembrane segments within a MENTAL (MLN64 N-terminal) domain, which is involved in targeting and anchoring proteins to late endosomes. STARD3NL is likely to play a role in endosomal transport (Alpy et al, J Biol Chem 277(52):50780-7 (2002); Clark et al, Genome Res 13(10):2265-70 (2003)).

[2194] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00112 wt het hom Total Observed 15 35 24 74 Expected 18.5 37 18.5 74

Chi-Sq.=2.82 Significance=0.24414329 (hom/n)=0.3 Avg. Litter Size=9

Mutation Information

[2195] Mutation Type Homologous Recombination (standard) Description: Coding exon 1 was targeted (NCBI accession NM.sub.--024270.1). 1. Wild-type Expression Panel: Expression of the target gene was detected in embryonic stem (ES) cells and in all 13 adult tissue samples tested by RT-PCR, except bone. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[2196] 66.41.1. Phenotypic Analysis (for Disrupted Gene: DNA45409-2511 (UNQ855)

[2197] (a) Overall Phenotypic Summary:

[2198] Mutation of the gene encoding the ortholog of human STARD3 N-terminal like (STARD3NL) resulted in the mutant (-/-) mice exhibiting hydronephrosis. Whiskers were absent in 4 of 8 (+/+) mice and 5 of 8 (-/-) mice; defecation was absent in 4 of 8 (+/+) mice and 5 of 8 (-/-) mice. Blood chemistry results showed abnormal levels of urobilinogen, nitrites, protein and ketone bodies in (+/+), (+/-) and (-/-) mice. Gene disruption was confirmed by Southern blot.

[2199] (b) CAT-Scan Protocol:

[2200] Mice were injected with a CT contrast agent, Omnipaque 300 (Nycomed Amershan, 300 mg of iodine per ml, 0.25 ml per animal, or 2.50-3.75 g iodine/kg of body weight) intraperitoneally. After resting in the cage for .about.10 minutes, the mouse was then sedated by intraperitoneal injection of Avertin (1.25% 2,2,2,-tribromoethanol, 20 ml/kg body weight). A CAT-scan was performed using a MicroCAT scanner (ImTek, Inc.) with the anesthetized animal lying prone on the test bed. Three dimensional images were reconstructed by the Feldkamp algorithm in a cluster of workstations using an ImTek 3D RECON software.

[2201] Results:

[2202] Of the three (-/-) mice examined, two (-/-) [M-226 and F-180] exhibited hydronephosis. Hydronephosis is a condition wherein there is cystic distension of the kidney caused by an accumulation of urine in the kidney pelvis as a result of obstruction to outflow and is accompanied by atrophy of the kidney structure and cyst formation. Therefore, deletion of the gene encoding PRO1864 polypeptides causes atrophy of the kidneys and cyst formation.

[2203] (c) Phenotypic Analysis: Metabolism--Blood Chemistry

[2204] In the area of metabolism, targets may be identified for the treatment of diabetes or other metabolic disorders. Blood chemistry phenotypic analysis includes blood glucose measurements. The COBAS Integra 400 (mfr: Roche) was used for running blood chemistry tests on the mice. In addition to measuring blood glucose levels the following blood chemistry tests are also routinely performed: Alkaline Phosphatase; Alanine Amino-Transferase; Albumin; Bilirubin; Phosphorous; Creatinine; BUN=Blood Urea Nitrogen; Calcium; Uric Acid; Sodium; Potassium; and Chloride. In the area of metabolism, targets may be identified for the treatment of diabetes.

[2205] Results:

[2206] Blood chemistry analysis showed abnormalities in wild-type mice, heterozygous mice and homozygous mice. Urobilinogen was found in 4 of 8 mutant (-/-) mice; nitrites in 2 of 4 (+/+) wild-type mice, 1 of 4 (+/-) heterozygous mice and 4 of 8 (-/-) mice; protein in 2 of 4 (+/+) wild-type mice, 1 of 4 (+/-) mice and 3 of 8 (-/-) mice; and ketone bodies in 2 of 4 (+/+) wild-type mice, 2 of 4 (+/-) heterozygous mice and 5 of 8 mutant (-/-) mice. Increased incidence of protein, nitrites and ketone bodies in the heterozygous (+/-) and homozygous (-/-) mice is related to the abnormal kidney results discovered in the CAT-scan. These results are consistent with CAT-Scan results showing hydronephrosis.

[2207] 66.42. Generation and Analysis of Mice Comprising DNA82302-2529 (UNQ904) Gene Disruptions

[2208] In these knockout experiments, the gene encoding PRO1925 polypeptides (designated as DNA82302-2529) (UNQ904) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: XM.sub.--155973 PREDICTED: Mus musculus similar to SARG904 (LOC239691); protein reference: XP.sub.--155973 similar to SARG904 [Mus musculus] gi|51769442|ref|XP.sub.--358755.2| similar to SARG904 [Mus musculus]; the human gene sequence reference: NM.sub.--152459 Homo sapiens hypothetical protein MGC45438 (MGC45438); the human protein sequence corresponds to reference: Q8N213 ACCESSION:Q8N213 NID: Homo sapiens (Human). Hypothetical protein F1190761.

[2209] The mouse gene of interest is "similar to SARG904," ortholog of human hypothetical protein MGC45438. Hypothetical protein MGC45438 is a putative secreted protein, consisting of a signal peptide and several weakly predicted, partial conserved domains, such as serpin (serine proteinase inhibitor) domain (SMART accession SM00093), B-cell lymphoma (BCL; anti-apoptotic) domain (SMART accession SM00337), and topoisomerase II domain (SMART accession SM00433). The function of this protein is not known.

[2210] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00113 wt het hom Total Observed 21 30 15 66 Expected 16.5 33 16.5 66

Chi-Sq.=4.38 Significance=0.11191674 (hom/n)=0.19 Avg. Litter Size=9

Mutation Information

[2211] Mutation Type Homologous Recombination (standard) Description: Coding exons 1 and 2 were targeted (NCBI accession BM453823.1). 1. Wild-type Expression Panel: Expression of the target gene was detected in all 13 adult tissue samples tested by RT-PCR, except bone and stomach, small intestine, and colon. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[2212] 66.42.1. Phenotypic Analysis (for Disrupted Gene: DNA82302-2529 (UNQ904)

[2213] (a) Overall Phenotypic Summary:

[2214] Mutation of the gene encoding the ortholog of a human hypothetical protein (MGC45438) resulted in the (-/-) mice exhibiting increased total fat mass and percent total body fat as well as increased total tissue mass. Leukocytes were in 1 of 4 (+/+) wild-type mice and 4 of 8 mutant (-/-) mice. Gene disruption was confirmed by Southern blot.

[2215] (b) Bone Metabolism & Radiology Phenotypic Analysis

[2216] In the area of bone metabolism, targets were identified herein for the treatment of arthritis, osteoporosis, osteopenia and osteopetrosis as well as identifying targets that promote bone healing. Tests included: [2217] DEXA for measurement of bone mineral density on femur and vertebra [2218] MicroCT for very high resolution and very high sensitivity measurements of bone mineral density for both trabecular and cortical bone.

[2219] Dexa Analysis--Test Description:

[2220] Procedure: A cohort of 4 wild type, 4 heterozygotes and 8 homozygotes were tested in this assay. Dual Energy X-ray Absorptiometry (DEXA) has been used successfully to identify changes in bone. Anesthetized animals were examined and bone mineral content (BMC), BMC/LBM ratios, volumetric bone mineral density (vBMD), total body BMD, femur BMD and vertebra BMD were measured.

[2221] The mouse was anesthetized by intraperitoneal injection of Avertin (1.25% 2,2,2,-tribromoethanol, 20 ml/kg body weight), body length and weight were measured, and then the mouse was placed in a prone position on the platform of the PIXImus.TM. Densitometer (Lunar Inc.) for a DEXA scan. Using Lunar PIXImus software, the bone mineral density (BMD) and fat composition (% fat) and total tissue mass (TTM) were determined in the regions of interest (ROI) [i.e., whole body, vertebrae, and both femurs].

[2222] Results:

DEXA: Both the male and female (-/-) mice exhibited increased mean total tissue mass, percent total body fat, and total fat mass when compared with their gender-matched (+/+) littermates and the historical means.

[2223] These studies suggest that mutant (-/-) non-human transgenic animals exhibit a negative phenotype that would be associated with obesity. Thus, PRO1925 polypeptides or agonists thereof are essential for normal fat and lipid metabolic processes and especially would be important in the prevention and/or treatment of lipid storage diseases and/or obesity.

[2224] 66.43. Generation and Analysis of Mice Comprising DNA82340-2530 (UNQ905) Gene Disruptions

[2225] In these knockout experiments, the gene encoding PRO1926 polypeptides (designated as DNA82340-2530) (UNQ905) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: NM.sub.--133749 ACCESSION:NM.sub.--133749 NID: gi 19526955 ref NM.sub.--133749.1 Mus musculus RIKEN cDNA 2900064A13 gene (2900064A13Rik); protein reference: Q9EP72 ACCESSION:Q9EP72 NID: Mus musculus (Mouse). Hypothetical protein (Putative ATG/GTP binding protein precursor); the human gene sequence reference: NM.sub.--020154 ACCESSION:NM.sub.--020154 NID: gi 9910345 ref NM.sub.--020154.1 Homo sapiens chromosome 11 hypothetical protein ORF3 (L0056851); the human protein sequence corresponds to reference: Q9NPA0 ACCESSION:Q9NPA0 NID: Homo sapiens (Human). Putative ATG/GTP binding protein precursor (HT022).

[2226] The mouse gene of interest is RIKEN cDNA 2900064A13 gene, ortholog of human C15orf24 (chromosome 15 open reading frame 24). Aliases include c11orf3, HT022, ORF1-FL1, and chromosome 15 hypothetical ATP/GTP binding protein.

[2227] C15orf24 is a putative integral plasma membrane protein, containing a signal peptide, a transmembrane segment, and a potential ATP/GTP binding site (O'Brien et al, Biochem Biophys Res Commun 273(1):90-4 (2000)).

[2228] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00114 wt het hom Total Observed 23 50 0 73 Expected 18.25 36.5 18.25 73

Chi-Sq.=47.17 Significance=5.7169585E-11 (hom/n)=0.0 Avg. Litter Size=8

Mutation Information

[2229] Mutation Type: Homologous Recombination (standard) Description: Coding exons 1 and 2 were targeted (NCBI accession NM.sub.--133749.1). 1. Wild-type Expression Panel: Expression of the target gene was detected in embryonic stem (ES) cells and in all 13 adult tissue samples tested by RT-PCR. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[2230] 66.43.1. Phenotypic Analysis (for Disrupted Gene: DNA82340-2530 (UNQ905)

[2231] (a) Overall Phenotypic Summary:

[2232] Mutation of the gene encoding the ortholog of human chromosome 15 open reading frame 24 (C15orf24) resulted in genetic data indicating that this mutation resulted in lethality of homozygous mutants. The male heterozygous mice exhibited an increased anxiety-like response during stress-induced hyperthermia testing. Disruption of the target gene was confirmed by Southern hybridization analysis.

[2233] (b) Pathology

Microscopic: No notable difference was observed in the (+/-) mouse analyzed. However, no (-/-) mice were available for analysis. At 12.5 days, 51 embryos were observed: 27 (+/-) embryos, 10 (+/+) embryos, 12 resorption moles, and 2 inconclusive. Gene Expression LacZ activity was not detected in the panel of tissues by immunohistochemical analysis.

[2234] Discussion Related to Embryonic Developmental Abnormality of Lethality:

[2235] Embryonic lethality in knockout mice usually results from various serious developmental problems including but not limited to neuro-degenerative diseases, angiogenic disorders, inflammatory diseases, or where the gene/protein has an important role in basic cell signaling processes in many cell types. In addition, embryonic lethals are useful as potential cancer models. Likewise, the corresponding heterozygous (+/-) mutant animals are particularly useful when they exhibit a phenotype and/or a pathology report which reveals highly informative clues as to the function of the knocked-out gene. For instance, EPO knockout animals were embryonic lethals, but the pathology reports on the embryos showed a profound lack of RBCs.

[2236] (c) Phenotypic Analysis: CNS/Neurology

[2237] In the area of neurology, analysis focused herein on identifying in vivo validated targets for the treatment of neurological and psychiatric disorders including depression, generalized anxiety disorders, attention deficit hyperactivity disorder, obsessive compulsive disorder, schizophrenia, cognitive disorders, hyperalgesia and sensory disorders. Neurological disorders include the category defined as "anxiety disorders" which include but are not limited to: mild to moderate anxiety, anxiety disorder due to a general medical condition, anxiety disorder not otherwise specified, generalized anxiety disorder, panic attack, panic disorder with agoraphobia, panic disorder without agoraphobia, posttraumatic stress disorder, social phobia, specific phobia, substance-induced anxiety disorder, acute alcohol withdrawal, obsessive compulsive disorder, agoraphobia, bipolar disorder I or II, bipolar disorder not otherwise specified, cyclothymic disorder, depressive disorder, major depressive disorder, mood disorder, substance-induced mood disorder. In addition, anxiety disorders may apply to personality disorders including but not limited to the following types: paranoid, antisocial, avoidant behavior, borderline personality disorders, dependent, histronic, narcissistic, obsessive-compulsive, schizoid, and schizotypal.

[2238] Procedure:

[2239] Behavioral screens were performed on a cohort of 4 wild type and 4 heterozygous mutant mice. All behavioral tests were done between 12 and 16 weeks of age unless reduced viability necessitates earlier testing. These tests included open field to measure anxiety, activity levels and exploration.

[2240] Functional Observational Battery (FOB) Test--Stress-induced Hyperthermia:

[2241] The FOB is a series of situations applied to the animal to determine gross sensory and motor deficits. A subset of tests from the Irwin neurological screen that evaluates gross neurological function is used. In general, short-duration, tactile, olfactory, and visual stimuli are applied to the animal to determine their ability to detect and respond normally. These simple tests take approximately 10 minutes and the mouse is returned to its home cage at the end of testing.

[2242] Results:

Stress-Induced Hyperthermia: The male (+/-) mice exhibited increased sensitivity to stress-induced hyperthermia when compared with the level for their gender-matched (+/+) littermates and the historical mean, suggesting an increased anxiety-like response in the mutants.

[2243] In summary, the functional observation testing revealed a phenotype associated with increased anxiety which could be associated with mild to moderate anxiety, anxiety due to a general medical condition, and/or bipolar disorders; hyperactivity; sensory disorders; obsessive-compulsive disorders, schizophrenia or a paranoid personality. Thus, PRO1926 polypeptides or agonists thereof would be useful in the treatment of such neurological disorders.

[2244] 66.44. Generation and Analysis of Mice Comprising DNA59844-2542 (UNQ1840) Gene Disruptions

[2245] In these knockout experiments, the gene encoding PRO3566 polypeptides (designated as DNA59844-2542) (UNQ1840) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: NM.sub.--175148 Mus musculus RIKEN cDNA 2300002M23 gene (2300002M23Rik); protein reference: Q8BM15 ACCESSION:Q8BM15 NID: Mus musculus (Mouse). Weakly similar to TASTE bud-specific protein precursor; the human gene sequence reference: NM.sub.--014070 Homo sapiens chromosome 6 open reading frame 15 (C6orf15); the human protein sequence corresponds to reference: Q9UIG3 ACCESSION:Q9UIG3 NID: Homo sapiens (Human). STG protein.

[2246] The mouse gene of interest is RIKEN cDNA 2300002M23 gene, ortholog of human C6orf15 (chromosome 6 open reading frame 15). Aliases include STG and STG protein.

[2247] C6orf15 is a putative secreted protein, containing a signal peptide and several internal repeats within a major prion protein (PRP) domain. The function of C6orf15 is not known; however, it is expressed in a small subset of taste cells, suggesting that C6orf15 may play a role in taste cell physiology (Neira et al, Mamm Genome 12(1):60-6 (2001); Clark et al, Genome Res 13(10):2265-70 (2003)).

[2248] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00115 wt het hom Total Observed 13 39 21 73 Expected 18.25 36.5 18.25 73

Chi-Sq.=3.68 Significance=0.15881743 (hom/n)=0.29 Avg. Litter Size=8

Mutation Information

[2249] Mutation Type Homologous Recombination (standard) Description: Coding exons 1 and 2 were targeted (NCBI accession NM.sub.--175148.2). 1. Wild-type Expression Panel: Expression of the target gene was detected in embryonic stem (ES) cells and in brain; thymus; spleen; lung; kidney; liver; and stomach, small intestine, and colon among the 13 adult tissue samples tested by RT-PCR. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[2250] 66.44.1. Phenotypic Analysis (for Disrupted Gene: DNA59844-2542 (UNQ1840)

[2251] (a) Overall Phenotypic Summary:

[2252] Mutation of the gene encoding the ortholog of human chromosome 6 open reading frame 15 (C6orf15) resulted in the female homozygous mutant mice exhibiting decreased total tissue mass and total body fat when compared with that of their gender-matched wild-type littermates and the historical means. Disruption of the target gene was confirmed by Southern hybridization analysis.

[2253] (b) Bone Metabolism & Body Diagnostics/Radiology Phenotypic Analysis

[2254] In the area of bone metabolism, targets were identified herein for the treatment of arthritis, osteoporosis, osteopenia and osteopetrosis as well as identifying targets that promote bone healing. Tests included: [2255] DEXA for measurement of bone mineral density on femur and vertebra [2256] MicroCT for very high resolution and very high sensitivity measurements of bone mineral density for both trabecular and cortical bone.

[2257] Dexa Analysis--Test Description:

[2258] Procedure: A cohort of 4 wild type, 4 heterozygotes and 8 homozygotes were tested in this assay. Dual Energy X-ray Absorptiometry (DEXA) has been used successfully to identify changes in bone. Anesthetized animals were examined and bone mineral content (BMC), BMC/LBM ratios, volumetric bone mineral density (vBMD), total body BMD, femur BMD and vertebra BMD were measured.

[2259] The mouse was anesthetized by intraperitoneal injection of Avertin (1.25% 2,2,2,-tribromoethanol, 20 ml/kg body weight), body length and weight were measured, and then the mouse was placed in a prone position on the platform of the PIXImus.TM. Densitometer (Lunar Inc.) for a DEXA scan. Using Lunar PIXImus software, the bone mineral density (BMD) and fat composition (% fat) and total tissue mass (TTM) were determined in the regions of interest (ROI) [i.e., whole body, vertebrae, and both femurs].

[2260] Results:

DEXA: The female (-/-) mice exhibited decreased mean total tissue mass, percent total body fat, and total fat mass when compared with the levels for their gender-matched (+/+) littermates and the historical means.

[2261] These studies suggest that mutant (-/-) non-human transgenic animals exhibit a negative phenotype that would be associated with growth retardation and/or tissue wasting disorders. Thus, PRO3566 polypeptides or agonists thereof are essential for normal fat and lipid metabolic processes and especially would be important in the prevention and/or treatment of tissue wasting disorders such as cachexia.

[2262] 66.45. Generation and Analysis of Mice Comprising DNA90842-2574 (UNQ1886) Gene Disruptions

[2263] In these knockout experiments, the gene encoding PRO4330 polypeptides (designated as DNA90842-2574) (UNQ1886) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: AF168680 ACCESSION:AF168680 NID:6979312 Mus musculus Mus musculus cysteine-rich repeat-containing protein CRIM1 (Crim1); protein reference: Q9JLL0 ACCESSION:Q9JLL0 NID: Mus musculus (Mouse). CYSTEINE-RICH REPEAT-CONTAINING PROTEIN CRIM1 PRECURSOR (FRAGMENT); the human gene sequence reference: NM.sub.--016441 ACCESSION:NM.sub.--016441 NID:10092638 Homo sapiens Homo sapiens cysteine-rich motor neuron 1 (CRIM1); the human protein sequence corresponds to reference: Q9NZV1 ACCESSION:Q9NZV1 NID: Homo sapiens (Human). CYSTEINE-RICH REPEAT-CONTAINING PROTEIN S52 PRECURSOR(CRIM1 PROTEIN).

[2264] The mouse gene of interest is Crim1 (cysteine-rich motor neuron 1), ortholog of human CRIM1. Aliases include S52 and cysteine-rich repeat-containing protein S52 precursor.

[2265] CRIM1 is a type I plasma membrane protein that likely functions as a cell adhesion molecule or receptor. CRIM1 is also a secreted protein, probably because the extracellular domain is proteolytically cleaved from the plasma membrane. CRIM1 binds with bone morphogenic protein (BMP)-4 and BMP-7 and inhibits BMP signaling (Wilkinson et al, J Biol Chem 278(36):34181-8 (2003)). Crim1 is expressed in the developing spinal chord, eye, lens, and testis, potentially playing a role in CNS development and organogenesis (Kolle et al, Mech Dev 90(2):181-93 (2000); Lovicu et al, Mech Dev 94(1-2):261-5 (2000); Georgas et al, Dev Dyn 219(4):582-7 (2000)). CRIM1 is also expressed in endothelial cells, where it likely plays a role in capillary formation during angiogenesis (Glienke et al, Mech Dev 119(2):165-75 (2002)).

[2266] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00116 wt het hom Total Observed 14 22 0 36 Expected 9 18 9 36

Chi-Sq.=14.85 Significance=5.9616077E-4 (hom/n)=0.09 Avg. Litter Size=8

Mutation Information

[2267] Mutation Type Homologous Recombination (standard) Description: Coding exon 5 was targeted (NCBI accession XM.sub.--128751.5). 1. Wild-type Expression Panel: Expression of the target gene was detected in embryonic stem (ES) cells and in all 13 adult tissue samples tested by RT-PCR. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[2268] 66.45.1. Phenotypic Analysis (for Disrupted Gene: DNA90842-2574 (UNQ1886)

[2269] (a) Overall Phenotypic Summary:

[2270] Mutation of the gene encoding the ortholog of human cysteine-rich motor neuron 1 (CRIM1) resulted in genetic data indicating that this mutation resulted in lethality of the homozygous mutants. UNQ1886 is highly expressed in blood vessels and is also involved in regulating bone morphogenic proteins. The heterozygous mice exhibited an increased mean percentage of B cells in the peripheral blood when compared with their wild-type littermates and the historical mean. Disruption of the target gene was confirmed by Southern hybridization analysis.

[2271] (b) Pathology

[2272] Microscopic: At 12.5 days there were 53 embryos observed: 10 (-/-) embryos, 21 (+/-) embryos, 13 (+/+) embryos, and 9 resorption moles. No developmental abnormalities were detected in the 12.5 day embryos by histologic examination.

Gene Expression LacZ activity was detected only in brain among the panel of tissues analyzed by immunohistochemistry.

UNQ1886 Knockout Embryo Studies:

[2273] Tissue Embryo studies of the UNQ1886 knockout embryos showed a skin blister and hemorrhagic phenotypes suggesting that UNQ1886 is involved in maintaining tight interaction between two tissue layers. The E12.5 knockout embryo shows skin blisters on both sides of the head (at eye level) as shown by a 6 um FFPE section through the embryo forehead. Skin blisters were also noted in the E13.5 knockout embryo at the back of the skull, mid spine and eye level. Hemorrhage was also noted in the forehead skull. The E14 knockout embryo (14 um frozen section through lacZ stained forehead--level of the ear) shows expression of UNQ186 in the developing skin. Gene 3 beta-gal activity staining of the uterus section of the wholemount uterus showed expression of UNQ1886. Multi-focal hemorrhage in the knockout embryos [E13.5 and E15.5] occurred in the frontal head section [eye and nasal cavity] as well as hemorrhage in the forelimbs and abdomen.

[2274] Discussion Related to Embryonic Developmental Abnormality of Lethality:

[2275] Embryonic lethality in knockout mice usually results from various serious developmental problems including but not limited to neuro-degenerative diseases, angiogenic disorders, inflammatory diseases, or where the gene/protein has an important role in basic cell signaling processes in many cell types. In addition, embryonic lethals are useful as potential cancer models. Likewise, the corresponding heterozygous (+/-) mutant animals are particularly useful when they exhibit a phenotype and/or a pathology report which reveals highly informative clues as to the function of the knocked-out gene. For instance, EPO knockout animals were embryonic lethals, but the pathology reports on the embryos showed a profound lack of RBCs.

[2276] (c) Immunology Phenotypic Analysis

[2277] Immune related and inflammatory diseases are the manifestation or consequence of fairly complex, often multiple interconnected biological pathways which in normal physiology are critical to respond to insult or injury, initiate repair from insult or injury, and mount innate and acquired defense against foreign organisms. Disease or pathology occurs when these normal physiological pathways cause additional insult or injury either as directly related to the intensity of the response, as a consequence of abnormal regulation or excessive stimulation, as a reaction to self, or as a combination of these.

[2278] Though the genesis of these diseases often involves multistep pathways and often multiple different biological systems/pathways, intervention at critical points in one or more of these pathways can have an ameliorative or therapeutic effect. Therapeutic intervention can occur by either antagonism of a detrimental process/pathway or stimulation of a beneficial process/pathway.

[2279] T lymphocytes (T cells) are an important component of a mammalian immune response. T cells recognize antigens which are associated with a self-molecule encoded by genes within the major histocompatibility complex (MHC). The antigen may be displayed together with MHC molecules on the surface of antigen presenting cells, virus infected cells, cancer cells, grafts, etc. The T cell system eliminates these altered cells which pose a health threat to the host mammal. T cells include helper T cells and cytotoxic T cells. Helper T cells proliferate extensively following recognition of an antigen-MHC complex on an antigen presenting cell. Helper T cells also secrete a variety of cytokines, i.e., lymphokines, which play a central role in the activation of B cells, cytotoxic T cells and a variety of other cells which participate in the immune response.

[2280] In many immune responses, inflammatory cells infiltrate the site of injury or infection. The migrating cells may be neutrophilic, eosinophilic, monocytic or lymphocytic as can be determined by histologic examination of the affected tissues. Current Protocols in Immunology, ed. John E. Coligan, 1994, John Wiley & Sons, Inc.

[2281] Many immune related diseases are known and have been extensively studied. Such diseases include immune-mediated inflammatory diseases (such as rheumatoid arthritis, immune mediated renal disease, hepatobiliary diseases, inflammatory bowel disease (IBD), psoriasis, and asthma), non-immune-mediated inflammatory diseases, infectious diseases, immunodeficiency diseases, neoplasia, and graft rejection, etc. In the area of immunology, targets were identified for the treatment of inflammation and inflammatory disorders.

[2282] In the area of immunology, targets have been identified herein for the treatment of inflammation and inflammatory disorders. Immune related diseases, in one instance, could be treated by suppressing the immune response. Using neutralizing antibodies that inhibit molecules having immune stimulatory activity would be beneficial in the treatment of immune-mediated and inflammatory diseases. Molecules which inhibit the immune response can be utilized (proteins directly or via the use of antibody agonists) to inhibit the immune response and thus ameliorate immune related disease.

[2283] The following tests were performed:

[2284] Flourescence-Activated Cell-Sorting (FACS) Analysis

[2285] Procedure:

[2286] FACS analysis of immune cell composition from peripheral blood was performed including CD4, CD8 and T cell receptor to evaluate T lymphocytes, CD19 for B lymphocytes, CD45 as a leukocyte marker and pan NK for natural killer cells. The FACS analysis was carried out on 2 wild type and 6 heterozygous mice and included cells derived from thymus, spleen, bone marrow and lymph node.

[2287] In these studies, analyzed cells were isolated from thymus, peripheral blood, spleen, bone marrow and lymph nodes. Flow cytometry was designed to determine the relative proportions of CD4 and CD8 positive T cells, B cells, NK cells and monocytes in the mononuclear cell population. A Becton-Dickinson FACSCalibur 3-laser FACS machine was used to assess immune status. For Phenotypic Assays and Screening, this machine records CD4+/CD8-, CD8+/CD4-, NK, B cell and monocyte numbers in addition to the CD4+/CD8+ ratio.

[2288] The mononuclear cell profile was derived by staining a single sample of lysed peripheral blood from each mouse with a panel of six lineage-specific antibodies: CD45 PerCP, anti-TCRb APC, CD4 PE, CD8 FITC, pan-NK PE, and CD19 FITC. The two FITC and PE labeled antibodies stain mutually exclusive cell types. The samples were analyzed using a Becton Dickinson FACSCalibur flow cytometer with CellQuest software.

[2289] Results:

FACS3: The (+/-) mice exhibited an altered distribution of leukocyte subsets in the peripheral blood, characterized by an increased mean percentage of B cells in the (-/-) mice when compared with that of their (+/+) littermates and the historical mean.

[2290] In summary, FACS analysis of immune cell composition indicates that heterozygous (+/-) mice exhibit immunological differences with respect to B cells.

[2291] 66.46. Generation and Analysis of Mice Comprising DNA96893-2621 (UNQ1940) Gene Disruptions

[2292] In these knockout experiments, the gene encoding PRO4423 polypeptides (designated as DNA96893-2621) (UNQ1940) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: NM.sub.--173375 ACCESSION:NM.sub.--173375 NID: gi 27734065 ref NM.sub.--173375.1 Mus musculus hypothetical protein B230314019 (B230314019); protein reference: Q8BR21 ACCESSION:Q8BR21NID: Mus musculus (Mouse). Hypothetical protein; the human gene sequence reference: NM.sub.--205855 Homo sapiens HWKM1940 (UNQ1940); the human protein sequence corresponds to reference:

[2293] Q6UWF9 ACCESSION:Q6UWF9 NID: Homo sapiens (Human). HWKM1940.

[2294] The mouse gene of interest is cDNA sequence BC064033, ortholog of human UNQ1940. Aliases include B230314019 and HWKM1940.

[2295] UNQ1940 is a putative 173-amino acid secreted protein, containing a signal peptide and no other defined conserved domain.

[2296] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00117 wt het hom Total Observed 13 30 19 62 Expected 15.5 31 15.5 62

Chi-Sq.=0.68 Significance=0.7117703 (hom/n)=0.24 Avg. Litter Size=8

Mutation Information

[2297] Mutation Type Homologous Recombination (standard) Description: Coding exons 2 and 3 were targeted (NCBI accession NM.sub.--173375.1). 1. Wild-type Expression Panel: Expression of the target gene was detected in embryonic stem (ES) cells and in all 13 adult tissue samples tested by RT-PCR, except skeletal muscle and bone. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[2298] 66.46.1. Phenotypic Analysis (for Disrupted Gene: DNA96893-2621 (UNQ1940)

[2299] (a) Overall Phenotypic Summary:

[2300] Mutation of the gene encoding the ortholog of a human putative secreted protein (UNQ1940) resulted in a decreased percentage of CD4 cells and an increased percentage of B cells in the peripheral blood of (-/-) mice. Gene disruption was confirmed by Southern blot.

[2301] (b) Immunology Phenotypic Analysis

[2302] Immune related and inflammatory diseases are the manifestation or consequence of fairly complex, often multiple interconnected biological pathways which in normal physiology are critical to respond to insult or injury, initiate repair from insult or injury, and mount innate and acquired defense against foreign organisms. Disease or pathology occurs when these normal physiological pathways cause additional insult or injury either as directly related to the intensity of the response, as a consequence of abnormal regulation or excessive stimulation, as a reaction to self, or as a combination of these.

[2303] Though the genesis of these diseases often involves multistep pathways and often multiple different biological systems/pathways, intervention at critical points in one or more of these pathways can have an ameliorative or therapeutic effect. Therapeutic intervention can occur by either antagonism of a detrimental process/pathway or stimulation of a beneficial process/pathway.

[2304] T lymphocytes (T cells) are an important component of a mammalian immune response. T cells recognize antigens which are associated with a self-molecule encoded by genes within the major histocompatibility complex (MHC). The antigen may be displayed together with MHC molecules on the surface of antigen presenting cells, virus infected cells, cancer cells, grafts, etc. The T cell system eliminates these altered cells which pose a health threat to the host mammal. T cells include helper T cells and cytotoxic T cells. Helper T cells proliferate extensively following recognition of an antigen-MHC complex on an antigen presenting cell. Helper T cells also secrete a variety of cytokines, i.e., lymphokines, which play a central role in the activation of B cells, cytotoxic T cells and a variety of other cells which participate in the immune response.

[2305] In many immune responses, inflammatory cells infiltrate the site of injury or infection. The migrating cells may be neutrophilic, eosinophilic, monocytic or lymphocytic as can be determined by histologic examination of the affected tissues. Current Protocols in Immunology, ed. John E. Coligan, 1994, John Wiley & Sons, Inc.

[2306] Many immune related diseases are known and have been extensively studied. Such diseases include immune-mediated inflammatory diseases (such as rheumatoid arthritis, immune mediated renal disease, hepatobiliary diseases, inflammatory bowel disease (IBD), psoriasis, and asthma), non-immune-mediated inflammatory diseases, infectious diseases, immunodeficiency diseases, neoplasia, and graft rejection, etc. In the area of immunology, targets were identified for the treatment of inflammation and inflammatory disorders.

[2307] In the area of immunology, targets have been identified herein for the treatment of inflammation and inflammatory disorders. Immune related diseases, in one instance, could be treated by suppressing the immune response. Using neutralizing antibodies that inhibit molecules having immune stimulatory activity would be beneficial in the treatment of immune-mediated and inflammatory diseases. Molecules which inhibit the immune response can be utilized (proteins directly or via the use of antibody agonists) to inhibit the immune response and thus ameliorate immune related disease.

[2308] The following test was performed:

[2309] Flourescence-Activated Cell-Sorting (FACS) Analysis

[2310] Procedure:

[2311] FACS analysis of immune cell composition from peripheral blood was performed including CD4, CD8 and T cell receptor to evaluate T lymphocytes, CD19 for B lymphocytes, CD45 as a leukocyte marker and pan NK for natural killer cells. The FACS analysis was carried out on 2 wild type and 6 homozygous mice and included cells derived from thymus, spleen, bone marrow and lymph node.

[2312] In these studies, analyzed cells were isolated from thymus, peripheral blood, spleen, bone marrow and lymph nodes. Flow cytometry was designed to determine the relative proportions of CD4 and CD8 positive T cells, B cells, NK cells and monocytes in the mononuclear cell population. A Becton-Dickinson FACSCalibur 3-laser FACS machine was used to assess immune status. For Phenotypic Assays and Screening, this machine records CD4+/CD8-, CD8+/CD4-, NK, B cell and monocyte numbers in addition to the CD4+/CD8+ ratio.

[2313] The mononuclear cell profile was derived by staining a single sample of lysed peripheral blood from each mouse with a panel of six lineage-specific antibodies: CD45 PerCP, anti-TCRb APC, CD4 PE, CD8 FITC, pan-NK PE, and CD19 FITC. The two FITC and PE labeled antibodies stain mutually exclusive cell types. The samples were analyzed using a Becton Dickinson FACSCalibur flow cytometer with CellQuest software.

[2314] Results:

[2315] The homozygous (-/-) mice exhibited decreased mean percentages of CD4 cells in the peripheral blood when compared with their (+/+) littermates and the historical means. In addition, the (-/-) mice showed increased percentages of B cells.

[2316] In summary, the FACS results indicate that the homozygous mutant mice demonstrate immunological abnormalities marked by decreased T cell populations and increased B cell populations. From these observations, PRO4423 polypeptides or the gene encoding PRO4423 appears to act as a positive regulator of T cell proliferation. But a negative regulator of B cell production. PRO4423 polypeptides and agonists thereof would be important for a healthy immune system and would be useful in stimulating the immune system particularly for increasing T cell proliferation.

[2317] 66.47. Generation and Analysis of Mice Comprising DNA336539 (UNQ2257) Gene Disruptions

[2318] In these knockout experiments, the gene encoding PRO36935 polypeptides (designated as DNA336539) (UNQ2257) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: NM.sub.--011627 Mus musculus trophoblast glycoprotein (Tpbg); protein reference: Q9Z0L0 ACCESSION:Q9Z0L0 NID: Mus musculus (Mouse). 5T4 oncofetal trophoblast glycoprotein precursor; the human gene sequence reference: NM.sub.--006670 Homo sapiens trophoblast glycoprotein (TPBG); the human protein sequence corresponds to reference: Q13641 ACCESSION:Q13641 NID: Homo sapiens (Human). 5T4 oncofoetal antigen precursor (5T4 oncofetal trophoblast glycoprotein precursor).

[2319] The mouse gene of interest is Tpbg (trophoblast glycoprotein), ortholog of human TPBG. Aliases include 5T4, M6P1, 5T4-AG, 5T4-antigen, and 5T4 oncofetal trophoblast glycoprotein.

[2320] TPBG is an integral plasma membrane protein, consisting of a signal peptide, several leucine-rich repeats, a transmembrane segment, and a short cytoplasmic C-terminus. TPBG is expressed in trophoblastic cells, amniotic epithelium, brain, ovary, and a variety of carcinomas. TPBG may play a role in processes such as placentation and metastasis by modulating cell adhesion, shape, and motility (Ward et al, J Cell Sci 116(Pt 22):4533-42 (2003); Shaw et al, Biochem J 363(Pt 1):137-45 (2002); King et al, Biochim Biophys Acta 1445(3) 257-70 (1999); Myers et al, J Biol Chem 269(12):9319-24 (1994)).

[2321] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00118 wt het hom Total Observed 23 29 16 68 Expected 17 34 17 68

Chi-Sq.=4.25 Significance=0.11943297 (hom/n)=0.23 Avg. Litter Size=9

Mutation Information

[2322] Mutation Type Homologous Recombination (standard) Description: Coding exon 1 was targeted (NCBI accession N1\4.sub.--011627.2). 1. Wild-type Expression Panel: Expression of the target gene was detected in embryonic stem (ES) cells and in brain, spinal cord, eye, and spleen among the 13 adult tissue samples tested by RT-PCR. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[2323] 66.47.1. Phenotypic Analysis (for Disrupted Gene: DNA336539 (UNQ2257)

[2324] (a) Overall Phenotypic Summary:

[2325] Mutation of the gene encoding the ortholog of human trophoblast glycoprotein (TPBG) resulted in an increased depressive-like response in tail suspension testing in (-/-) mice. Gene disruption was confirmed by Southern blot.

[2326] (b) Phenotypic Analysis: CNS/Neurology

[2327] In the area of neurology, analysis focused herein on identifying in vivo validated targets for the treatment of neurological and psychiatric disorders including depression, generalized anxiety disorders, attention deficit hyperactivity disorder, obsessive compulsive disorder, schizophrenia, cognitive disorders, hyperalgesia and sensory disorders. Neurological disorders include the category defined as "anxiety disorders" which include but are not limited to: mild to moderate anxiety, anxiety disorder due to a general medical condition, anxiety disorder not otherwise specified, generalized anxiety disorder, panic attack, panic disorder with agoraphobia, panic disorder without agoraphobia, posttraumatic stress disorder, social phobia, specific phobia, substance-induced anxiety disorder, acute alcohol withdrawal, obsessive compulsive disorder, agoraphobia, bipolar disorder I or II, bipolar disorder not otherwise specified, cyclothymic disorder, depressive disorder, major depressive disorder, mood disorder, substance-induced mood disorder. In addition, anxiety disorders may apply to personality disorders including but not limited to the following types: paranoid, antisocial, avoidant behavior, borderline personality disorders, dependent, histronic, narcissistic, obsessive-compulsive, schizoid, and schizotypal.

[2328] Procedure:

[2329] Behavioral screens were performed on a cohort of 4 wild type, 4 heterozygous and 8 homozygous mutant mice. All behavioral tests were done between 12 and 16 weeks of age unless reduced viability necessitates earlier testing. These tests included open field to measure anxiety, activity levels and exploration.

[2330] Functional Observational Battery (FOB) Test--Tail Suspension Testing:

[2331] The FOB is a series of situations applied to the animal to determine gross sensory and motor deficits. A subset of tests from the Irwin neurological screen that evaluates gross neurological function is used. In general, short-duration, tactile, olfactory, and visual stimuli are applied to the animal to determine their ability to detect and respond normally. These simple tests take approximately 10 minutes and the mouse is returned to its home cage at the end of testing.

[2332] Tail Suspension Testing:

[2333] The tail suspension test is a procedure that has been developed as a model for depressive-like behavior in rodents. In this particular setup, a mouse is suspended by its tail for 6 minutes, and in response the mouse will struggle to escape from this position. After a certain period of time the struggling of the mouse decreases and this is interpreted as a type of learned helplessness paradigm. Animals with invalid data (i.e. climbed their tail during the testing period) are excluded from analysis.

[2334] Results:

[2335] The (-/-) mice exhibited an increased immobility time in the tail suspension testing compared with that of the (+/+) littermates and the historical mean, which is indicative of an increased depressive-like response. Thus, knockout mice demonstrated a phenotype consistent with depression, generalized anxiety disorders, cognitive disorders, hyperalgesia and sensory disorders and/or bipolar disorders. Thus, PRO36935 polypeptides and agonists thereof would be useful for the treatment or amelioration of the symptoms associated with depressive disorders.

[2336] 66.48. Generation and Analysis of Mice Comprising DNA62849-2647 (UNQ2420) Gene Disruptions

[2337] In these knockout experiments, the gene encoding PRO4977 polypeptides (designated as DNA62849-2647) (UNQ2420) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: NM.sub.--130887 ACCESSION:NM.sub.--130887 NID:18700029 Mus musculus Mus musculus papilin (LOC170721); protein reference: Q9EPX2 ACCESSION:Q9EPX2 NID: Mus musculus (Mouse). PAPILIN; the human gene sequence reference: NM.sub.--173462 Homo sapiens papilin, proteoglycan-like sulfated glycoprotein (PAPLN); the human protein sequence corresponds to reference: NP.sub.--775733 ACCESSION:NP.sub.--775733 NID: gi 50083295 ref NP.sub.--775733.2 papilin [Homo sapiens].

[2338] The mouse gene of interest is Papin (papilin, proteoglycan-like sulfated glycoprotein), ortholog of human PAPLN. Aliases include E030033C16Rik and MGC50452.

[2339] PAPLN is a secreted protein that associates with extracellular matrix and likely functions as a protease inhibitor (Kramerova et al, 2000). PAPLN consists of a signal peptide, several thrombospondin repeats (extracellular matrix association and cell adhesion; Pfam accession PF00090), a Kunitz/bovine pancreatic trypsin inhibitor domain (indicative of serine protease inhibitors; Pfam accession PF00014), and three C-terminal immunoglobulin domains (protein-protein or protein-ligand interactions; Pfam accession PF00047). PAPLN may play a role in development and organogenesis (Kramerova et al, Development 127(24):5475-85 (2000); Fessler et al, Int J Biochem Cell Biol 36(6):1079-84 (2004); Tucker, Int J Biochem Cell Biol 36(6):969-74 (2004)). Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00119 wt het hom Total Observed 27 34 16 77 Expected 19.25 38.5 19.25 77

Chi-Sq.=5.11 Significance=0.077692226 (hom/n)=0.2 Avg. Litter Size=8

Mutation Information

[2340] Mutation Type: Homologous Recombination (standard) Description: Coding exon 1 and the preceding noncoding exon was targeted (NCBI accession NM.sub.--130887.1). 1. Wild-type Expression Panel: Expression of the target gene was detected in all 13 adult tissue samples tested by RT-PCR. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[2341] 66.48.1. Phenotypic Analysis (for Disrupted Gene: DNA62849-2647 (UNQ2420)

[2342] (a) Overall Phenotypic Summary:

[2343] Mutation of the gene encoding the ortholog of human papilin, proteoglycan-like sulfated glycoprotein (PAPLN) resulted in an increased percentage of CD4 cells in the peripheral blood of (-/-) mice. The mutant (-/-) mice also exhibited a trend towards increased prepulse inhibition. Gene disruption was confirmed by Southern blot.

[2344] (b) Immunology Phenotypic Analysis

[2345] Immune related and inflammatory diseases are the manifestation or consequence of fairly complex, often multiple interconnected biological pathways which in normal physiology are critical to respond to insult or injury, initiate repair from insult or injury, and mount innate and acquired defense against foreign organisms. Disease or pathology occurs when these normal physiological pathways cause additional insult or injury either as directly related to the intensity of the response, as a consequence of abnormal regulation or excessive stimulation, as a reaction to self, or as a combination of these.

[2346] Though the genesis of these diseases often involves multistep pathways and often multiple different biological systems/pathways, intervention at critical points in one or more of these pathways can have an ameliorative or therapeutic effect. Therapeutic intervention can occur by either antagonism of a detrimental process/pathway or stimulation of a beneficial process/pathway.

[2347] T lymphocytes (T cells) are an important component of a mammalian immune response. T cells recognize antigens which are associated with a self-molecule encoded by genes within the major histocompatibility complex (MHC). The antigen may be displayed together with MHC molecules on the surface of antigen presenting cells, virus infected cells, cancer cells, grafts, etc. The T cell system eliminates these altered cells which pose a health threat to the host mammal. T cells include helper T cells and cytotoxic T cells. Helper T cells proliferate extensively following recognition of an antigen-MHC complex on an antigen presenting cell. Helper T cells also secrete a variety of cytokines, i.e., lymphokines, which play a central role in the activation of B cells, cytotoxic T cells and a variety of other cells which participate in the immune response.

[2348] In many immune responses, inflammatory cells infiltrate the site of injury or infection. The migrating cells may be neutrophilic, eosinophilic, monocytic or lymphocytic as can be determined by histologic examination of the affected tissues. Current Protocols in Immunology, ed. John E. Coligan, 1994, John Wiley & Sons, Inc.

[2349] Many immune related diseases are known and have been extensively studied. Such diseases include immune-mediated inflammatory diseases (such as rheumatoid arthritis, immune mediated renal disease, hepatobiliary diseases, inflammatory bowel disease (IBD), psoriasis, and asthma), non-immune-mediated inflammatory diseases, infectious diseases, immunodeficiency diseases, neoplasia, and graft rejection, etc. In the area of immunology, targets were identified for the treatment of inflammation and inflammatory disorders.

[2350] In the area of immunology, targets have been identified herein for the treatment of inflammation and inflammatory disorders. Immune related diseases, in one instance, could be treated by suppressing the immune response. Using neutralizing antibodies that inhibit molecules having immune stimulatory activity would be beneficial in the treatment of immune-mediated and inflammatory diseases. Molecules which inhibit the immune response can be utilized (proteins directly or via the use of antibody agonists) to inhibit the immune response and thus ameliorate immune related disease.

[2351] The following test was performed:

[2352] Flourescence-Activated Cell-Sorting (FACS) Analysis

[2353] Procedure:

[2354] FACS analysis of immune cell composition from peripheral blood was performed including CD4, CD8 and T cell receptor to evaluate T lymphocytes, CD19 for B lymphocytes, CD45 as a leukocyte marker and pan NK for natural killer cells. The FACS analysis was carried out on 2 wild type and 6 homozygous mice and included cells derived from thymus, spleen, bone marrow and lymph node.

[2355] In these studies, analyzed cells were isolated from thymus, peripheral blood, spleen, bone marrow and lymph nodes. Flow cytometry was designed to determine the relative proportions of CD4 and CD8 positive T cells, B cells, NK cells and monocytes in the mononuclear cell population. A Becton-Dickinson FACSCalibur 3-laser FACS machine was used to assess immune status. For Phenotypic Assays and Screening, this machine records CD4+/CD8-, CD8+/CD4-, NK, B cell and monocyte numbers in addition to the CD4+/CD8+ ratio.

[2356] The mononuclear cell profile was derived by staining a single sample of lysed peripheral blood from each mouse with a panel of six lineage-specific antibodies: CD45 PerCP, anti-TCRb APC, CD4 PE, CD8 FITC, pan-NK PE, and CD19 FITC. The two FITC and PE labeled antibodies stain mutually exclusive cell types. The samples were analyzed using a Becton Dickinson FACSCalibur flow cytometer with CellQuest software.

[2357] Results:

[2358] FACS: The (-/-) mice exhibited an altered distribution of leukocyte subsets in the peripheral blood, characterized by an increased mean percentage of CD4 cells when compared with their (+/+) littermates and the historical mean. Thus, knocking out the gene which encodes PRO4977 polypeptides causes an increase in the T cell population. From these observations, PRO4977 polypeptides or the gene encoding PRO4977 appears to act as a negative regulator of T cell proliferation. Thus, PRO4977 polypeptides or agonists thereof would be beneficial as a negative regulator of T cell proliferation in those instances wherein a pronounced T-cell proliferation is present such as occurs in autoimmune diseases (for example rheumatoid arthritis patients). In addition, PRO4977 polypeptides would be especially useful in preventing skin graft rejections.

[2359] (c) Phenotypic Analysis: CNS/Neurology

[2360] In the area of neurology, analysis focused herein on identifying in vivo validated targets for the treatment of neurological and psychiatric disorders including depression, generalized anxiety disorders, attention deficit hyperactivity disorder, obsessive compulsive disorder, schizophrenia, cognitive disorders, hyperalgesia and sensory disorders. Neurological disorders include the category defined as "anxiety disorders" which include but are not limited to: mild to moderate anxiety, anxiety disorder due to a general medical condition, anxiety disorder not otherwise specified, generalized anxiety disorder, panic attack, panic disorder with agoraphobia, panic disorder without agoraphobia, posttraumatic stress disorder, social phobia, specific phobia, substance-induced anxiety disorder, acute alcohol withdrawal, obsessive compulsive disorder, agoraphobia, bipolar disorder I or II, bipolar disorder not otherwise specified, cyclothymic disorder, depressive disorder, major depressive disorder, mood disorder, substance-induced mood disorder. In addition, anxiety disorders may apply to personality disorders including but not limited to the following types: paranoid, antisocial, avoidant behavior, borderline personality disorders, dependent, histronic, narcissistic, obsessive-compulsive, schizoid, and schizotypal.

[2361] Procedure:

[2362] Behavioral screens were performed on a cohort of 4 wild type, 4 heterozygous and 8 homozygous mutant mice. All behavioral tests were done between 12 and 16 weeks of age unless reduced viability necessitates earlier testing.

[2363] Prepulse Inhibition of the Acoustic Startle Reflex

[2364] Prepulse inhibition of the acoustic startle reflex occurs when a loud 120 decibel (dB) startle-inducing tone is preceded by a softer (prepulse) tone. The PPI paradigm consists of six different trial types (70 dB background noise, 120 dB alone, 74 dB+120 dB-pp 4, 78 dB+120 dB-pp 8, 82 dB+120 dB-pp 12, and 90 dB+120 dB-pp 20) each repeated in pseudo random order six times for a total of 36 trials. The max response to the stimulus (V max) is averaged for each trial type. Animals with a 120 dB average value equal to or below 100 are excluded from analysis. The percent that the prepulse inhibits the animal's response to the startle stimulus is calculated and graphed.

[2365] Results:

[2366] The mutant (-/-) mice exhibited a trend towards increased prepulse inhibition of the acoustic startle reflex which is indicative of an enhanced sensorimotor gating/attention.

[2367] 66.49. Generation and Analysis of Mice Comprising DNA222844 (UNQ2421) Gene Disruptions

[2368] In these knockout experiments, the gene encoding PRO4979 polypeptides (also known as PRO38844 polypeptides) (designated as DNA222844) (UNQ2421) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: NM.sub.--173182 Mus musculus RIKEN cDNA 1600019O04 gene (1600019O04Rik); protein reference: Q6NWW9 ACCESSION:Q6NWW9 NID: Mus musculus (Mouse). FAD104; the human gene sequence reference: NM.sub.--022763 Homo sapiens FAD104 (FAD104); the human protein sequence corresponds to reference: Q8IXB2 ACCESSION:Q8IXB2 NID: Homo sapiens (Human). FAD104.

[2369] The mouse gene of interest is RIKEN cDNA 1600019O04 gene, ortholog of human FAD104 (factor for adipocyte differentiation 104). Aliases include FLJ23399 and DKFZp762K137.

[2370] FAD 104 is a putative integral plasma membrane protein that likely functions as a receptor or cell adhesion molecule. The protein contains nine fibronectin type III domains and a C-terminal transmembrane segment. FAD104 may play a role in adipogenesis (Tominaga et al, EBBS Lett 577(1-2):49-54 (2004)).

[2371] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00120 wt het hom Total Observed 17 36 1 54 Expected 13.5 27 13.5 54

Chi-Sq.=20.47 Significance=3.5891873E-5 (hom/n)=0.08 Avg. Litter Size=8

Mutation Information

[2372] Mutation Type Homologous Recombination (standard) Description: Coding exon 1 was targeted (NCBI accession NM.sub.--173182.1). 1. Wild-type Expression Panel: Expression of the target gene was detected in embryonic stem (ES) cells and in all 13 adult tissue samples tested by RT-PCR. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[2373] 66.49.1. Phenotypic Analysis (for Disrupted Gene: DNA222844 (UNQ2421)

[2374] (a) Overall Phenotypic Summary:

[2375] Mutation of the gene encoding the ortholog of human factor for adipocyte differentiation 104 (FAD104) resulted in genetic data indicating that this mutation resulted in lethality of the homozygous mutants. The heterozygous mice exhibited an increased mean serum IgG2a level when compared with that of their wild-type littermates. Disruption of the target gene was confirmed by Southern hybridization analysis.

[2376] (b) Pathology

Genetics: Homozygous lethal. The (-/-) pups were dead at the time of genotyping. Microscopic: No developmental abnormalities were detected in the 12.5 d embryos by histologic examination. Gene Expression LacZ activity was not detected in the panel of tissues by immunohistochemical analysis.

[2377] Discussion Related to Embryonic Developmental Abnormality of Lethality:

[2378] Embryonic lethality in knockout mice usually results from various serious developmental problems including but not limited to neuro-degenerative diseases, angiogenic disorders, inflammatory diseases, or where the gene/protein has an important role in basic cell signaling processes in many cell types. In addition, embryonic lethals are useful as potential cancer models. Likewise, the corresponding heterozygous (+/-) mutant animals are particularly useful when they exhibit a phenotype and/or a pathology report which reveals highly informative clues as to the function of the knocked-out gene. For instance, EPO knockout animals were embryonic lethals, but the pathology reports on the embryos showed a profound lack of RBCs.

[2379] (c) Immunology Phenotypic Analysis

[2380] Immune related and inflammatory diseases are the manifestation or consequence of fairly complex, often multiple interconnected biological pathways which in normal physiology are critical to respond to insult or injury, initiate repair from insult or injury, and mount innate and acquired defense against foreign organisms. Disease or pathology occurs when these normal physiological pathways cause additional insult or injury either as directly related to the intensity of the response, as a consequence of abnormal regulation or excessive stimulation, as a reaction to self, or as a combination of these.

[2381] Though the genesis of these diseases often involves multistep pathways and often multiple different biological systems/pathways, intervention at critical points in one or more of these pathways can have an ameliorative or therapeutic effect. Therapeutic intervention can occur by either antagonism of a detrimental process/pathway or stimulation of a beneficial process/pathway.

[2382] T lymphocytes (T cells) are an important component of a mammalian immune response. T cells recognize antigens which are associated with a self-molecule encoded by genes within the major histocompatibility complex (MHC). The antigen may be displayed together with MHC molecules on the surface of antigen presenting cells, virus infected cells, cancer cells, grafts, etc. The T cell system eliminates these altered cells which pose a health threat to the host mammal. T cells include helper T cells and cytotoxic T cells. Helper T cells proliferate extensively following recognition of an antigen-MHC complex on an antigen presenting cell. Helper T cells also secrete a variety of cytokines, i.e., lymphokines, which play a central role in the activation of B cells, cytotoxic T cells and a variety of other cells which participate in the immune response.

[2383] In many immune responses, inflammatory cells infiltrate the site of injury or infection. The migrating cells may be neutrophilic, eosinophilic, monocytic or lymphocytic as can be determined by histologic examination of the affected tissues. Current Protocols in Immunology, ed. John E. Coligan, 1994, John Wiley & Sons, Inc.

[2384] Many immune related diseases are known and have been extensively studied. Such diseases include immune-mediated inflammatory diseases (such as rheumatoid arthritis, immune mediated renal disease, hepatobiliary diseases, inflammatory bowel disease (IBD), psoriasis, and asthma), non-immune-mediated inflammatory diseases, infectious diseases, immunodeficiency diseases, neoplasia, and graft rejection, etc. In the area of immunology, targets were identified for the treatment of inflammation and inflammatory disorders.

[2385] In the area of immunology, targets have been identified herein for the treatment of inflammation and inflammatory disorders Immune related diseases, in one instance, could be treated by suppressing the immune response. Using neutralizing antibodies that inhibit molecules having immune stimulatory activity would be beneficial in the treatment of immune-mediated and inflammatory diseases. Molecules which inhibit the immune response can be utilized (proteins directly or via the use of antibody agonists) to inhibit the immune response and thus ameliorate immune related disease.

[2386] The following test was performed:

[2387] Serum Immunoglobulin Isotyping Assay:

[2388] The Serum Immunoglobulin Isotyping Assay is performed using a Cytometric Bead Array (CBA) kit. This assay is used to rapidly identify the heavy and light chain isotypes of a mouse monoclonal antibody in a single sample. The values expressed are "relative fluorescence units" and are based on the detection of kappa light chains. Any value <6 is not significant.

[2389] Results:

Serum Imm. 2: The (+/-) mice exhibited an increased mean serum IgG2a level when compared with that of their (+/+) littermates, the (+/+) mice for the project run, and the historical median.

[2390] Heterozygous (+/-) mice exhibited elevation of IgG2a serum immunoglobulins compared to their gender-matched (+/+) littermates. IgG2a efficiently opsonizes pathogens for engulfment by phagocytes and activates the complement system. The observed phenotype suggests that the PRO4979 polypeptide is a negative regulator of inflammatory responses.

[2391] 66.50. Generation and Analysis of Mice Comprising DNA97003-2649 (UNQ2422) Gene Disruptions

[2392] In these knockout experiments, the gene encoding PRO4980 polypeptides (designated as DNA97003-2649) (UNQ2422) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: NM.sub.--177648 Mus musculus transmembrane protein 15 (Tmem15); protein reference: Q8R2Y3 ACCESSION:Q8R2Y3 NID: Mus musculus (Mouse). Similar to KIAA1094 protein; the human gene sequence reference: NM.sub.--014908 Homo sapiens transmembrane protein 15 (TMEM15); the human protein sequence corresponds to reference: Q9UPQ8 ACCESSION:Q9UPQ8 NID: Homo sapiens (Human). Hypothetical protein KIAA1094.

[2393] The mouse gene of interest is Tmem15 (transmembrane protein 15), ortholog of human TMEM15. Aliases include MGC36683, mKIAA1094, cDNA sequence BC026973, and KIAA1094.

[2394] TMEM15 is a likely integral plasma membrane protein, consisting of a signal peptide and 11 to 14 transmembrane segments within a weakly predicted actin-like ATPase domain (SCOP).

[2395] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00121 wt het hom Total Observed 18 33 0 51 Expected 12.75 25.5 12.75 51

Chi-Sq.=41.74 Significance=8.6352275E-10 (hom/n)=0.0 Avg. Litter Size=7

Mutation Information

[2396] Mutation Type: Homologous Recombination (standard) Description: Coding exon 1 was targeted (NCBI accession NM.sub.--177648.2). 1. Wild-type Expression Panel: Expression of the target gene was detected in all 13 adult tissue samples tested by RT-PCR, except bone. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[2397] 66.50.1. Phenotypic Analysis for Disrupted Gene: DNA97003-2649 UN 2422

[2398] (a) Overall Phenotypic Summary:

[2399] Mutation of the gene encoding the ortholog of human transmembrane protein 15 (TMEM15) resulted in genetic data indicating that this mutation resulted in lethality of the homozygous mutants. The heterozygous mice exhibited a decreased depressive-like response: Disruption of the target gene was confirmed by Southern hybridization analysis.

[2400] (b) Pathology

Microscopic: Not tested due to embryonic lethality. At 12.5 days, there were 39 embryos observed: 23 (+/-) embryos, 11 (+/+) embryos, 3 to-be-determined, and 2 inconclusive. Wholemount data at 7.5 dpc and 12.5 dpc shows broad and ubiquitous staining in the wildtype embryos. There is strong LacZ staining in the extraembryonic ectoderm at 6.5 dpc and 7.5 dpc in the heterozygous (+/-) embryos. Gene Expression: LacZ activity was not detected in the panel of tissues by immunohistochemical analysis.

[2401] Discussion Related to Embryonic Developmental Abnormality of Lethality:

[2402] Embryonic lethality in knockout mice usually results from various serious developmental problems including but not limited to neuro-degenerative diseases, angiogenic disorders, inflammatory diseases, or where the gene/protein has an important role in basic cell signaling processes in many cell types. In addition, embryonic lethals are useful as potential cancer models. Likewise, the corresponding heterozygous (+/-) mutant animals are particularly useful when they exhibit a phenotype and/or a pathology report which reveals highly informative clues as to the function of the knocked-out gene. For instance, EPO knockout animals were embryonic lethals, but the pathology reports on the embryos showed a profound lack of RBCs.

[2403] (c) Phenotypic Analysis: CNS/Neurology

[2404] In the area of neurology, analysis focused herein on identifying in vivo validated targets for the treatment of neurological and psychiatric disorders including depression, generalized anxiety disorders, attention deficit hyperactivity disorder, obsessive compulsive disorder, schizophrenia, cognitive disorders, hyperalgesia and sensory disorders. Neurological disorders include the category defined as "anxiety disorders" which include but are not limited to: mild to moderate anxiety, anxiety disorder due to a general medical condition, anxiety disorder not otherwise specified, generalized anxiety disorder, panic attack, panic disorder with agoraphobia, panic disorder without agoraphobia, posttraumatic stress disorder, social phobia, specific phobia, substance-induced anxiety disorder, acute alcohol withdrawal, obsessive compulsive disorder, agoraphobia, bipolar disorder I or II, bipolar disorder not otherwise specified, cyclothymic disorder, depressive disorder, major depressive disorder, mood disorder, substance-induced mood disorder. In addition, anxiety disorders may apply to personality disorders including but not limited to the following types: paranoid, antisocial, avoidant behavior, borderline personality disorders, dependent, histronic, narcissistic, obsessive-compulsive, schizoid, and schizotypal.

[2405] Procedure:

[2406] Behavioral screens were performed on a cohort of 4 wild type and 4 heterozygous mutant mice. All behavioral tests were done between 12 and 16 weeks of age unless reduced viability necessitates earlier testing.

[2407] These tests included open field to measure anxiety, activity levels and exploration.

[2408] Functional Observational Battery (FOB) Test--Tail Suspension Testing:

[2409] The FOB is a series of situations applied to the animal to determine gross sensory and motor deficits. A subset of tests from the Irwin neurological screen that evaluates gross neurological function is used. In general, short-duration, tactile, olfactory, and visual stimuli are applied to the animal to determine their ability to detect and respond normally. These simple tests take approximately 10 minutes and the mouse is returned to its home cage at the end of testing.

[2410] Tail Suspension Testing:

[2411] The tail suspension test is a procedure that has been developed as a model for depressive-like behavior in rodents. In this particular setup, a mouse is suspended by its tail for 6 minutes, and in response the mouse will struggle to escape from this position. After a certain period of time the struggling of the mouse decreases and this is interpreted as a type of learned helplessness paradigm. Animals with invalid data (i.e. climbed their tail during the testing period) are excluded from analysis.

[2412] Results:

[2413] Tail Suspension2: The (+/-) mice exhibited decreased immobility time during tail suspension testing when compared with their (+/+) littermates and the historical mean, suggesting a decreased depressive-like response in the mutants.

[2414] Thus, heterozygous mice demonstrated a phenotype consistent with depression, generalized anxiety disorders, cognitive disorders, hyperalgesia and sensory disorders and/or bipolar disorders. Thus, PRO4980 polypeptides and agonists thereof would be useful for the treatment or amelioration of the symptoms associated with depressive disorders.

[2415] 66.51. Generation and Analysis of Mice Comprising DNA94849-2960 (UNQ2423) Gene Disruptions

[2416] In these knockout experiments, the gene encoding PRO4981 polypeptides (designated as DNA94849-2960) (UNQ2423) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: NM.sub.--027379 Mus musculus male sterility domain containing 2 (Mlstd2); protein reference: Q922J9 ACCESSION:Q922J9 NID: Mus musculus (Mouse). RIKEN cDNA 3732409C05 gene; the human gene sequence reference: NM.sub.--032228 Homo sapiens male sterility domain containing 2 (MLSTD2); the human protein sequence corresponds to reference: Q8WVX9 ACCESSION:Q8WVX9 NID: Homo sapiens (Human). Similar to RIKEN cDNA 3732409C05 gene.

[2417] The mouse gene of interest is Mlstd2 (male sterility domain containing 2), ortholog of human MLSTD2. Aliases include FAR1, 2600011M19Rik, 3732409C05Rik, FAR1, FLJ22728, and fatty acyl CoA reductase 1.

[2418] MLSTD2 is a peroxisomal enzyme that catalyzes the formation of fatty alcohols by reducing fatty acyl-CoA with co-substrate NADPH, preferring unsaturated fatty acids of 16 or 18 carbons. The enzyme is expressed primarily in preputial gland, a type of sebaceous gland, and in brain, a lipid ether-rich tissue. MLSTD2 likely plays a role in the biosynthesis of wax monoesters and lipid ethers (Cheng and Russell, J Biol Chem 279(36):37789-97 (2004)).

[2419] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00122 wt het hom Total Observed 18 30 16 64 Expected 16 32 16 64

Chi-Sq.=3.51 Significance=0.17290725 (hom/n)=0.31 Avg. Litter Size=8

Mutation Information

[2420] Mutation Type: Homologous Recombination (standard) Description: Coding exons 1 and 2 were targeted (NCBI accession NM.sub.--027379.1). 1. Wild-type Expression Panel: Expression of the target gene was detected in embryonic stem (ES) cells and in brain, spinal cord, eye, thymus, spleen, lung, and kidney among the 13 adult tissue samples tested by RT-PCR. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[2421] 66.51.1. Phenotypic Analysis (for Disrupted Gene: DNA94849-2960 (UNQ2423)

[2422] (a) Overall Phenotypic Summary:

[2423] Mutation of the gene encoding the ortholog of human male sterility domain containing 2 (MLSTD2) resulted in the homozygous mutant mice exhibiting a hearing impairment. The knockout (-/-) mice also showed an increased stress-induced hyperthermia and a trend towards an enhanced circadian rhythm. Microscopic analysis revealed testicular degeneration in the male mutants, consistent with the infertility noted diagnostically. In addition, decreased bone mineral content and density measurements were observed in the homozygous mutant mice, along with notably increased body fat in the female mutants. Disruption of the target gene was confirmed by Southern hybridization analysis.

[2424] (b) Pathology

Gross: The 2 male (-/-) mice available for analysis exhibited significantly decreased tesis weight in male knockouts. Microscopic: The 2 male (-/-) mice analyzed (M-214 and M-226) exhibited marked testicular degeneration characterized by large multinuclear giant cells in the seminiferous tubules and no sperm in the epididymides. The hepatocytes had cytoplasmic vacuoles characteristic of glycogen accumulation of marked and moderate intensity in the females but slight in the males. Gene Expression LacZ activity was detected in testes among the panel of tissues analyzed by immunohistochemistry.

[2425] (c) Phenotypic Analysis: CNS/Neurology

[2426] In the area of neurology, analysis focused herein on identifying in vivo validated targets for the treatment of neurological and psychiatric disorders including depression, generalized anxiety disorders, attention deficit hyperactivity disorder, obsessive compulsive disorder, schizophrenia, cognitive disorders, hyperalgesia and sensory disorders. Neurological disorders include the category defined as "anxiety disorders" which include but are not limited to: mild to moderate anxiety, anxiety disorder due to a general medical condition, anxiety disorder not otherwise specified, generalized anxiety disorder, panic attack, panic disorder with agoraphobia, panic disorder without agoraphobia, posttraumatic stress disorder, social phobia, specific phobia, substance-induced anxiety disorder, acute alcohol withdrawal, obsessive compulsive disorder, agoraphobia, bipolar disorder I or II, bipolar disorder not otherwise specified, cyclothymic disorder, depressive disorder, major depressive disorder, mood disorder, substance-induced mood disorder. In addition, anxiety disorders may apply to personality disorders including but not limited to the following types: paranoid, antisocial, avoidant behavior, borderline personality disorders, dependent, histronic, narcissistic, obsessive-compulsive, schizoid, and schizotypal.

[2427] Procedure:

[2428] Behavioral screens were performed on a cohort of 4 wild type, 4 heterozygous and 8 homozygous mutant mice. All behavioral tests were done between 12 and 16 weeks of age unless reduced viability necessitates earlier testing. Prepulse inhibition of the acoustic startle reflex

[2429] Prepulse inhibition of the acoustic startle reflex occurs when a loud 120 decibel (dB) startle-inducing tone is preceded by a softer (prepulse) tone. The PPI paradigm consists of six different trial types (70 dB background noise, 120 dB alone, 74 dB+120 dB-pp 4, 78 dB+120 dB-pp 8, 82 dB+120 dB-pp 12, and 90 dB+120 dB-pp 20) each repeated in pseudo random order six times for a total of 36 trials. The max response to the stimulus (V max) is averaged for each trial type. Animals with a 120 dB average value equal to or below 100 are excluded from analysis. The percent that the prepulse inhibits the animal's response to the startle stimulus is calculated and graphed.

[2430] Results:

PPI: Only 3/8 (-/-) mice lacked a startle response, suggesting a hearing impairment in the mutants.

[2431] Functional Observational Battery (FOB) Test--Stress-induced Hyperthermia:

[2432] The FOB is a series of situations applied to the animal to determine gross sensory and motor deficits. A subset of tests from the Irwin neurological screen that evaluates gross neurological function is used. In general, short-duration, tactile, olfactory, and visual stimuli are applied to the animal to determine their ability to detect and respond normally. These simple tests take approximately 10 minutes and the mouse is returned to its home cage at the end of testing.

[2433] Results:

Stress-Induced Hyperthermia: The (-/-) mice exhibited an increased stress-induced hyperthermia when compared with the value for their gender-matched (+/+) littermates and the historical mean, suggesting a increased anxiety-like response in the mutants. These results are consistent with the circadian rhythm neurological testing. Thus, PRO4981 polypeptides or agonists thereof would be useful in the treatment of anxiety related disorders.

[2434] Circadian Test Description:

[2435] Female mice are individually housed at 4 pm on the first day of testing in 48.2 cm.times.26.5 cm home cages and administered food and water ad libitum. Animals are exposed to a 12-hour light/dark cycle with lights turning on at 7 am and turning off at 7 pm. The system software records the number of beam interruptions caused by the animal's movements, with beam breaks automatically divided into ambulations. Activity is recorded in 60, one-hour intervals during the three-day test. Data generated are displayed by median activity levels recorded for each hour (circadian rhythm) and median total activity during each light/dark cycle (locomotor activity) over the three-day testing period.

[2436] Results:

Circadian: The (-/-) mice exhibited increased ambulatory counts during the 12-hour habituation period of home-cage activity testing when compared with their gender-matched (+/+) littermates and the historical mean. These results demonstrate an enhanced circadian rhythm Home-cage activity testing is also suggestive of increased activity or hyperactivity which could be related to an anxiety-like response.

[2437] (d) Cardiology/Blood Pressure and Heart Rate

[2438] Description:

[2439] Systolic blood pressure is measured via a noninvasive tail-cuff method for four days on the Visitech BP-2000 Blood Pressure Analysis System. The blood pressure is measured ten times each day for four days.

Blood Pressure Results:

[2440] The (-/-) mouse exhibited decreased systolic blood pressure when compared to its gender-matched (+/+) littermates and the historical mean.

[2441] (e) Phenotypic Analysis: Metabolism--Blood Chemistry

[2442] In the area of metabolism, targets may be identified for the treatment of diabetes. Blood chemistry phenotypic analysis includes blood glucose measurements. The COBAS Integra 400 (mfr: Roche) was used for running blood chemistry tests on the mice. In addition to measuring blood glucose levels the following blood chemistry tests are also routinely performed: Alkaline Phosphatase; Alanine Amino-Transferase; Albumin; Bilirubin; Phosphorous; Creatinine; BUN=Blood Urea Nitrogen; Calcium; Uric Acid; Sodium; Potassium; and Chloride. In the area of metabolism, targets may be identified for the treatment of diabetes.

[2443] Results:

Blood Chemistry: Both male and female the (-/-) mice exhibited a decreased mean serum calcium level. The decreased calcium levels is consistent with the observation of decreased bone mineral content and density measurements.

[2444] Phenotypic Analysis Metabolism--Blood Chemistry/Glucose Tolerance

[2445] In the area of metabolism, targets may be identified for the treatment of diabetes. Blood chemistry phenotypic analysis includes blood glucose measurements. The COBAS Integra 400 (mfr: Roche) was used for running blood chemistry tests on the mice. In the area of metabolism, targets may be identified for the treatment of diabetes. Blood chemistry phenotypic analysis includes glucose tolerance tests to measure insulin sensitivity and changes in glucose metabolism. Abnormal glucose tolerance test results may indicate but may not be limited to the following disorders or conditions: Diabetes Type 1 and Type 2, Syndrome X, various cardiovascular diseases and/or obesity.

[2446] Procedure: A cohort of 2 wild type and 4 homozygous mice were used in this assay. The glucose tolerance test is the standard for defining impaired glucose homeostasis in mammals. Glucose tolerance tests were performed using a Lifescan glucometer. Animals were injected IP at 2 g/kg with D-glucose delivered as a 20% solution and blood glucose levels were measured at 0, 30, 60 and 90 minutes after injection.

[2447] Results:

[2448] Blood Glucose Levels/Glucose Tolerance Test:

[2449] The (-/-) mice exhibited a significantly impaired glucose tolerance when placed on a high fat diet compared with their gender-matched (+/+) littermates and the historical means.

[2450] These studies indicated that (-/-) mice exhibit a decreased or impaired glucose tolerance in the presence of normal fasting glucose at all 3 intervals tested when compared with their gender-matched (+/+) littermates and the historical means. Thus, knockout mutant mice exhibited the phenotypic pattern of an impaired glucose homeostasis, and therefore PRO4981 polypeptides (or agonists thereof) or its encoding gene would be useful in the treatment of conditions associated with an impaired glucose homeostasis and/or various cardiovascular diseases, including diabetes.

[2451] (g) Bone Metabolism & Body Diagnostics

[2452] (1) Tissue Mass & Lean Body Mass Measurements--Dexa

[2453] Dexa Analysis--Test Description:

[2454] Procedure: A cohort of 4 wild type, 4 heterozygotes and 8 homozygotes were tested in this assay. Dual Energy X-ray Absorptiometry (DEXA) has been used successfully to identify changes in total tissue mass (TTM).

[2455] The mouse was anesthetized by intraperitoneal injection of Avertin (1.25% 2,2,2,-tribromoethanol, 20 ml/kg body weight), body length and weight were measured, and then the mouse was placed in a prone position on the platform of the PIXImus.TM. Densitometer (Lunar Inc.) for a DEXA scan. Using Lunar PIXImus software, the bone mineral density (BMD) and fat composition (% fat) and total tissue mass (TTM) were determined in the regions of interest (ROI, i.e., whole body, vertebrae, and both femurs).

[2456] Body Measurements (Body Length & Weight):

[2457] Body Measurements: A measurement of body length and weight was performed at approximately 16 weeks of age.

[2458] Results:

Body Weight and Length: The male (-/-) mice exhibited decreased mean body weight and mean body length when compared with their gender-matched (+/+) littermates and the historical mean. Fertility: The male (-/-) mouse available for analysis produced no pups after 40 days of breeding and 4 matings with female (-/-) mice.

[2459] (2) Bone Metabolism: Radiology Phenotypic Analysis

[2460] In the area of bone metabolism, targets were identified herein for the treatment of arthritis, osteoporosis, osteopenia and osteopetrosis as well as identifying targets that promote bone healing. Tests included: [2461] DEXA for measurement of bone mineral density on femur and vertebra [2462] MicroCT for very high resolution and very high sensitivity measurements of bone mineral density for both trabecular and cortical bone.

[2463] Dexa Analysis--Test Description:

[2464] Procedure: A cohort of 4 wild type, 4 heterozygotes and 8 homozygotes were tested in this assay. Dual Energy X-ray Absorptiometry (DEXA) has been used successfully to identify changes in bone. Anesthetized animals were examined and bone mineral content (BMC), BMC/LBM ratios, volumetric bone mineral density (vBMD), total body BMD, femur BMD and vertebra BMD were measured.

[2465] The mouse was anesthetized by intraperitoneal injection of Avertin (1.25%.RTM. 2,2,2,-tribromoethanol, 20 ml/kg body weight), body length and weight were measured, and then the mouse was placed in a prone position on the platform of the PIXImus.TM. Densitometer (Lunar Inc.) for a DEXA scan. Using Lunar PIXImus software, the bone mineral density (BMD) and fat composition (% fat) and total tissue mass (TTM) were determined in the regions of interest (ROI) [i.e., whole body, vertebrae, and both femurs].

[2466] Bone MicroCT Analysis:

[2467] Procedure: MicroCT was also used to get very sensitive measurements of BMD. One vertebra and 1 femur were taken from a cohort of 4 wild type and 8 homozygous mice. Measurements were taken of lumbar 5 vertebrae trabecular bone volume, trabecular thickness, connectivity density and midshaft femur total bone area and cortical thickness. The .mu.CT40 scans provided detailed information on bone mass and architecture. Multiple bones were placed into sample holders and scanned automatically. Instrument software was used to select regions of interest for analysis. Trabecular bone parameters were analyzed in the fifth lumbar vertebrae (LV5) at 16 micrometer resolution and cortical bone parameters were analyzed in the femur midshaft at a resolution of 20 micrometers.

[2468] Results:

DEXA: The male and female (-/-) mice exhibited decreased mean lean body mass, bone mineral content, and bone mineral density in total body and vertebrae when compared with that of their gender-matched (+/+) littermates and the historical means. The female (-/-) mice also exhibited an increased mean total tissue mass and slight increase in total fat mass, and percent total body fat. Micro CT: The male (-/-) mice exhibited decreased mean femoral mid-shaft cross-sectional area when compared with that of their gender-matched (+/+) littermates and the historical mean.

[2469] The (-/-) mice analyzed by DEXA and bone micro CT analysis exhibited decreased bone measurements when compared with their (+/+) littermates, suggestive of abnormal bone disorders. However, the mutant (-/-) mice also exhibited decreased body weight and length and lean body mass as well as infertility in male (-/-) mice. On the other hand, female (-/-) mice exhibited a slight increase in mean percentage of body fat. These observations suggest that for the most part male mutant mice deficient in the gene which encodes PRO4981 polypeptides leads to metabolic disorders associated with growth retardation in (-/-) mice but also abnormal bone measurements reflective of osteoporosis. Thus, PRO4981 polypeptides or agonists thereof would be useful in the treatment of bone related disorders such as osteoporosis or would be useful in maintaining bone homeostasis. Antagonists (or inhibitors) of PRO4981 polypeptides or its encoding gene would lead to abnormal or pathological bone disorders including inflammatory diseases associated with abnormal bone metabolism including arthritis, osteoporosis and osteopenia.

[2470] 66.52. Generation and Analysis of Mice Comprising DNA115291-2681 (UNQ2501) Gene Disruptions

[2471] In these knockout experiments, the gene encoding PRO5801 polypeptides (designated as DNA115291-2681) (UNQ2501) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: BC026546 Mus musculus interleukin 17 receptor B, mRNA (cDNA clone MGC:35924 IMAGE:5042466); protein reference: Q9.TIP3 ACCESSION:Q9JIP3 NID: Mus musculus (Mouse). INTERLEUKIN-17B RECEPTOR PRECURSOR (IL-17B RECEPTOR) (IL-17 RECEPTOR HOMOLOG 1) (IL-17RH1) (IL17RH1) (IL-17ER); the human gene sequence reference: NM.sub.--018725 Homo sapiens interleukin 17 receptor B (IL17RB), transcript variant 1; the human protein sequence corresponds to reference: Q9NRM6 ACCESSION:Q9NRM6 NID: Homo sapiens (Human). INTERLEUKIN-17B RECEPTOR PRECURSOR (IL-17B RECEPTOR) (IL-17 RECEPTOR HOMOLOG 1) (IL-17RH1) (IL17RH1) (CYTOKINE RECEPTOR CRL4).

[2472] The mouse gene of interest is Il17rb (interleukin 17 receptor B), ortholog of human IL17RB. Aliases include Evi27, Il17br, IL-17ER, IL17RH1, CRL4, MGC5245, IL-17B receptor, cytokine receptor CRL4, interleukin 17B receptor, interleukin 17 receptor homolog, interleukin 17 receptor homolog 1, and ecotropic viral integration site 27.

[2473] IL17RB is a type I plasma membrane protein that functions as a receptor for cytokines IL17E and IL17B. The receptor is capable of activating nuclear factor kappaB and stimulating production of proinflammatory chemokine IL-8. IL17RB is expressed in liver, kidney, pancreas, testis, colon, brain, and small intestine. IL17RB likely plays a role in inflammation and may participate in various disease processes, such as rheumatoid arthritis, psoriasis, multiple sclerosis, tumor growth promotion, and transplant rejection (Lee et al, J Biol Chem 276(2):1660-4 (2001); Tian et al, Oncogene 19(17):2098-109 (2000); Shi et al, J Biol Chem 275(25):19167-76 (2000); Moseley et al, Cytokine Growth Factor Rev 14(2):155-74 (2003)).

[2474] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00123 wt het hom Total Observed 19 34 24 77 Expected 19.25 38.5 19.25 77

Chi-Sq.=2.18 Significance=0.33621648 (hom/n)=0.29 Avg. Litter Size=9

Mutation Information

[2475] Mutation Type: Homologous Recombination (standard) Description: Coding exons 1 through 4 were targeted (NCBI accession NM.sub.--019583.1). 1. Wild-type Expression Panel: Expression of the target gene was detected in all 13 adult tissue samples tested by RT-PCR, except skeletal muscle, bone, and heart. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[2476] 66.52.1. Phenotypic Analysis (for Disrupted Gene: DNA115291-2681 (UNQ2501)

[2477] (a) Overall Phenotypic Summary:

[2478] Mutation of the gene encoding the ortholog of human interleukin 17 receptor B (IL17RB) resulted in the (-/-) mice exhibited an enhanced glucose tolerance. Gene disruption was confirmed by Southern blot.

[2479] (b) Phenotypic Analysis: Metabolism--Blood Chemistry/Glucose Tolerance

[2480] In the area of metabolism, targets may be identified for the treatment of diabetes. Blood chemistry phenotypic analysis includes blood glucose measurements. The COBAS Integra 400 (mfr: Roche) was used for running blood chemistry tests on the mice. In the area of metabolism, targets may be identified for the treatment of diabetes. Blood chemistry phenotypic analysis includes glucose tolerance tests to measure insulin sensitivity and changes in glucose metabolism. Abnormal glucose tolerance test results may indicate but may not be limited to the following disorders or conditions: Diabetes Type 1 and Type 2, Syndrome X, various cardiovascular diseases and/or obesity.

[2481] Procedure: A cohort of 2 wild type and 4 homozygous mice were used in this assay. The glucose tolerance test is the standard for defining impaired glucose homeostasis in mammals. Glucose tolerance tests were performed using a Lifescan glucometer. Animals were injected IP at 2 g/kg with D-glucose delivered as a 20% solution and blood glucose levels were measured at 0, 30, 60 and 90 minutes after injection.

[2482] Results:

[2483] Glucose Tolerance Test: The male mutant (-/-) mice on a high fat diet exhibited an enhanced glucose tolerance when compared with their gender-matched (+/+) littermates.

[2484] In these studies the mutant (-/-) mice showed an increased or enhanced glucose tolerance in the presence of normal fasting glucose at all 3 intervals tested when compared with their gender-matched (+/+) littermates and the historical means. Thus, knockout mice exhibited an increased insulin sensitivity or the opposite phenotypic pattern of an impaired glucose homeostasis, and as such antagonists (inhibitors) to PRO5801 polypeptides or its encoding gene would be useful in the treatment of an impaired glucose homeostasis.

66.53. Generation and Analysis of Mice Comprising DNA96988-2685 (UNQ2507) Gene Disruptions

[2485] In these knockout experiments, the gene encoding PRO5995 polypeptides (designated as DNA96988-2685) (UNQ2507) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: NM.sub.--146241 ACCESSION:NM.sub.--146241 NID: gi 22122816 ref NM.sub.--146241.1 Mus musculus thyrotropin-releasing hormone degrading ectoenzyme (Trhde-pending); protein reference: Q8K093 ACCESSION:Q8K093 NID: Mus musculus (Mouse). Hypothetical protein; the human gene sequence reference: NM.sub.--013381 ACCESSION:NM.sub.--013381 NID: gi 7019560 ref NM.sub.--013381.1 Homo sapiens thyrotropin-releasing hormone degrading ectoenzyme (TRHDE); the human protein sequence corresponds to reference: Q6UWJ4 ACCESSION:Q6UWJ4 NID: Homo sapiens (Human). TRHDE.

[2486] The mouse gene of interest is Trhde (thyrotropin-releasing hormone degrading ectoenzyme), ortholog of human TRHDE. Aliases include MGC40831, 9330155P21Rik, PAP-II, pyroglutamyl-peptidase II, TRH-degrading ectoenzyme, TRH-DE, TRH-specific aminopeptidase, and thyroliberinase.

[2487] TRHDE is an extracellular type II plasma membrane protein and zinc metalloprotease that catalyzes the removal of the N-terminal pyroglutamyl group from thyrotropin-releasing hormone (TRH). TRHDE likely plays a role in TRH signaling by inactivating the neuropeptide after its release. TRHDE is expressed primarily in brain but is also expressed in heart, lung, liver, skeletal muscle, and serum (Baeza et al, Life Sci 68(17):2051-60 (2001); Schomburg et al, Eur J Biochem 265(1):415-22 (1999); Kelly et al, J Biol Chem 275(22):16746-51 (2000); Schmitmeier et al, Eur J Biochem 269(4):1278-86 (2002)).

[2488] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00124 wt het hom Total Observed 27 35 27 89 Expected 22.25 44.5 22.25 89

Chi-Sq.=0.98 Significance=0.6126264 (hom/n)=0.27 Avg. Litter Size=10

Mutation Information

[2489] Mutation Type Homologous Recombination (standard) Description: Coding exon 1 was targeted (NCBI accession NM.sub.--146241.1). 1. Wild-type Expression Panel: Expression of the target gene was detected in embryonic stem (ES) cells and in all 13 adult tissue samples tested by RT-PCR, except lung, skeletal muscle, bone, and adipose. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[2490] 66.53.1. Phenotypic Analysis (for Disrupted Gene: DNA96988-2685 (UNQ2507)

[2491] (a) Overall Phenotypic Summary:

[2492] Mutation of the gene encoding the ortholog of human thyrotropin-releasing hormone degrading ectoenzyme (TRHDE) resulted in the mutant (-/-) mice exhibiting decreased mean body weight and length as well as decreased total tissue mass and lean body mass. Tail suspension testing showed increased immobility in the (-/-) mice. Gene disruption was confirmed by Southern blot.

[2493] (b) Bone Metabolism & Body Diagnostics

[2494] (1) Tissue Mass & Lean Body Mass Measurements--Dexa

[2495] Dexa Analysis--Test Description:

[2496] Procedure: A cohort of 4 wild type, 4 heterozygotes and 8 homozygotes were tested in this assay. Dual Energy X-ray Absorptiometry (DEXA) has been used successfully to identify changes in total tissue mass (TTM).

[2497] The mouse was anesthetized by intraperitoneal injection of Avertin (1.25% 2,2,2,-tribromoethanol, 20 ml/kg body weight), body length and weight were measured, and then the mouse was placed in a prone position on the platform of the PIXImus.TM. Densitometer (Lunar Inc.) for a DEXA scan. Using Lunar PIXImus software, the bone mineral density (BMD) and fat composition (To fat) and total tissue mass (TTM) were determined in the regions of interest (ROI, i.e., whole body, vertebrae, and both femurs).

[2498] Body Measurements (Body Length & Weight):

[2499] Body Measurements: A measurement of body length and weight was performed at approximately 16 weeks of age.

[2500] Results:

Body Weight and Length: The male (-/-) mice exhibited decreased mean body weight and mean body length when compared with their gender-matched (+/+) littermates and the historical mean.

[2501] (2) Bone Metabolism: Radiology Phenotypic Analysis

[2502] In the area of bone metabolism, targets were identified herein for the treatment of arthritis, osteoporosis, osteopenia and osteopetrosis as well as identifying targets that promote bone healing. Tests included: [2503] DEXA for measurement of bone mineral density on femur and vertebra [2504] MicroCT for very high resolution and very high sensitivity measurements of bone mineral density for both trabecular and cortical bone.

[2505] Dexa Analysis--Test Description:

[2506] Procedure: A cohort of 4 wild type, 4 heterozygotes and 8 homozygotes were tested in this assay. Dual Energy X-ray Absorptiometry (DEXA) has been used successfully to identify changes in bone. Anesthetized animals were examined and bone mineral content (BMC), BMC/LBM ratios, volumetric bone mineral density (vBMD), total body BMD, femur BMD and vertebra BMD were measured.

[2507] The mouse was anesthetized by intraperitoneal injection of Avertin (1.25% 2,2,2,-tribromoethanol, 20 ml/kg body weight), body length and weight were measured, and then the mouse was placed in a prone position on the platform of the PIXImus.TM. Densitometer (Lunar Inc.) for a DEXA scan. Using Lunar PIXImus software, the bone mineral density (BMD) and fat composition (% fat) and total tissue mass (TTM) were determined in the regions of interest (ROI) [i.e., whole body, vertebrae, and both femurs].

[2508] Bone MicroCT Analysis:

[2509] Procedure: MicroCT was also used to get very sensitive measurements of BMD. One vertebra and 1 femur were taken from a cohort of 4 wild type and 8 homozygous mice. Measurements were taken of lumbar 5 vertebra trabecular bone volume, trabecular thickness, connectivity density and midshaft femur total bone area and cortical thickness. The .mu.CT40 scans provided detailed information on bone mass and architecture. Multiple bones were placed into sample holders and scanned automatically. Instrument software was used to select regions of interest for analysis. Trabecular bone parameters were analyzed in the fifth lumbar vertebrae (LV5) at 16 micrometer resolution and cortical bone parameters were analyzed in the femur midshaft at a resolution of 20 micrometers.

[2510] Results:

DEXA: The male (-/-) mice exhibited decreased mean total tissue mass and lean body mass when compared with that of their gender-matched (+/+) littermates and the historical means.

[2511] Thus mutant (-/-) mice show a negative phenotype marked by decreased body weights and body length and total tissue mass and lean body mass which can be due to growth retardation or a tissue-wasting condition such as cachexia. Thus, antagonists or inhibitors of PRO5995 polypeptides or its encoding gene would mimic these abnormal metabolic related effects. On the other hand, PRO5995 polypeptides or agonists thereof would be useful in the prevention and/or treatment of such metabolic disorders as cachexia or other tissue wasting diseases as well as being important for normal growth development

[2512] (c) Phenotypic Analysis: CNS/Neurology

[2513] In the area of neurology, analysis focused herein on identifying in vivo validated targets for the treatment of neurological and psychiatric disorders including depression, generalized anxiety disorders, attention deficit hyperactivity disorder, obsessive compulsive disorder, schizophrenia, cognitive disorders, hyperalgesia and sensory disorders. Neurological disorders include the category defined as "anxiety disorders" which include but are not limited to: mild to moderate anxiety, anxiety disorder due to a general medical condition, anxiety disorder not otherwise specified, generalized anxiety disorder, panic attack, panic disorder with agoraphobia, panic disorder without agoraphobia, posttraumatic stress disorder, social phobia, specific phobia, substance-induced anxiety disorder, acute alcohol withdrawal, obsessive compulsive disorder, agoraphobia, bipolar disorder I or II, bipolar disorder not otherwise specified, cyclothymic disorder, depressive disorder, major depressive disorder, mood disorder, substance-induced mood disorder. In addition, anxiety disorders may apply to personality disorders including but not limited to the following types: paranoid, antisocial, avoidant behavior, borderline personality disorders, dependent, histronic, narcissistic, obsessive-compulsive, schizoid, and schizotypal.

[2514] Procedure:

[2515] Behavioral screens were performed on a cohort of 4 wild type, 4 heterozygous and 8 homozygous mutant mice. All behavioral tests were done between 12 and 16 weeks of age unless reduced viability necessitates earlier testing.

[2516] Functional Observational Battery (FOB) Test--Tail Suspension Testing:

[2517] The FOB is a series of situations applied to the animal to determine gross sensory and motor deficits. A subset of tests from the Irwin neurological screen that evaluates gross neurological function is used. In general, short-duration, tactile, olfactory, and visual stimuli are applied to the animal to determine their ability to detect and respond normally. These simple tests take approximately 10 minutes and the mouse is returned to its home cage at the end of testing.

[2518] Tail Suspension Testing:

[2519] The tail suspension test is a procedure that has been developed as a model for depressive-like behavior in rodents. In this particular setup, a mouse is suspended by its tail for 6 minutes, and in response the mouse will struggle to escape from this position. After a certain period of time the struggling of the mouse decreases and this is interpreted as a type of learned helplessness paradigm. Animals with invalid data (i.e. climbed their tail during the testing period) are excluded from analysis.

[2520] Results:

Tail Suspension2: The (-/-) mice exhibited increased immobility time when compared with the value for their (+/+) littermates and the historical mean, which is indicative of a depressive-like response in the mutants. Thus, knockout mice demonstrated a phenotype consistent with depression, generalized anxiety disorders, cognitive disorders, hyperalgesia and sensory disorders and/or bipolar disorders. Thus, PRO5995 polypeptides and agonists thereof would be useful for the treatment or amelioration of the symptoms associated with depressive disorders.

[2521] 66.54. Generation and Analysis of Mice Comprising DNA98380 (UNQ2512) Gene Disruptions

[2522] In these knockout experiments, the gene encoding PRO6001 polypeptides (designated as DNA98380) (UNQ2512) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: NM.sub.--133187 ACCESSION:NM.sub.--133187 NID: gi 18875327 ref NM.sub.--133187.1 Mus musculus RIKEN cDNA 1110032E23 gene (1110032E23Rik); protein reference: Q9ET25 ACCESSION:Q9ET25 NID: Mus musculus (Mouse). Hypothetical basic protein 1-19; the human gene sequence reference: NM.sub.--016613 Homo sapiens hypothetical protein DKFZp434L142 (DKFZp434L142); the human protein sequence corresponds to reference: Q6UWH4 ACCESSION:Q6UWH4 NID: Homo sapiens (Human). TCPD2512.

[2523] The mouse gene of interest is RIKEN cDNA 1110032E23 gene, ortholog of human hypothetical protein DKFZp434L142. Aliases include AD021 and AD036.

[2524] Hypothetical protein DKFZp434L142 is a putative 517-amino acid protein, containing no conserved domains except for a transmembrane segment near the N terminus.

[2525] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00125 wt het hom Total Observed 18 43 21 82 Expected 20.5 41 20.5 82

Chi-Sq.=8.57 Significance=0.013773624 (hom/n)=0.24 Avg. Litter Size=9

Mutation Information

[2526] Mutation Type: Homologous Recombination (standard) Description: Coding exon 1 was targeted (NCBI accession NM.sub.--133187.1). 1. Wild-type Expression Panel: Expression of the target gene was detected in embryonic stem (ES) cells and in all 13 adult tissue samples tested by RT-PCR. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[2527] 66.54.1. Phenotypic Analysis (for Disrupted Gene: DNA98380 (UNQ2512)

[2528] (a) Overall Phenotypic Summary:

[2529] Mutation of the gene encoding the ortholog of a human hypothetical protein (DKFZp434L142) resulted in impaired glucose tolerance in (-/-) mice. Male (-/-) mice also exhibited a decreased basal body temperature. Gene disruption was confirmed by Southern blot.

[2530] (b) Phenotypic Analysis: Metabolism--Blood Chemistry/Glucose Tolerance

[2531] In the area of metabolism, targets may be identified for the treatment of diabetes. Blood chemistry phenotypic analysis includes blood glucose measurements. The COBAS Integra 400 (mfr: Roche) was used for running blood chemistry tests on the mice. In the area of metabolism, targets may be identified for the treatment of diabetes. Blood chemistry phenotypic analysis includes glucose tolerance tests to measure insulin sensitivity and changes in glucose metabolism. Abnormal glucose tolerance test results may indicate but may not be limited to the following disorders or conditions: Diabetes Type 1 and Type 2, Syndrome X, various cardiovascular diseases and/or obesity.

[2532] Procedure: A cohort of 2 wild type and 4 homozygous mice were used in this assay. The glucose tolerance test is the standard for defining impaired glucose homeostasis in mammals. Glucose tolerance tests were performed using a Lifescan glucometer. Animals were injected IP at 2 g/kg with D-glucose delivered as a 20% solution and blood glucose levels were measured at 0, 30, 60 and 90 minutes after injection.

[2533] Results:

[2534] Blood Glucose Levels/Glucose Tolerance Test:

[2535] The (-/-) mice exhibited impaired glucose tolerance when placed on a high fat diet compared with their gender-matched (+/+) littermates and the historical means.

[2536] These studies indicated that (-/-) mice exhibit a decreased or impaired glucose tolerance in the presence of normal fasting glucose at all 3 intervals tested when compared with their gender-matched (+/+) littermates and the historical means. Thus, knockout mutant mice exhibited the phenotypic pattern of an impaired glucose homeostasis, and therefore PRO6001 polypeptides (or agonists thereof) or its encoding gene would be useful in the treatment of conditions associated with an impaired glucose homeostasis and/or various cardiovascular diseases, including diabetes.

[2537] 66.55. Generation and Analysis of Mice Comprising DNA105680-2710 (UNQ2543) Gene Disruptions

[2538] In these knockout experiments, the gene encoding PRO6095 polypeptides (designated as DNA105680-2710) (UNQ2543) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: NM.sub.--153528 Mus musculus RIKEN cDNA 4921521N14 gene (4921521N14Rik); protein reference: Q8CI52 ACCESSION:Q8CI52 NID: Mus musculus (Mouse). RIKEN cDNA 4921521N14; the human gene sequence reference: BC035040 Homo sapiens hypothetical protein DKFZp434C0328; the human protein sequence corresponds to reference: Q8IYSO ACCESSION:Q8IYS0 NID: Homo sapiens (Human). DKFZp434C0328 protein.

[2539] The mouse gene of interest is RIKEN cDNA 4921521N14 gene, ortholog of human hypothetical protein DKFZp434C0328. Aliases include MGC47315.

[2540] Hypothetical protein DKFZp434C0328 is a putative membrane protein, consisting of a GRAM domain, a transmembrane segment, and a potential glycosylphospholipid (GPI) anchor site. GRAM domains are found in proteins such as glucosyltransferases, myotubularins, and other membrane-associated proteins and are likely to function in membrane targeting (Doerks et al, Trends Biochem Sci 25(10):483-5 (2000)). The cell location of hypothetical protein DKFZp434C0328 is ambiguous. The transmembrane segment suggests that the hypothetical protein may be an integral membrane protein, whereas the GPI anchor site suggests that the protein may be associated with the extracellular surface of the plasma membrane. Because GRAM domains may be involved in association of proteins with target membranes (Oku et al, EMBO J. 22(13)3231-41 (2003)), hypothetical protein DKFZp434C0328 may be located on intracellular membranes.

[2541] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00126 wt het hom Total Observed 20 30 18 68 Expected 17 34 17 68

Chi-Sq.=1.86 Significance=0.39455372 (hom/n)=0.29 Avg. Litter Size=9

Mutation Information

[2542] Mutation Type: Homologous Recombination (standard) Description: Coding exons 1 and 2 were targeted (NCBI accession NM.sub.--153528.1). 1. Wild-type Expression Panel: Panel: Expression of the target gene was detected in embryonic stem (ES) cells and in all 13 adult tissue samples tested by RT-PCR, except bone. QC Images: Disruption of the target gene was confirmed by Southern hybridization analysis.

[2543] 66.55.1. Phenotypic Analysis (for Disrupted Gene: DNA105680-2710 (UNQ2543)

[2544] (a) Overall Phenotypic Summary:

[2545] Mutation of the gene encoding the ortholog of a human hypothetical protein (DKFZp434C0328) resulted in immunological abnormalities in (-/-) mice. The homozygous mutant mice exhibited increased IgM+, IgD+ B cells, and B220hi CD43- cells in bone marrow when compared with the levels for their wild-type littermates. In addition, the mutant (-/-) mice showed increased total tissue mass and fat content (accompanied by elevated cholesterol levels) with increased body weight and length as well as increased bone-mineral density measurements. Disruption of the target gene was confirmed by Southern hybridization analysis.

[2546] (b) Phenotypic Analysis: Cardiology

[2547] In the area of cardiovascular biology, targets were identified herein for the treatment of hypertension, atherosclerosis, heart failure, stroke, various coronary artery diseases, dyslipidemias such as high cholesterol (hypercholesterolemia) and elevated serum triglycerides (hypertriglyceridemia), diabetes and/or obesity. The phenotypic tests included the measurement of serum cholesterol and triglycerides.

[2548] Blood Lipids

[2549] Procedure: A cohort of 4 wild type, 4 heterozygotes and 8 homozygotes were tested in this assay. High cholesterol levels and increased triglyceride blood levels are recognized risk factors in the development of cardiovascular disease and/or diabetes. Measuring blood lipids facilitates the finding of biological switches that regulate blood lipid levels. Inhibition of factors which elevate blood lipid levels may be useful for reducing the risk for cardiovascular disease. In these blood chemistry tests, measurements were recorded using the COBAS Integra 400 (mfr: Roche).

[2550] Results:

Blood Chemistry: The male (-/-) mice exhibited an increased mean serum cholesterol level when compared with that of their gender-matched (+/+) littermates and the historical mean.

[2551] As summarized above, the (-/-) mice exhibited increased mean serum cholesterol levels when compared with their gender-matched (+/+) littermates and the historical means. Thus, mutant mice deficient in the PRO6095 gene can serve as a model for cardiovascular disease. PRO6095 polypeptides or its encoding gene would be useful in regulating blood lipids such as cholesterol. Thus, PRO6095 polypeptides or agonists thereof would be useful in the treatment of such cardiovascular diseases as hypertension, atherosclerosis, heart failure, stroke, various coronary diseases, hypercholesterolemia, diabetes and/or obesity.

[2552] (c) Immunology Phenotypic Analysis

[2553] Immune related and inflammatory diseases are the manifestation or consequence of fairly complex, often multiple interconnected biological pathways which in normal physiology are critical to respond to insult or injury, initiate repair from insult or injury, and mount innate and acquired defense against foreign organisms. Disease or pathology occurs when these normal physiological pathways cause additional insult or injury either as directly related to the intensity of the response, as a consequence of abnormal regulation or excessive stimulation, as a reaction to self, or as a combination of these.

[2554] Though the genesis of these diseases often involves multistep pathways and often multiple different biological systems/pathways, intervention at critical points in one or more of these pathways can have an ameliorative or therapeutic effect. Therapeutic intervention can occur by either antagonism of a detrimental process/pathway or stimulation of a beneficial process/pathway.

[2555] T lymphocytes (T cells) are an important component of a mammalian immune response. T cells recognize antigens which are associated with a self-molecule encoded by genes within the major histocompatibility complex (MHC). The antigen may be displayed together with MHC molecules on the surface of antigen presenting cells, virus infected cells, cancer cells, grafts, etc. The T cell system eliminates these altered cells which pose a health threat to the host mammal. T cells include helper T cells and cytotoxic T cells. Helper T cells proliferate extensively following recognition of an antigen-MHC complex on an antigen presenting cell. Helper T cells also secrete a variety of cytokines, i.e., lymphokines, which play a central role in the activation of B cells, cytotoxic T cells and a variety of other cells which participate in the immune response.

[2556] In many immune responses, inflammatory cells infiltrate the site of injury or infection. The migrating cells may be neutrophilic, eosinophilic, monocytic or lymphocytic as can be determined by histologic examination of the affected tissues. Current Protocols in Immunology, ed. John E. Coligan, 1994, John Wiley & Sons, Inc.

[2557] Many immune related diseases are known and have been extensively studied. Such diseases include immune-mediated inflammatory diseases (such as rheumatoid arthritis, immune mediated renal disease, hepatobiliary diseases, inflammatory bowel disease (IBD), psoriasis, and asthma), non-immune-mediated inflammatory diseases, infectious diseases, immunodeficiency diseases, neoplasia, and graft rejection, etc. In the area of immunology, targets were identified for the treatment of inflammation and inflammatory disorders.

[2558] In the area of immunology, targets have been identified herein for the treatment of inflammation and inflammatory disorders. Immune related diseases, in one instance, could be treated by suppressing the immune response. Using neutralizing antibodies that inhibit molecules having immune stimulatory activity would be beneficial in the treatment of immune-mediated and inflammatory diseases. Molecules which inhibit the immune response can be utilized (proteins directly or via the use of antibody agonists) to inhibit the immune response and thus ameliorate immune related disease.

[2559] The following tests were performed:

[2560] Flourescence-Activated Cell-Sorting (FACS) Analysis

[2561] Procedure:

[2562] FACS analysis of immune cell composition from peripheral blood was performed including CD4, CD8 and T cell receptor to evaluate T lymphocytes, CD19 for B lymphocytes, CD45 as a leukocyte marker and pan NK for natural killer cells. The FACS analysis was carried out on 2 wild type and 6 homozygous mice and included cells derived from thymus, spleen, bone marrow and lymph node.

[2563] In these studies, analyzed cells were isolated from thymus, peripheral blood, spleen, bone marrow and lymph nodes. Flow cytometry was designed to determine the relative proportions of CD4 and CD8 positive T cells, B cells, NK cells and monocytes in the mononuclear cell population. A Becton-Dickinson FACSCalibur 3-laser FACS machine was used to assess immune status. For Phenotypic Assays and Screening, this machine records CD4+/CD8-, CD8+/CD4-, NK, B cell and monocyte numbers in addition to the CD4+/CD8+ ratio.

[2564] The mononuclear cell profile was derived by staining a single sample of lysed peripheral blood from each mouse with a panel of six lineage-specific antibodies: CD45 PerCP, anti-TCRb APC, CD4 PE, CD8 FITC, pan-NK PE, and CD19 FITC. The two FITC and PE labeled antibodies stain mutually exclusive cell types. The samples were analyzed using a Becton Dickinson FACSCalibur flow cytometer with CellQuest software.

Results:

[2565] Tissue Specific FACS-Project: The (-/-) mice exhibited increased IgM+, IgD+ B cells, and B220hi CD43- cells in bone marrow when compared with those of their (+/+) littermates. Mature naive B cells co-express IgM and IgD and leave the bone marrow to circulate through the lymphoid organs. By knocking out the gene encoding PRO6095 polypeptides, the mutant (-/-) mice exhibited increased percentages of B cell progenitors as well as the immunoglobulins that are expressed by these cells. Thus, PRO6095 polypeptides appear to act as a negative regulator for B cell differentiation and/or proliferation. Antagonists (inhibitors) of PRO6095 polypeptides would be useful in the stimulation of B cell production.

[2566] Serum Immunoglobulin Isotyping Assay:

[2567] The Serum Immunoglobulin Isotyping Assay is performed using a Cytometric Bead Array (CBA) kit. This assay is used to rapidly identify the heavy and light chain isotypes of a mouse monoclonal antibody in a single sample. The values expressed are "relative fluorescence units" and are based on the detection of kappa light chains. Any value <6 is not significant.

[2568] Results:

[2569] The (-/-) mice exhibited increased mean serum IgG3 levels compared to their gender-matched (+/+) littermate controls, the (+/+) mice for the project run and the historical median.

[2570] The serum immunoglobulin isotyping assay revealed that homozygous adults exhibited increased serum IgG3 levels. Thus, homozygotes showed elevated serum immunoglobulins compared with the (+/+) littermates. IgG3 immunoglobulins have neutralization effects and to a lesser extent are important for activation of the complement system. These immunological abnormalities suggest that antagonists or inhibitors of PRO6095 polypeptides would stimulate the immune system and would find utility in the cases wherein this effect would be beneficial to the individual such as in the case of leukemia, and other types of cancer, and in immunocompromised patients, such as AIDS sufferers. Accordingly, PRO6095 polypeptides or agonists thereof would inhibit the immune response and would be useful candidates for suppressing harmful immune responses, e.g. in the case of graft rejection or graft-versus-host diseases.

[2571] (d) Bone Metabolism & Body Diagnostics

[2572] (1) Tissue Mass & Lean Body Mass Measurements--Dexa

[2573] Dexa Analysis--Test Description:

[2574] Procedure: A cohort of 4 wild type, 4 heterozygotes and 8 homozygotes were tested in this assay. Dual Energy X-ray Absorptiometry (DEXA) has been used successfully to identify changes in total tissue mass (TTM).

[2575] The mouse was anesthetized by intraperitoneal injection of Avertin (1.25% 2,2,2,-tribromoethanol, 20 ml/kg body weight), body length and weight were measured, and then the mouse was placed in a prone position on the platform of the PIXImus.TM. Densitometer (Lunar Inc.) for a DEXA scan. Using Lunar PIXImus software, the bone mineral density (BMD) and fat composition (% fat) and total tissue mass (TTM) were determined in the regions of interest (ROI, i.e., whole body, vertebrae, and both femurs).

[2576] Body Measurements (Body Length & Weight):

[2577] Body Measurements: A measurement of body length and weight was performed at approximately 16 weeks of age.

[2578] Results:

Body Weight and Length: The male (-/-) mice exhibited increased mean body weight and mean body length when compared with their gender-matched (+/+) littermates and the historical mean.

[2579] (2) B one Metabolism: Radiology Phenotypic Analysis

[2580] In the area of bone metabolism, targets were identified herein for the treatment of arthritis, osteoporosis, osteopenia and osteopetrosis as well as identifying targets that promote bone healing. Tests included: [2581] DEXA for measurement of bone mineral density on femur and vertebra [2582] MicroCT for very high resolution and very high sensitivity measurements of bone mineral density for both trabecular and cortical bone.

[2583] Dexa Analysis--Test Description:

[2584] Procedure: A cohort of 4 wild type, 4 heterozygotes and 8 homozygotes were tested in this assay. Dual Energy X-ray Absorptiometry (DEXA) has been used successfully to identify changes in bone. Anesthetized animals were examined and bone mineral content (BMC), BMC/LBM ratios, volumetric bone mineral density (vBMD), total body BMD, femur BMD and vertebra BMD were measured.

[2585] The mouse was anesthetized by intraperitoneal injection of Avertin (1.25% 2,2,2,-tribromoethanol, 20 ml/kg body weight), body length and weight were measured, and then the mouse was placed in a prone position on the platform of the PIXImus.TM. Densitometer (Lunar Inc.) for a DEXA scan. Using Lunar PIXImus software, the bone mineral density (BMD) and fat composition (% fat) and total tissue mass (TTM) were determined in the regions of interest (ROI) [i.e., whole body, vertebrae, and both femurs].

[2586] Bone microCT Analysis:

[2587] Procedure: MicroCT was also used to get very sensitive measurements of BMD. One vertebra and 1 femur were taken from a cohort of 4 wild type and 8 homozygous mice. Measurements were taken of lumbar 5 vertebra trabecular bone volume, trabecular thickness, connectivity density and midshaft femur total bone area and cortical thickness. The .mu.CT40 scans provided detailed information on bone mass and architecture. Multiple bones were placed into sample holders and scanned automatically. Instrument software was used to select regions of interest for analysis. Trabecular bone parameters were analyzed in the fifth lumbar vertebrae (LV5) at 16 micrometer resolution and cortical bone parameters were analyzed in the femur midshaft at a resolution of 20 micrometers.

[2588] Results:

DEXA: The male (-/-) mice exhibited increased mean total tissue mass, total fat mass, and percent total body fat when compared with those of their gender-matched (+/+) littermates and the historical means. Micro CT: The male (-/-) mice exhibited increased mean vertebral trabecular bone connectivity density when compared with the levels for their gender-matched (+/+) littermates and the historical means.

[2589] These results demonstrate that knockout mutant mice exhibit abnormal bone metabolism with increased mean vertebral trabecular bone measurements similar to osteopetrosis characterized by increase in bone mass density. Thus, it appears that PRO6095 polypeptides or agonists thereof would be useful in maintaining bone homeostasis and for bone remodeling by balancing osteoclast and osteoblast activity. In addition, antagonists or inhibitors PRO6095 polypeptides or its encoding gene would be useful in bone healing or for the treatment of other bone related abnormalities associated with increased bone mineralization.

[2590] The (-/-) mice also exhibited increased mean total tissue mass and increased mean percent total body fat and total fat mass when compared with their gender-matched (+/+) littermates and the historical means. These findings are consistent with the increased mean body weight and length exhibited by the (-/-) mutant mice.

[2591] These studies show that mutant (-/-) non-human transgenic animals exhibit a negative phenotype that is associated with obesity. Thus, PRO6095 polypeptides or agonists thereof are essential for normal growth and metabolic processes and especially would be useful in the prevention and/or treatment of lipid storage diseases and/or obesity.

[2592] 66.56. Generation and Analysis of Mice Comprising DNA 110700-2716 (UNQ2553) Gene Disruptions

[2593] In these knockout experiments, the gene encoding PRO6182 polypeptides (designated as DNA110700-2716) (UNQ2553) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: NM.sub.--020003 ACCESSION:NM.sub.--020003 NID: gi 9910457 ref NM.sub.--020003.1 Mus musculus RIKEN cDNA 0610031106 gene (0610031J06Rik); protein reference: Q9JHJ3 ACCESSION:Q9JHJ3 NID: Mus musculus (Mouse). Kidney predominant protein (RIKEN cDNA 0610031306 gene); the human gene sequence reference: NM.sub.--144580 ACCESSION:NM.sub.--144580 NID: gi 24307870 ref NM.sub.--144580.1 Homo sapiens hypothetical protein MGC31963 (MGC31963); the human protein sequence corresponds to reference: Q8WWB7 ACCESSION:Q8WWB7 NID: Homo sapiens (Human). Hypothetical protein NT2RP1000567.

[2594] The mouse gene of interest is RIKEN cDNA 0610031106 gene, ortholog of human MGC31963 (kidney predominant protein NCU-G1). Aliases include NCU-G1.

[2595] MGC31963 is a putative type I integral plasma membrane protein, containing a signal peptide and a transmembrane segment near the C-terminus. The protein is expressed at high levels in the kidney cortex and at lower levels in several other tissues (Kawamura et al, Biochem Genet. 39(1-2):33-42 (2001); Clark et al, Genome Res 13(10):2265-70 (2003)).

[2596] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00127 wt het hom Total Observed 24 40 13 77 Expected 19.25 38.5 19.25 77

Chi-Sq.=0.53 Significance=0.76720595 (hom/n)=0.26 Avg. Litter Size=9

Mutation Information

[2597] Mutation Type: Homologous Recombination (standard) Description: Coding exons 1 through 6 were targeted (NCBI accession NM.sub.--020003.1). 1. Wild-type Expression Panel: Expression of the target gene was detected in embryonic stem (ES) cells and in all 13 adult tissue samples tested by RT-PCR. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[2598] 66.56.1. Phenotypic Analysis (for Disrupted Gene: DNA110700-2716 (UNQ2553)

[2599] (a) Overall Phenotypic Summary:

[2600] Mutation of the gene encoding the ortholog of human kidney predominant protein NCU-G1 (MGC31963) resulted in hepatitis in (-/-) mice. The homozygous mutant mice exhibited signs of anemia and immunological abnormalities when compared with the levels for their wild-type littermates and the historical means. In addition, both the male and female homozygous mutant mice exhibited increased mean serum alkaline phosphatase levels and decreased mean serum glucose levels. The (-/-) mice also exhibited decreased vBMD and BMD in total body as well as decreased mean vertebral trabecular number and connectivity density. The (-/-) mice showed a trend towards increased prepulse inhibition. The livers of the mutants were smaller than normal upon gross examination; microscopic analysis revealed mild-to-moderate necrotizing hepatitis. Disruption of the target gene was confirmed by Southern hybridization analysis.

[2601] (b) Pathology

Gross: The livers of the (-/-) mice were smaller than normal, and the hepatic capsular surface was irregular and pitted due to the underlying loss/collapse of parenchyma. Microscopic: The (-/-) mice analyzed exhibited mild-to-moderate multifocal necrotizing hepatitis, characterized by minimal ongoing hepatocellular necrosis and degeneration. Minimal-to-mild subacute and active inflammatory infiltrates were also present in areas of parenchymal loss. Multifocally, there were clusters of hematopoietic cells (granulocytic) in the liver and diffuse hyperplasia of granulocytic precursors, with concurrent decreases in erythroid cell precursors, in the spleen and bone marrow. The minimal hepatic fibrosis present in these mutants reflect the known decreased hepatic fibrogenic response of C57B1/6 mice to hepatic injury. Gene Expression LacZ activity was not detected in the panel of tissues by immunohistochemical analysis.

[2602] (c) Pathology/CAT Scan

[2603] CAT-Scan Protocol:

[2604] Mice were injected with a CT contrast agent, Omnipaque 300 (Nycomed Amershan, 300 mg of iodine per ml, 0.25 ml per animal, or 2.50-3.75 g iodine/kg of body weight) intraperitoneally. After resting in the cage for .about.10 minutes, the mouse was then sedated by intraperitoneal injection of Avertin (1.25% 2,2,2,-tribromoethanol, [2605] 20 ml/kg body weight). A CAT-scan was performed using a MicroCAT scanner (ImTek, Inc.) with the anesthetized animal lying prone on the test bed. Three dimensional images were reconstructed by the Feldkamp algorithm in a cluster of workstations using an ImTek 3D RECON software.

[2606] Results:

CATScan: All 3 (-/-) mice analyzed (M-218, M-249, and F-254) exhibited reduced liver size.

[2607] (d) Immunology Phenotypic Analysis

[2608] Immune related and inflammatory diseases are the manifestation or consequence of fairly complex, often multiple interconnected biological pathways which in normal physiology are critical to respond to insult or injury, initiate repair from insult or injury, and mount innate and acquired defense against foreign organisms. Disease or pathology occurs when these normal physiological pathways cause additional insult or injury either as directly related to the intensity of the response, as a consequence of abnormal regulation or excessive stimulation, as a reaction to self, or as a combination of these.

[2609] Though the genesis of these diseases often involves multistep pathways and often multiple different biological systems/pathways, intervention at critical points in one or more of these pathways can have an ameliorative or therapeutic effect. Therapeutic intervention can occur by either antagonism of a detrimental process/pathway or stimulation of a beneficial process/pathway.

[2610] T lymphocytes (T cells) are an important component of a mammalian immune response. T cells recognize antigens which are associated with a self-molecule encoded by genes within the major histocompatibility complex (MHC). The antigen may be displayed together with MHC molecules on the surface of antigen presenting cells, virus infected cells, cancer cells, grafts, etc. The T cell system eliminates these altered cells which pose a health threat to the host mammal. T cells include helper T cells and cytotoxic T cells. Helper T cells proliferate extensively following recognition of an antigen-MHC complex on an antigen presenting cell. Helper T cells also secrete a variety of cytokines, i.e., lymphokines, which play a central role in the activation of B cells, cytotoxic T cells and a variety of other cells which participate in the immune response.

[2611] In many immune responses, inflammatory cells infiltrate the site of injury or infection. The migrating cells may be neutrophilic, eosinophilic, monocytic or lymphocytic as can be determined by histologic examination of the affected tissues. Current Protocols in Immunology, ed. John E. Coligan, 1994, John Wiley & Sons, Inc.

[2612] Many immune related diseases are known and have been extensively studied. Such diseases include immune-mediated inflammatory diseases (such as rheumatoid arthritis, immune mediated renal disease, hepatobiliary diseases, inflammatory bowel disease (IBD), psoriasis, and asthma), non-immune-mediated inflammatory diseases, infectious diseases, immunodeficiency diseases, neoplasia, and graft rejection, etc. In the area of immunology, targets were identified for the treatment of inflammation and inflammatory disorders.

[2613] In the area of immunology, targets have been identified herein for the treatment of inflammation and inflammatory disorders. Immune related diseases, in one instance, could be treated by suppressing the immune response. Using neutralizing antibodies that inhibit molecules having immune stimulatory activity would be beneficial in the treatment of immune-mediated and inflammatory diseases. Molecules which inhibit the immune response can be utilized (proteins directly or via the use of antibody agonists) to inhibit the immune response and thus ameliorate immune related disease.

[2614] The following tests were performed:

[2615] (1) Hematology Analysis:

[2616] Test Description Blood tests are carried out by Abbott's Cell-Dyn 3500R, an automated hematology analyzer. Some of its features include a five-part WBC differential. `Patient` reports can cover over 22 parameters in all.

[2617] Results:

(1) Hematology (Platelet Count):

[2618] The (-/-) mice exhibited a notably decreased mean platelet count and increased mean platelet volume when compared with their (+/+) littermates and the historical mean.

[2619] Thus, mutant mice deficient in the DNA110700-2716 gene resulted in a phenotype related to coagulation disorders. In this regard, PRO6182 polypeptides or agonists thereof would be useful in treating disorders related to abnormal blood coagulation such as hemophilia.

(2) Hematology (Red Blood Cell & Hemoglobin):

[2620] The (-/-) mice also exhibited decreased mean total white blood cell and absolute lymphocyte counts and an increased mean absolute monocyte count when compared with the levels for their (+/+) littermates and the historical means. The (-/-) mice also exhibited signs of anemia, including a decreased mean red blood cell count, hemoglobin concentration, and hematocrit and an increased red cell distribution width when compared with their (+/+) littermates and the historical means.

[2621] These results are related to a phenotype associated with anemia as well as a depressed immune system. Thus, PRO6182 polypeptides, agonists thereof or the encoding gene for PRO6182 polypeptides must be essential for normal red blood cell production and as such would be useful in the treatment of blood disorders associated with anemia or a low hematocrit. In addition, the (-/-) mice exhibit an impaired lymphocyte count important for the adaptive immune response.

[2622] (2) Serum Immunoglobulin Isotyping Assay:

[2623] The Serum Immunoglobulin Isotyping Assay is performed using a Cytometric Bead Array (CBA) kit. This assay is used to rapidly identify the heavy and light chain isotypes of a mouse monoclonal antibody in a single sample. The values expressed are "relative fluorescence units" and are based on the detection of kappa light chains. Any value <6 is not significant.

[2624] Results:

Serum Imm. 2: The (-/-) mice exhibited decreased mean serum IgG1, IgG2a, IgG2b, and IgG3 levels when compared with those of their (+/+) littermates, the (+/+) mice in the project run, and the historical medians.

[2625] The serum immunoglobulin isotyping assay revealed that hemizygous mutant adults exhibited decreased serum IgG immunoglobulin levels. Thus, homozygous (-/-) mice showed an abnormally low serum immunoglobulins compared with the (+/+) littermates. Thus, the gene encoding PRO6182 is essential for making immunoglobulins (or gamma globulins). Gamma globulins have neutralization effects and to a lesser extent are important for activation of the complement system. These immunological abnormalities suggest that PRO6182 polypeptides or agonists thereof would be useful in stimulating the immune system and would find utility in the cases wherein this effect would be beneficial to the individual such as in the case of leukemia, and other types of cancer, and in immunocompromised patients, such as AIDS sufferers. Accordingly, inhibitors (antagonists) of PRO6182 polypeptides would inhibit the immune response and would be useful candidates for suppressing harmful immune responses, e.g. in the case of graft rejection or graft-versus-host diseases.

[2626] (3) Flourescence-Activated Cell-Sorting (FACS) Analysis

[2627] Procedure:

[2628] FACS analysis of immune cell composition from peripheral blood was performed including CD4, CD8 and T cell receptor to evaluate T lymphocytes, CD19 for B lymphocytes, CD45 as a leukocyte marker and pan NK for natural killer cells. The FACS analysis was carried out on 2 wild type and 6 homozygous mice and included cells derived from thymus, spleen, bone marrow and lymph node.

[2629] In these studies, analyzed cells were isolated from thymus, peripheral blood, spleen, bone marrow and lymph nodes. Flow cytometry was designed to determine the relative proportions of CD4 and CD8 positive T cells, B cells, NK cells and monocytes in the mononuclear cell population. A Becton-Dickinson FACSCalibur 3-laser FACS machine was used to assess immune status. For Phenotypic Assays and Screening, this machine records CD4+/CD8-, CD8+/CD4-, NK, B cell and monocyte numbers in addition to the CD4+/CD8+ ratio.

[2630] The mononuclear cell profile was derived by staining a single sample of lysed peripheral blood from each mouse with a panel of six lineage-specific antibodies: CD45 PerCP, anti-TCRb APC, CD4 PE, CD8 FITC, pan-NK PE, and CD19 FITC. The two FITC and PE labeled antibodies stain mutually exclusive cell types. The samples were analyzed using a Becton Dickinson FACSCalibur flow cytometer with CellQuest software.

Results:

[2631] FACS3: The (-/-) mice exhibited an altered distribution of leukocyte subsets in the peripheral blood, characterized by a decreased mean percentage of CD8 cells and an increased mean percentage of monocytes when compared with the levels for their (+/+) littermates. Tissue Specific FACS-Mouse: The (-/-) mice exhibited increased CD11b+CD11c- cells in spleen when compared with that of their (+/+) littermates.

[2632] In summary, the (-/-) mice exhibited increased IgM+, IgD+, and B220hi CD43- cells in bone marrow when compared with those of their (+/+) littermates. Mature naive B cells co-express IgM and IgD and leave the bone marrow to circulate through the lymphoid organs. By knocking out the gene encoding PRO6095 polypeptides, the mutant (-/-) mice exhibited increased percentages of B cell progenitors as well as the immunoglobulins that are expressed by these cells. Thus, PRO6095 polypeptides appear to act as a negative regulator for B cell differentiation and/or proliferation. In addition, the (-/-) mice exhibited a decreased mean percentage of CD8 cells. CD8 proteins are the co-receptor molecules which bind/recognize the MHC Class 1 molecules for cooperation with the T cell receptor in antigen recognition.

[2633] (4) Acute Phase Response:

[2634] Test Description: Bacterial lipopolysaccharide (LPS) is an endotoxin, and as such is a potent inducer of an acute phase response and systemic inflammation. The Level I LPS mice were injected intraperitoneally (i.p.) with a sub-lethal dose of LPS in 200 .mu.L sterile saline using a 26 gauge needle. The doses were based on the average weight of the mice tested at 1 .mu.g/g body weight 3 hours after injection; a 100 ul blood sample was then taken and analyzed for the presence of TNFa, MCP-1, and IL-6 on the FACS Calibur instrument.

[2635] Results:

[2636] The (+/-) mice exhibited increased mean serum TNF-alpha, MCP-1 and especially IL-6 responses to LPS challenge when compared with their (+/+) littermates and the historical means.

[2637] In summary, the LPS endotoxin challenge demonstrated that knockout mice deficient in the gene encoding PRO6182 polypeptides exhibit immunological abnormalities when compared with their wild-type littermates. In particular, the mutant mice exhibited an increased ability to elicit an immunological response (TNF-alpha, MCP-1 and IL-6 production) when challenged with the LPS endotoxin indicating a pro-inflammatory response. TNF-alpha, MCP-1 and IL-6 contribute to the later stages of B cell activation. TNF-alpha is an important inflammatory mediator. In addition, both TNF-alpha, MCP-1 and IL-6 play a critical role in inducing the acute phase response and systemic inflammation. TNF-alpha can substitute for the membrane-bound signal in macrophage activation (thus serving as an effector molecule).

[2638] (e) Phenotypic Analysis: Metabolism--Blood Chemistry

[2639] In the area of metabolism, targets may be identified for the treatment of diabetes or other metabolic disorders. Blood chemistry phenotypic analysis includes blood glucose measurements. The COBAS Integra 400 (mfr: Roche) was used for running blood chemistry tests on the mice. In addition to measuring blood glucose levels the following blood chemistry tests are also routinely performed: Alkaline Phosphatase; Alanine Amino-Transferase; Albumin; Bilirubin; Phosphorous; Creatinine; BUN=Blood Urea Nitrogen; Calcium; Uric Acid; Sodium; Potassium; and Chloride. In the area of metabolism, targets may be identified for the treatment of diabetes.

[2640] Results:

Blood Chemistry: Both the male and female (-/-) mice exhibited increased mean serum alkaline phosphatase levels and decreased mean serum glucose levels when compared with the levels for their gender-matched (+/+) littermates and the historical means. The increased mean serum alkaline phosphatase levels are consistent with the observation of decreased mean bone-mineral density measurements as well as the observed liver abnormalities and chronic hepatitis.

[2641] (f) Phenotypic Analysis: CNS/Neurology

[2642] In the area of neurology, analysis focused herein on identifying in vivo validated targets for the treatment of neurological and psychiatric disorders including depression, generalized anxiety disorders, attention deficit hyperactivity disorder, obsessive compulsive disorder, schizophrenia, cognitive disorders, hyperalgesia and sensory disorders. Neurological disorders include the category defined as "anxiety disorders" which include but are not limited to: mild to moderate anxiety, anxiety disorder due to a general medical condition, anxiety disorder not otherwise specified, generalized anxiety disorder, panic attack, panic disorder with agoraphobia, panic disorder without agoraphobia, posttraumatic stress disorder, social phobia, specific phobia, substance-induced anxiety disorder, acute alcohol withdrawal, obsessive compulsive disorder, agoraphobia, bipolar disorder I or II, bipolar disorder not otherwise specified, cyclothymic disorder, depressive disorder, major depressive disorder, mood disorder, substance-induced mood disorder. In addition, anxiety disorders may apply to personality disorders including but not limited to the following types: paranoid, antisocial, avoidant behavior, borderline personality disorders, dependent, histronic, narcissistic, obsessive-compulsive, schizoid, and schizotypal.

[2643] Procedure:

[2644] Behavioral screens were performed on a cohort of 4 wild type, 4 heterozygous and 8 homozygous mutant mice. All behavioral tests were done between 12 and 16 weeks of age unless reduced viability necessitates earlier testing.

[2645] Prepulse Inhibition of the Acoustic Startle Reflex

[2646] Prepulse inhibition of the acoustic startle reflex occurs when a loud 120 decibel (dB) startle-inducing tone is preceded by a softer (prepulse) tone. The PPI paradigm consists of six different trial types (70 dB background noise, 120 dB alone, 74 dB+120 dB-pp 4, 78 dB+120 dB-pp 8, 82 dB+120 dB-pp 12, and 90 dB+120 dB-pp 20) each repeated in pseudo random order six times for a total of 36 trials. The max response to the stimulus (V max) is averaged for each trial type. Animals with a 120 dB average value equal to or below 100 are excluded from analysis. The percent that the prepulse inhibits the animal's response to the startle stimulus is calculated and graphed.

[2647] Results:

Sensorimotor Gating/Attention: The mutant (-/-) mice exhibited a trend towards increased prepulse inhibition of the acoustic startle reflex which is indicative of an enhanced sensorimotor gating/attention.

[2648] (g) Bone Metabolism & Body Diagnostics

[2649] (1) Tissue Mass & Lean Body Mass Measurements--Dexa

[2650] Dexa Analysis--Test Description:

[2651] Procedure: A cohort of 4 wild type, 4 heterozygotes and 8 homozygotes were tested in this assay. Dual Energy X-ray Absorptiometry (DEXA) has been used successfully to identify changes in total tissue mass (TTM).

[2652] The mouse was anesthetized by intraperitoneal injection of Avertin (1.25% 2,2,2,-tribromoethanol, 20 ml/kg body weight), body length and weight were measured, and then the mouse was placed in a prone position on the platform of the PIXImus.TM. Densitometer (Lunar Inc.) for a DEXA scan. Using Lunar PIXImus software, the bone mineral density (BMD) and fat composition (% fat) and total tissue mass (TTM) were determined in the regions of interest (ROI, i.e., whole body, vertebrae, and both femurs).

[2653] Body Measurements (Body Length & Weight):

[2654] Body Measurements: A measurement of body length and weight was performed at approximately 16 weeks of age.

[2655] Results:

Weight: The female (-/-) mice exhibited decreased mean body weight when compared with that of their gender-matched (+/+) littermates and the historical mean.

[2656] (2) Bone Metabolism: Radiology Phenotypic Analysis

[2657] In the area of bone metabolism, targets were identified herein for the treatment of arthritis, osteoporosis, osteopenia and osteopetrosis as well as identifying targets that promote bone healing. Tests included: [2658] DEXA for measurement of bone mineral density on femur and vertebra [2659] MicroCT for very high resolution and very high sensitivity measurements of bone mineral density for both trabecular and cortical bone.

[2660] Dexa Analysis--Test Description:

[2661] Procedure: A cohort of 4 wild type, 4 heterozygotes and 8 homozygotes were tested in this assay. Dual Energy X-ray Absorptiometry (DEXA) has been used successfully to identify changes in bone. Anesthetized animals were examined and bone mineral content (BMC), BMC/LBM ratios, volumetric bone mineral density (vBMD), total body BMD, femur BMD and vertebra BMD were measured.

[2662] The mouse was anesthetized by intraperitoneal injection of Avertin (1.25% 2,2,2,-tribromoethanol, 20 ml/kg body weight), body length and weight were measured, and then the mouse was placed in a prone position on the platform of the PIXImus.TM. Densitometer (Lunar Inc.) for a DEXA scan. Using Lunar PIXImus software, the bone mineral density (BMD) and fat composition (% fat) and total tissue mass (TTM) were determined in the regions of interest (ROI) [i.e., whole body, vertebrae, and both femurs].

[2663] Bone MicroCT Analysis:

[2664] Procedure: MicroCT was also used to get very sensitive measurements of BMD. One vertebra and 1 femur were taken from a cohort of 4 wild type and 8 homozygous mice. Measurements were taken of lumbar 5 vertebra trabecular bone volume, trabecular thickness, connectivity density and midshaft femur total bone area and cortical thickness. The .mu.CT40 scans provided detailed information on bone mass and architecture. Multiple bones were placed into sample holders and scanned automatically. Instrument software was used to select regions of interest for analysis. Trabecular bone parameters were analyzed in the fifth lumbar vertebrae (LV5) at 16 micrometer resolution and cortical bone parameters were analyzed in the femur midshaft at a resolution of 20 micrometers.

[2665] Results:

DEXA: The female (-/-) mice exhibited decreased mean bone mineral content, volumetric bone mineral density, and bone mineral density in total body, femurs, and vertebrae when compared with the levels for their gender-matched (+/+) littermates and the historical means. Micro CT: The male (-/-) mice exhibited decreased mean vertebral trabecular bone volume, number, and connectivity density when compared with the levels for their gender-matched (+/+) littermates and the historical means.

[2666] The (-/-) mice analyzed by DEXA and bone micro CT analysis exhibited decreased bone measurements and decreased body mass measurements when compared with their (+/+) littermates, suggestive of abnormal bone disorders. The (-/-) mice exhibited a negative bone phenotype with abnormal decreased bone measurements reflective of bone metabolic disorders. The negative bone phenotype indicates that PRO6182 polypeptides or agonists thereof would be useful for maintaining bone homeostasis. In addition, PRO6182 polypeptides would be useful in bone healing or for the treatment of arthritis or osteoporosis, whereas antagonists (or inhibitors) of PRO6182 polypeptides or its encoding gene would lead to abnormal or pathological bone disorders including inflammatory diseases associated with abnormal bone metabolism including arthritis, osteoporosis and osteopenia. The (-/-) mice also showed signs of growth retardation.

[2667] 66.57. Generation and Analysis of Mice Comprising DNA 108722-2743 (UNQ2782) Gene Disruptions

[2668] In these knockout experiments, the gene encoding PRO7170 polypeptides (designated as DNA108722-2743) (UNQ2782) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: AB098732 Mus musculus mRNA for transmembrane mucin MUC20; protein reference: Q76184 ACCESSION:Q76184 NID: Mus musculus (Mouse). Transmembrane mucin MUC20; the human gene sequence reference: BC029267 Homo sapiens mucin 20, mRNA (cDNA clone MGC:34717 IMAGE:3851952); the human protein sequence corresponds to reference: Q8N307 ACCESSION:Q8N307 NID: Homo sapiens (Human). MUC20 protein.

[2669] The mouse gene of interest is Muc20 (mucin 20), ortholog of human MUC20. Aliases include

[2670] MGC31081, FLJ14408, KIAA1359, and cDNA sequence BC026367.

[2671] MUC20 is an integral plasma membrane protein expressed primarily in renal proximal tubule epithelial cells. MUC20 is also expressed at moderate levels in placenta, colon, lung, prostate, and liver. MUC20 can interact with the Grb2 docking site on hepatocyte growth factor receptor MET, inhibiting MET signal transduction via the Grb2-Ras pathway. Moreover, MUC20 inhibits hepatocyte growth factor-induced matrix metalloproteinase expression and cell proliferation. These functions suggest that MUC20 plays a regulatory role in HGF signal transduction. MUC20 is upregulated in patients with moderate immunoglobulin A nephropathy and in experimental mouse models of glomerulonephritis, suggesting that MUC20 may play a role in the progression of glomerulonephritis and other renal injuries (Higuchi, Orita, Katsuya et al, Mol Cell Biol 24(17):7456-68 (2004); Higuchi, Orita, Nakanishi et al, J Biol Chem 279(3):1968-79 (2004)).

[2672] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00128 wt het hom Total Observed 18 35 21 74 Expected 18.5 37 18.5 74

Chi-Sq.=1.69 Significance=0.42955735 (hom/n)=0.25 Avg. Litter Size=9

Mutation Information

[2673] Mutation Type Homologous Recombination (standard) Description: Coding exons 1 and 2 were targeted (NCBI accession NM.sub.--146071.1). 1. Wild-type Expression Panel: Expression of the target gene was detected in eye; lung; kidney; and stomach, small intestine, and colon among 13 adult tissue samples tested by RT-PCR. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[2674] 66.57.1. Phenotypic Analysis (for Disrupted Gene: DNA108722-2743 (UNQ2782)

[2675] (a) Overall Phenotypic Summary:

[2676] Mutation of the gene encoding the ortholog of human mucin 20 (MUC20) resulted in immunological abnormalities in (-/-) mice. Although T cell percentages are normal in blood and spleen, there is a reduction in naive T cells in lymph nodes. IgM B cells are increased in bone marrow, but significantly decreased in lymph nodes. In addition, the male mutants exhibited a decreased mean serum insulin level. Male knockout (-/-) mice showed increased total tissue mass and lean body mass. Disruption of the target gene was confirmed by Southern hybridization analysis.

[2677] (b) Immunology Phenotypic Analysis

[2678] Immune related and inflammatory diseases are the manifestation or consequence of fairly complex, often multiple interconnected biological pathways which in normal physiology are critical to respond to insult or injury, initiate repair from insult or injury, and mount innate and acquired defense against foreign organisms. Disease or pathology occurs when these normal physiological pathways cause additional insult or injury either as directly related to the intensity of the response, as a consequence of abnormal regulation or excessive stimulation, as a reaction to self, or as a combination of these.

[2679] Though the genesis of these diseases often involves multistep pathways and often multiple different biological systems/pathways, intervention at critical points in one or more of these pathways can have an ameliorative or therapeutic effect. Therapeutic intervention can occur by either antagonism of a detrimental process/pathway or stimulation of a beneficial process/pathway.

[2680] T lymphocytes (T cells) are an important component of a mammalian immune response. T cells recognize antigens which are associated with a self-molecule encoded by genes within the major histocompatibility complex (MHC). The antigen may be displayed together with MHC molecules on the surface of antigen presenting cells, virus infected cells, cancer cells, grafts, etc. The T cell system eliminates these altered cells which pose a health threat to the host mammal. T cells include helper T cells and cytotoxic T cells. Helper T cells proliferate extensively following recognition of an antigen-MHC complex on an antigen presenting cell. Helper T cells also secrete a variety of cytokines, i.e., lymphokines, which play a central role in the activation of B cells, cytotoxic T cells and a variety of other cells which participate in the immune response.

[2681] In many immune responses, inflammatory cells infiltrate the site of injury or infection. The migrating cells may be neutrophilic, eosinophilic, monocytic or lymphocytic as can be determined by histologic examination of the affected tissues. Current Protocols in Immunology, ed. John E. Coligan, 1994, John Wiley & Sons, Inc.

[2682] Many immune related diseases are known and have been extensively studied. Such diseases include immune-mediated inflammatory diseases (such as rheumatoid arthritis, immune-mediated renal disease, hepatobiliary diseases, inflammatory bowel disease (IBD), psoriasis, and asthma), non-immune-mediated inflammatory diseases, infectious diseases, immunodeficiency diseases, neoplasia, and graft rejection, etc. In the area of immunology, targets were identified for the treatment of inflammation and inflammatory disorders.

[2683] In the area of immunology, targets have been identified herein for the treatment of inflammation and inflammatory disorders. Immune related diseases, in one instance, could be treated by suppressing the immune response. Using neutralizing antibodies that inhibit molecules having immune stimulatory activity would be beneficial in the treatment of immune-mediated and inflammatory diseases. Molecules which inhibit the immune response can be utilized (proteins directly or via the use of antibody agonists) to inhibit the immune response and thus ameliorate immune related disease.

[2684] The following test was performed:

[2685] Flourescence-Activated Cell-Sorting (FACS) Analysis

[2686] Procedure:

[2687] FACS analysis of immune cell composition from peripheral blood was performed including CD4, CD8 and T cell receptor to evaluate T lymphocytes, CD19 for B lymphocytes, CD45 as a leukocyte marker and pan NK for natural killer cells. The FACS analysis was carried out on 2 wild type and 6 homozygous mice and included cells derived from thymus, spleen, bone marrow and lymph node.

[2688] In these studies, analyzed cells were isolated from thymus, peripheral blood, spleen, bone marrow and lymph nodes. Flow cytometry was designed to determine the relative proportions of CD4 and CD8 positive T cells, B cells, NK cells and monocytes in the mononuclear cell population. A Becton-Dickinson FACSCalibur 3-laser FACS machine was used to assess immune status. For Phenotypic Assays and Screening, this machine records CD4+/CD8-, CD8+/CD4-, NK, B cell and monocyte numbers in addition to the CD4+/CD8+ ratio.

[2689] The mononuclear cell profile was derived by staining a single sample of lysed peripheral blood from each mouse with a panel of six lineage-specific antibodies: CD45 PerCP, anti-TCRb APC, CD4 PE, CD8 FITC, pan-NK PE, and CD19 FITC. The two FITC and PE labeled antibodies stain mutually exclusive cell types. The samples were analyzed using a Becton Dickinson FACSCalibur flow cytometer with CellQuest software.

Results:

[2690] Tissue Specific FACS-Project: The (-/-) mice exhibited increased IgM+ and CD117+ B cells in bone marrow when compared with those of their (+/+) littermates. Although T cell percentages are normal in blood and spleen, there is a reduction in naive T cells in lymph nodes (especially CD4+). In addition, the (-/-) mice exhibited a higher proportion of dead cells, decreased B cells, and increased CD4 and CD8 T cells in lymph node (although there is a slight decrease of CD8 cells). The (-/-) mice also exhibited an increased CD11b+CD11c- cells (monocytes) in the spleen consistent with the observation of increased monocyte count in the hematological results.

[2691] Thus, knocking out the gene which encodes PRO7170 polypeptides causes numerous immunological abnormalities presenting a complex pattern. Essentially there is a pronounced decrease in the B cell population (including pre-B or pro-B cells, immature and mature B cells), as well as a decrease in the T cell population (especially in naive T cells) in the lymph nodes. From these observations, PRO7170 polypeptides or the gene encoding PRO7170 appears to be important for the development of the population of both B and T cells in the lymph nodes. Thus, PRO7170 polypeptides would be beneficial in enhancing or development of both B cell and T cell proliferation.

[2692] (c) Blood Chemistry

[2693] Blood chemistry analysis was performed using the COBAS Integra 400 (mfr: Roche) in its clinical settings for running blood chemistry tests on mice.

[2694] Insulin Data:

[2695] Test Description: Lexicon Genetics uses the Cobra II Series Auto-Gamma Counting System in its clinical settings for running quantitative Insulin assays on mice.

[2696] Results:

Insulin: The male (-/-) mice exhibited a decreased mean serum insulin level when compared with that of their gender-matched (+/+) littermates and the historical mean.

[2697] Mutant (-/-) mice deficient in the gene encoding PRO7170 polypeptides show a phenotype marked by low insulin levels which can be indicative of diabetes. Thus, antagonists or inhibitors of PRO7170 polypeptides or its encoding gene would mimic these metabolic related effects. On the other hand, PRO7170 polypeptides or agonists thereof would be useful in the prevention and/or treatment of such metabolic disorders as diabetes.

[2698] (d) Bone Metabolism & Radiology Phenotypic Analysis

[2699] In the area of bone metabolism, targets were identified herein for the treatment of arthritis, osteoporosis, osteopenia and osteopetrosis as well as identifying targets that promote bone healing. Tests included: [2700] DEXA for measurement of bone mineral density on femur and vertebra [2701] MicroCT for very high resolution and very high sensitivity measurements of bone mineral density for both trabecular and cortical bone.

[2702] Dexa Analysis--Test Description:

[2703] Procedure: A cohort of 4 wild type, 4 heterozygotes and 8 homozygotes were tested in this assay. Dual Energy X-ray Absorptiometry (DEXA) has been used successfully to identify changes in bone. Anesthetized animals were examined and bone mineral content (BMC), BMC/LBM ratios, volumetric bone mineral density (vBMD), total body BMD, femur BMD and vertebra BMD were measured.

[2704] The mouse was anesthetized by intraperitoneal injection of Avertin (1.25% 2,2,2,-tribromoethanol, 20 ml/kg body weight), body length and weight were measured, and then the mouse was placed in a prone position on the platform of the PIXImus.TM. Densitometer (Lunar Inc.) for a DEXA scan. Using Lunar PIXImus software, the bone mineral density (BMD) and fat composition (% fat) and total tissue mass (TTM) were determined in the regions of interest (ROI) [i.e., whole body, vertebrae, and both femurs].

[2705] Results:

DEXA: Male (-/-) mice exhibited increased mean total tissue mass and lean body mass.

[2706] These studies suggest that mutant (-/-) non-human transgenic animals exhibit a negative phenotype that would be associated with obesity. Thus, PRO7170 polypeptides or agonists thereof are essential for normal growth and metabolic processes and especially would be important in the prevention and/or treatment of obesity or other growth related disorders.

[2707] 66.58. Generation and Analysis of Mice Comprising DNA108670-2744 (UNQ2783) Gene Disruptions

[2708] In these knockout experiments, the gene encoding PRO7171 polypeptides (designated as DNA108670-2744) (UNQ2783) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: AA030296 ACCESSION:AA030296 NID:1497436 Mus musculus mi02d10.r1 Soares mouse placenta 4NbMP13.5 14.5 Mus musculus cDNA clone IMAGE:459283 5\`; the human gene sequence reference: AY358621 Homo sapiens clone DNA108670 WWLS2783 (UNQ2783); the human protein sequence corresponds to reference: Q6UWV7 ACCESSION:Q6UWV7 NID: Homo sapiens (Human). WWLS2783.

[2709] The mouse gene of interest is represented by a partial cDNA (NCBI accession AA030296), which is orthologous with Homo sapiens clone DNA108670 WWLS2783 (UNQ2783). Aliases include hypothetical protein MGC52498 and PRO7171.

[2710] UNQ2783 is a putative secreted protein, consisting of 134 amino acids and containing a signal peptide (Clark et al, Genome Res 13(10):2265-70 (2003)).

[2711] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00129 wt het hom Total Observed 23 32 12 67 Expected 16.75 33.5 16.75 67

Chi-Sq.=3.5 Significance=0.17377394 (hom/n)=0.2 Avg. Litter Size=8

Mutation Information

[2712] Mutation Type Homologous Recombination (standard) Description: Coding exon 1 was targeted. 1. Wild-type Expression Panel: Expression of the target gene was detected in embryonic stem (ES) cells and in all 13 adult tissue samples tested by RT-PCR, except spleen, kidney, liver, bone, and adipose. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[2713] 66.58.1. Phenotypic Analysis (for Disrupted Gene: DNA108670-2744 (UNQ2783)

[2714] (a) Overall Phenotypic Summary:

[2715] Mutation of the gene encoding the ortholog of a human putative secreted protein (UNQ2783) resulted in the female homozygous mutant mice exhibiting increased total tissue mass and body fat when compared with that of their gender-matched wild-type littermates and the historical mean. The mutant (-/-) mice also exhibited increased triglyceride levels. Microarray analysis shows overexpression of UNQ2783 in lymphoid tumors. Gene disruption was confirmed by Southern blot.

[2716] (b) Bone Metabolism: Radiology Phenotypic Analysis

[2717] In the area of bone metabolism, targets were identified herein for the treatment of arthritis, osteoporosis, osteopenia and osteopetrosis as well as identifying targets that promote bone healing. Tests included: [2718] DEXA for measurement of bone mineral density on femur and vertebra [2719] MicroCT for very high resolution and very high sensitivity measurements of bone mineral density for both trabecular and cortical bone.

[2720] Dexa Analysis--Test Description:

[2721] Procedure: A cohort of 4 wild type, 4 heterozygotes and 8 homozygotes were tested in this assay. Dual Energy X-ray Absorptiometry (DEXA) has been used successfully to identify changes in bone. Anesthetized animals were examined and bone mineral content (BMC), BMC/LBM ratios, volumetric bone mineral density (vBMD), total body BMD, femur BMD and vertebra BMD were measured.

[2722] The mouse was anesthetized by intraperitoneal injection of Avertin (1.25% 2,2,2,-tribromoethanol, 20 ml/kg body weight), body length and weight were measured, and then the mouse was placed in a prone position on the platform of the PIXImus.TM. Densitometer (Lunar Inc.) for a DEXA scan. Using Lunar PIXImus software, the bone mineral density (BMD) and fat composition (% fat) and total tissue mass (TTM) were determined in the regions of interest (ROI) [i.e., whole body, vertebrae, and both femurs].

[2723] Results:

DEXA: The female (-/-) mice exhibited increased mean total tissue mass, percent total body fat, and total fat mass when compared with the levels for their gender-matched (+/+) littermates and the historical means.

[2724] These results demonstrate that knockout mutant mice exhibit abnormal body mass and fat measurements marked by increased mean total tissue mass, lean body mass and increased mean percent total body fat and total fat mass when compared with their gender-matched (+/+) littermates and the historical means.

[2725] These studies show that mutant (-/-) non-human transgenic animals exhibit a negative phenotype that is associated with obesity. Thus, PRO7171 polypeptides or agonists thereof are essential for normal growth and metabolic processes and especially would be useful in the prevention and/or treatment of lipid storage diseases and/or obesity.

[2726] (c) Diagnostics--Heart Rate/Blood Pressure

[2727] Description

[2728] Systolic blood pressure is measured via a noninvasive tail-cuff method for four days on the Visitech BP-2000 Blood Pressure Analysis System. The blood pressure is measured ten times each day for four days. The four days are then averaged to obtain a mouse's conscious systolic blood pressure. The single (-/-) male mouse also exhibited a decreased heart rate (>two standard deviations below historic means.

[2729] Heart rate is measured via a noninvasive tail-cuff method for four days on the Visitech BP-2000 Blood Pressure Analysis System. Heart rate is measured ten times each day for four days. The four days are then averaged to obtain a mouse's conscious heart rate.

[2730] Results:

Blood Pressure: The (-/-) mice exhibited decreased mean systolic blood pressure when compared with that of their gender-matched (+/+) littermates and the historical mean. Heart Rate The (-/-) mice exhibited an increased mean heart rate when compared with that of their gender-matched (+/+) littermates and the historical mean.

[2731] (d) Phenotypic Analysis: Cardiology

[2732] In the area of cardiovascular biology, targets were identified herein for the treatment of hypertension, atherosclerosis, heart failure, stroke, various coronary artery diseases, dyslipidemias such as high cholesterol (hypercholesterolemia) and elevated serum triglycerides (hypertriglyceridemia), diabetes and/or obesity. The phenotypic tests included the measurement of serum triglycerides.

[2733] Blood Lipids

[2734] Procedure: A cohort of 4 wild type, 4 heterozygotes and 8 homozygotes were tested in this assay. High cholesterol levels and increased triglyceride blood levels are recognized risk factors in the development of cardiovascular disease and/or diabetes. Measuring blood lipids facilitates the finding of biological switches that regulate blood lipid levels. Inhibition of factors which elevate blood lipid levels may be useful for reducing the risk for cardiovascular disease. In these blood chemistry tests, measurements were recorded using the COB AS Integra 400 (mfr: Roche).

[2735] Results:

Blood Chemistry: The (-/-) mice exhibited increased mean serum triglyceride levels when compared with their gender-matched (+/+) littermates and the historical means.

[2736] As summarized above, the (-/-) mice exhibited notably increased mean serum triglyceride levels when compared with their gender-matched (+/+) littermates and the historical means. Thus, mutant mice deficient in the PRO7171 gene can serve as a model for cardiovascular disease. PRO7171 polypeptides or its encoding gene would be useful in regulating blood lipids such as triglycerides. Thus, PRO7171 polypeptides or agonists thereof would be useful in the treatment of such cardiovascular diseases as hypertension, atherosclerosis, heart failure, stroke, various coronary diseases, hypercholesterolemia, hypertriglyceridemia, diabetes and/or obesity.

[2737] 66.59. Generation and Analysis of Mice Comprising DNA119535-2756 (UNQ2973) Gene Disruptions

[2738] In these knockout experiments, the gene encoding PRO7436 polypeptides (designated as DNA119535-2756) (UNQ2973) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: NM.sub.--177036 Mus musculus RIKEN cDNA C130022P09 gene (C130022P09Rik); protein reference: NP.sub.--796010 RIKEN cDNA C130022P09 gene [Mus musculus] gi|26347895|dbj|BAC37596.1| unnamed protein product [Mus musculus]; the human gene sequence reference: NM.sub.--020219 Homo sapiens carcinoembryonic antigen-like 1 (CEAL1); the human protein sequence corresponds to reference: Q7Z692 ACCESSION:Q7Z692 NID: Homo sapiens (Human). Carcinoembryonic antigen-like 1 precursor (UNQ2973/PRO7436).

[2739] The mouse gene of interest is RIKEN cDNA C130022P09 gene, ortholog of human CEAL1 (carcinoembryonic antigen-like 1). Aliases include DKFZp547N157.

[2740] CEAL1 is a putative type I integral membrane protein, containing a signal peptide, an immunoglobulin-like domain, and a transmembrane segment. A second CEAL1 variant lacks the immunoglobulin-like domain. By similarity to other carcinoembryonic antigen (CEA) family members, CEAL1 is likely to be located in the plasma membrane. CEAL1 is broadly expressed and may be overexpressed in subsets of clinically aggressive ovarian cancers. [Scorilas et al., Gene 310:79-89 (2003)]

[2741] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00130 wt het hom Total Observed 18 46 21 85 Expected 21.25 42.5 21.25 85

Chi-Sq.=2.38 Significance=0.30422124 (hom/n)=0.23 Avg. Litter Size=9

Mutation Information

[2742] Mutation Type Homologous Recombination (standard) Description: Coding exons 1 and 2 were targeted (NCBI accession NM.sub.--177036.2). 1. Wild-type Expression Panel: Expression of the target gene was detected in embryonic stem (ES) cells and in spinal cord; eye; thymus; spleen; lung; kidney; and stomach, small intestine, and colon among the 13 adult tissue samples tested by RT-PCR. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[2743] 66.59.1. Phenotypic Analysis (for Disrupted Gene: DNA119535-2756 (UNQ2973)

[2744] (a) Overall Phenotypic Summary:

[2745] Mutation of the gene encoding the ortholog of human carcinoembryonic antigen-like 1 (CEAL1) resulted in the homozygous mutant mice exhibiting a significant increase in mean skin fibroblast proliferation rate. The female (-/-) mice also showed decreased body weight and decreased total tissue mass with decreased levels of total body fat and cholesterol. Disruption of the target gene was confirmed by Southern hybridization analysis.

[2746] (b) Adult Skin Cell Proliferation:

[2747] Procedure: Skin cells were isolated from 16 week old animals (2 wild type and 4 homozygotes). These were developed into primary fibroblast cultures and the fibroblast proliferation rates were measured in a strictly controlled protocol. The ability of this assay to detect hyper-proliferative and hypo-proliferative phenotypes has been demonstrated with p53 and Ku80. Proliferation was measured using Brdu incorporation.

[2748] Specifically, in these studies the skin fibroblast proliferation assay was used. An increase in the number of cells in a standardized culture was used as a measure of relative proliferative capacity. Primary fibroblasts were established from skin biopsies taken from wild type and mutant mice. Duplicate or triplicate cultures of 0.05 million cells were plated and allowed to grow for six days. At the end of the culture period, the number of cells present in the culture was determined using a electronic particle counter.

[2749] Results:

Skin Proliferation: The female (-/-) mice exhibited a notably increased mean skin fibroblast proliferation rate when compared with that of their gender-matched (+/+) littermates and the historical mean.

[2750] Thus, homozygous mutant mice demonstrated a hyper-proliferative phenotype. As suggested by these observations, PRO7436 polypeptides or agonists thereof could function as tumor suppressors and would be useful in decreasing abnormal cell proliferation.

[2751] (c) Bone Metabolism & Body Diagnostics

[2752] (1) Tissue Mass & Lean Body Mass Measurements--Dexa

[2753] Dexa Analysis--Test Description:

[2754] Procedure: A cohort of 4 wild type, 4 heterozygotes and 8 homozygotes were tested in this assay. Dual Energy X-ray Absorptiometry (DEXA) has been used successfully to identify changes in total tissue mass (TTM).

[2755] The mouse was anesthetized by intraperitoneal injection of Avertin (1.25% 2,2,2,-tribromoethanol, 20 ml/kg body weight), body length and weight were measured, and then the mouse was placed in a prone position on the platform of the PIXImus.TM. Densitometer (Lunar Inc.) for a DEXA scan. Using Lunar PIXImus software, the bone mineral density (BMD) and fat composition (% fat) and total tissue mass (TTM) were determined in the regions of interest (ROI, i.e., whole body, vertebrae, and both femurs).

[2756] Body Measurements (Body Length & Weight):

[2757] Body Measurements: A measurement of body length and weight was performed at approximately 16 weeks of age.

[2758] Results:

Weight: The female (-/-) mice exhibited decreased mean body weight when compared with that of their gender-matched (+/+) littermates and the historical mean.

[2759] (2) Bone Metabolism: Radiology Phenotypic Analysis

[2760] In the area of bone metabolism, targets were identified herein for the treatment of arthritis, osteoporosis, osteopenia and osteopetrosis as well as identifying targets that promote bone healing. Tests included: [2761] DEXA for measurement of bone mineral density on femur and vertebra [2762] MicroCT for very high resolution and very high sensitivity measurements of bone mineral density for both trabecular and cortical bone.

[2763] Dexa Analysis--Test Description:

[2764] Procedure: A cohort of 4 wild type, 4 heterozygotes and 8 homozygotes were tested in this assay. Dual Energy X-ray Absorptiometry (DEXA) has been used successfully to identify changes in bone. Anesthetized animals were examined and bone mineral content (BMC), BMC/LBM ratios, volumetric bone mineral density (vBMD), total body BMD, femur BMD and vertebra BMD were measured.

[2765] The mouse was anesthetized by intraperitoneal injection of Avertin (1.25% 2,2,2,-tribromoethanol, 20 ml/kg body weight), body length and weight were measured, and then the mouse was placed in a prone position on the platform of the PIXImus.TM. Densitometer (Lunar Inc.) for a DEXA scan. Using Lunar PIXImus software, the bone mineral density (BMD) and fat composition (% fat) and total tissue mass (TTM) were determined in the regions of interest (ROI) [i.e., whole body, vertebrae, and both femurs].

[2766] Results:

DEXA: The single female (-/-) mice available for analysis exhibited decreased total tissue mass, total fat mass, and percent total body fat when compared with their gender-matched (+/+) littermates and the historical means.

[2767] The (-/-) mice analyzed by DEXA exhibited notably decreased total tissue mass and lean body mass as well as decreased fat measurements when compared with their (+/+) littermates, suggestive of growth retardation in these mutants. This in conjunction with the observations of decreased body weight and length suggest a tissue wasting condition such as cachexia or other growth related disorders. Thus, PRO7436 polypeptides or agonists thereof would be useful in the treatment or prevention of growth disorders including cachexia or other tissue wasting diseases.

[2768] (d) Phenotypic Analysis: Cardiology

[2769] In the area of cardiovascular biology, targets were identified herein for the treatment of hypertension, atherosclerosis, heart failure, stroke, various coronary artery diseases, dyslipidemias such as high cholesterol (hypercholesterolemia) and elevated serum triglycerides (hypertriglyceridemia), diabetes and/or obesity. The phenotypic tests included the measurement of serum cholesterol and triglycerides.

[2770] Blood Lipids

[2771] Procedure: A cohort of 4 wild type, 4 heterozygotes and 8 homozygotes were tested in this assay. High cholesterol levels and increased triglyceride blood levels are recognized risk factors in the development of cardiovascular disease and/or diabetes. Measuring blood lipids facilitates the finding of biological switches that regulate blood lipid levels. Inhibition of factors which elevate blood lipid levels may be useful for reducing the risk for cardiovascular disease. In these blood chemistry tests, measurements were recorded using the COBAS Integra 400 (mfr: Roche).

[2772] Results:

Blood Chemistry: The female (-/-) mice exhibited a decreased mean serum cholesterol level when compared with that of their gender-matched (+/+) littermates and the historical mean.

[2773] As summarized above, the (-/-) mice exhibited notably increased mean serum cholesterol levels when compared with their gender-matched (+/+) littermates and the historical means. Thus, mutant mice deficient in the PRO7436 gene can serve as a model for cardiovascular disease. PRO7436 polypeptides or its encoding gene would be useful in regulating blood lipids such as cholesterol.

[2774] 66.60. Generation and Analysis of Mice Comprising DNA108700-2802 (UNQ3077) Gene Disruptions

[2775] In these knockout experiments, the gene encoding PRO9912 polypeptides (designated as DNA108700-2802) (UNQ3077) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: XM.sub.--137914 PREDICTED: Mus musculus similar to ectonucleotide pyrophosphatase/phosphodiesterase 7; alkaline sphingomyelinase (LOC238011); protein reference: XP.sub.--137914 ACCESSION:XP.sub.--137914 NID: gi 51766567 ref XP.sub.--137914.4 similar to ectonucleotide pyrophosphatase/phosphodiesterase 7; alkaline sphingomyelinase [Mus musculus]; the human gene sequence reference: BC041453 ACCESSION:BC041453 NID:27371235 Homo sapiens Homo sapiens, Similar to ectonucleotide pyrophosphatase/phosphodiesterase 5, clone IMAGE:5186743; the human protein sequence corresponds to reference: Q8IUS8 ACCESSION:Q8IUS8 NID: Homo sapiens (Human). Similar to ectonucleotide pyrophosphatase/phosphodiesterase 5 (Fragment).

[2776] The mouse gene of interest is "similar to ectonucleotide pyrophosphatase/phosphodiesterase 7; alkaline sphingomyelinase," ortholog of human ENPP7 (ectonucleotide pyrophosphatase/phosphodiesterase 7). Aliases include MGC50179, ALK-SMase, and alkaline sphingomyelinase.

[2777] ENPP7 is a an ectoenzyme expressed primarily in intestine and liver that catalyzes the hydrolysis of sphingomyelin. The protein consists of a signal peptide, a type I phosphodiesterase/nucleotide pyrophosphatase domain (Pfam accession PF01663), and a hydrophobic region near the C terminus that may loosely anchor the protein to the extracellular surface of the plasma membrane (Duan et al, 2003). Unlike other sphingomyelinases, ENPP7 displays optimal catalytic activity at alkaline pH, trypsin resistance, and specific bile salt dependence. The enzyme is particularly concentrated on the extracellular surface of the microvillar membrane of intestinal epithelial cells and in bile. ENPP7 likely plays a role in dietary sphingomyelin digestion, cholesterol absorption, and colonic tumorigenesis (Duan et al, J Biol Chem 278(40):38528 (2003); Wu et al, Carcinogenesis 25(8):1327-33 (2004)).

[2778] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00131 wt het hom Total Observed 22 37 11 70 Expected 17.5 35 17.5 70

Chi-Sq.=5.18 Significance=0.075020045 (hom/n)=0.19 Avg. Litter Size=8

Mutation Information

[2779] Mutation Type Homologous Recombination (standard) Description: Coding exons 1 through 3 were targeted (XM.sub.--137914.4). 1. Wild-type Expression Panel: Expression of the target gene was detected in brain; thymus; spleen; and stomach, small intestine, and colon among the 13 adult tissue samples tested by RT-PCR. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[2780] 66.60.1. Phenotypic Analysis (for Disrupted Gene: DNA108700-2802 (UNQ3077)

[2781] (a) Overall Phenotypic Summary:

[2782] Mutation of the gene encoding the ortholog of human ectonucleotide pyrophosphatase/phosphodiesterase 7 (ENPP7) resulted in both the male and female heterozygous and homozygous mutant mice exhibiting increased total tissue mass and total body fat when compared with the measurements for their gender-matched wild-type littermates and the historical means. In addition, the knockout (-/-) mice exhibited a decreased anxiety-like response. Gene disruption was confirmed by Southern blot.

[2783] (b) Phenotypic Analysis: CNS/Neurology

[2784] In the area of neurology, analysis focused herein on identifying in vivo validated targets for the treatment of neurological and psychiatric disorders including depression, generalized anxiety disorders, attention deficit hyperactivity disorder, obsessive compulsive disorder, schizophrenia, cognitive disorders, hyperalgesia and sensory disorders. Neurological disorders include the category defined as "anxiety disorders" which include but are not limited to: mild to moderate anxiety, anxiety disorder due to a general medical condition, anxiety disorder not otherwise specified, generalized anxiety disorder, panic attack, panic disorder with agoraphobia, panic disorder without agoraphobia, posttraumatic stress disorder, social phobia, specific phobia, substance-induced anxiety disorder, acute alcohol withdrawal, obsessive compulsive disorder, agoraphobia, bipolar disorder I or II, bipolar disorder not otherwise specified, cyclothymic disorder, depressive disorder, major depressive disorder, mood disorder, substance-induced mood disorder. In addition, anxiety disorders may apply to personality disorders including but not limited to the following types: paranoid, antisocial, avoidant behavior, borderline personality disorders, dependent, histronic, narcissistic, obsessive-compulsive, schizoid, and schizotypal.

[2785] Procedure:

[2786] Behavioral screens were performed on a cohort of 4 wild type, 4 heterozygous and 8 homozygous mutant mice. All behavioral tests were done between 12 and 16 weeks of age unless reduced viability necessitates earlier testing. These tests included open field to measure anxiety, activity levels and exploration.

[2787] Open Field Test:

[2788] Several targets of known drugs have exhibited phenotypes in the open field test. These include knockouts of the seratonin transporter, the dopamine transporter (Giros et al., Nature. 1996 Feb. 15; 379(6566):606-12), and the GABA receptor (Homanics et al., Proc Natl Acad Sci USA. 1997 Apr. 15; 94(8):4143-8). An automated open-field assay was customized to address changes related to affective state and exploratory patterns related to learning. First, the field (40.times.40 cm) was selected to be relatively large for a mouse, thus designed to pick up changes in locomotor activity associated with exploration. In addition, there were 4 holes in the floor to allow for nose-poking, an activity specifically related to exploration. Several factors were also designed to heighten the affective state associated with this test. The open-field test is the first experimental procedure in which the mice are tested, and the measurements that were taken were the subjects' first experience with the chamber. In addition, the open-field was brightly lit. All these factors will heighten the natural anxiety associated with novel and open spaces. The pattern and extent of exploratory activity, and especially the center-to-total distance traveled ratio, may then be able to discern changes related to susceptibility to anxiety or depression. A large arena (40 cm.times.40 cm, VersaMax animal activity monitoring system from AccuScan Instruments) with infrared beams at three different levels was used to record rearing, hole poke, and locomotor activity. The animal was placed in the center and its activity was measured for 20 minutes. Data from this test was analyzed in five, 4-minute intervals. The total distance traveled (cm), vertical movement number (rearing), number of hole pokes, and the center to total distance ratio were recorded.

[2789] The propensity for mice to exhibit normal habituation responses to a novel environment is assessed by determining the overall change in their horizontal locomotor activity across the 5 time intervals. This calculated slope of the change in activity over time is determined using normalized, rather than absolute, total distance traveled. The slope is determined from the regression line through the normalized activity at each of the 5 time intervals. Normal habituation is represented by a negative slope value.

[2790] Results:

Openfield2: The male (-/-) mice exhibited increased sum time-in-center when compared with the value for their gender-matched (+/+) littermates and the historical mean, suggesting a decreased anxiety-like response in the male mutants.

[2791] A notable difference was observed during open field activity testing. The male (-/-) mice exhibited an increased median sum time in the center area when compared with their gender-matched (+/+) littermates, which is indicative of a decreased anxiety-like response in the mutants. Thus, knockout mice demonstrated a phenotype consistent with depression, generalized anxiety disorders, cognitive disorders, hyperalgesia and sensory disorders and/or bipolar disorders. Thus, PRO9912 polypeptides and agonists thereof would be useful for the treatment or amelioration of the symptoms associated with depressive disorders.

[2792] (c) Bone Metabolism: Radiology Phenotypic Analysis

[2793] In the area of bone metabolism, targets were identified herein for the treatment of arthritis, osteoporosis, osteopenia and osteopetrosis as well as identifying targets that promote bone healing. Tests included: [2794] DEXA for measurement of bone mineral density on femur and vertebra [2795] MicroCT for very high resolution and very high sensitivity measurements of bone mineral density for both trabecular and cortical bone.

[2796] Dexa Analysis--Test Description:

[2797] Procedure: A cohort of 4 wild type, 4 heterozygotes and 8 homozygotes were tested in this assay. Dual Energy X-ray Absorptiometry (DEXA) has been used successfully to identify changes in bone. Anesthetized animals were examined and bone mineral content (BMC), BMC/LBM ratios, volumetric bone mineral density (vBMD), total body BMD, femur BMD and vertebra BMD were measured.

[2798] The mouse was anesthetized by intraperitoneal injection of Avertin (1.25% 2,2,2,-tribromoethanol, 20 ml/kg body weight), body length and weight were measured, and then the mouse was placed in a prone position on the platform of the PIXImus.TM. Densitometer (Lunar Inc.) for a DEXA scan. Using Lunar PIXImus software, the bone mineral density (BMD) and fat composition (% fat) and total tissue mass (TTM) were determined in the regions of interest (ROI) [i.e., whole body, vertebrae, and both femurs].

[2799] Results:

DEXA: The male and female (+/-) and (-/-) mice exhibited increased total tissue mass and mean percent total body fat and total fat mass when compared with that of their gender-matched (+/+) littermates and the historical mean.

[2800] These studies show that both homozygous mutant (-/-) mice and heterozygous (+/-) mice exhibit a negative phenotype that is associated with obesity. Thus, PRO9912 polypeptides or agonists thereof are essential for normal growth and metabolic processes and especially would be useful in the prevention and/or treatment of lipid storage diseases, dyslipidemia and/or obesity.

[2801] 66.61. Generation and Analysis of Mice Comprising DNA119474-2803 (UNQ3079) Gene Disruptions

[2802] In these knockout experiments, the gene encoding PRO9917 polypeptides (designated as DNA119474-2803) (UNQ3079) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: NM.sub.--145100 Mus musculus RIKEN cDNA 2700050C12 gene (2700050C12Rik); protein reference: Q9JJ96 ACCESSION:Q9JJ96 NID: Mus musculus (Mouse). Mus musculus brain cDNA, clone MNCb-0671; the human gene sequence reference: NM.sub.--144586 Homo sapiens hypothetical protein MGC29643 (MGC29643); the human protein sequence corresponds to reference: Q8N2G4 ACCESSION:Q8N2G4 NID: Homo sapiens (Human). Hypothetical protein PSEC0181.

[2803] The mouse gene of interest is RIKEN cDNA 2700050C12 gene, ortholog of human hypothetical protein MGC29643. Aliases include C530008O16Rik.

[2804] MGC29643 is a putative secreted protein, consisting of a signal peptide and an Ly-6 antigen/uPA receptor-like domain. This domain occurs in urokinase-type plasminogen activator receptor and several glycosylphosphatidylinositol (GPI)-linked cell surface glycoproteins, such as leukocyte antigens. Proteins with this domain can function as cell adhesion or signaling molecules (SMART accession SM00134).

[2805] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00132 wt het hom Total Observed 18 29 16 63 Expected 15.75 31.5 15.75 63

Chi-Sq.=5.42 Significance=0.06653681 (hom/n)=0.23 Avg. Litter Size=8

Mutation Information

[2806] Mutation Type Homologous Recombination (standard) Description: Coding exons 1 and 2 were targeted (NCBI accession NM.sub.--145100.2). 1. Wild-type Expression Panel: Expression of the target gene was detected in brain; spinal cord; eye; thymus; lung; stomach, small intestine, and colon; and heart among the 13 adult tissue samples tested by RT-PCR. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[2807] 66.61.1. Phenotypic Analysis (for Disrupted Gene: DNA119474-2803 (UNQ3079)

[2808] (a) Overall Phenotypic Summary:

[2809] Mutation of the gene encoding the ortholog of human hypothetical protein MGC29643 resulted in the homozygous mutant mice exhibiting a decreased depressive-like response during tail suspension testing and a decreased anxiety-like response during stress-induced hyperthermia testing. In addition, both the male and female mutant mice exhibited increased heart rates when compared with those of their gender-matched wild-type littermates and the historical means. The mutant (-/-) mice also exhibited increased mean serum cholesterol levels and an impaired glucose tolerance. Both male and female (-/-) mice showed increased total tissue mass and total body fat. Disruption of the target gene was confirmed by Southern hybridization analysis.

[2810] (b) Phenotypic Analysis: Cardiology

[2811] In the area of cardiovascular biology, targets were identified herein for the treatment of hypertension, atherosclerosis, heart failure, stroke, various coronary artery diseases, dyslipidemias such as high cholesterol (hypercholesterolemia) and elevated serum triglycerides (hypertriglyceridemia), diabetes and/or obesity. The phenotypic tests included the measurement of serum cholesterol and triglycerides.

[2812] Blood Lipids

[2813] Procedure: A cohort of 4 wild type, 4 heterozygotes and 8 homozygotes were tested in this assay. High cholesterol levels and increased triglyceride blood levels are recognized risk factors in the development of cardiovascular disease and/or diabetes. Measuring blood lipids facilitates the finding of biological switches that regulate blood lipid levels. Inhibition of factors which elevate blood lipid levels may be useful for reducing the risk for cardiovascular disease. In these blood chemistry tests, measurements were recorded using the COBAS Integra 400 (mfr: Roche).

[2814] Results:

Blood Chemistry: The male (-/-) mice exhibited an increased mean serum cholesterol level when compared with that of their gender-matched (+/+) littermates and the historical mean.

[2815] As summarized above, the (-/-) mice exhibited notably increased mean serum cholesterol levels when compared with their gender-matched (+/+) littermates and the historical means. Thus, mutant mice deficient in the PRO9917 gene can serve as a model for cardiovascular disease. PRO9917 polypeptides or its encoding gene would be useful in regulating blood lipids such as cholesterol. Thus, PRO9917 polypeptides or agonists thereof would be useful in the treatment of such cardiovascular diseases as hypertension, atherosclerosis, heart failure, stroke, various coronary diseases, hypercholesterolemia, diabetes and/or obesity.

[2816] (c) Phenotypic Analysis: Metabolism--Blood Chemistry/Glucose Tolerance

[2817] In the area of metabolism, targets may be identified for the treatment of diabetes. Blood chemistry phenotypic analysis includes blood glucose measurements. The COBAS Integra 400 (mfr: Roche) was used for running blood chemistry tests on the mice. In the area of metabolism, targets may be identified for the treatment of diabetes. Blood chemistry phenotypic analysis includes glucose tolerance tests to measure insulin sensitivity and changes in glucose metabolism. Abnormal glucose tolerance test results may indicate but may not be limited to the following disorders or conditions: Diabetes Type 1 and Type 2, Syndrome X, various cardiovascular diseases and/or obesity.

[2818] Procedure: A cohort of 2 wild type and 4 homozygous mice were used in this assay. The glucose tolerance test is the standard for defining impaired glucose homeostasis in mammals. Glucose tolerance tests were performed using a Lifescan glucometer. Animals were injected IP at 2 g/kg with D-glucose delivered as a 20% solution and blood glucose levels were measured at 0, 30, 60 and 90 minutes after injection.

[2819] Results:

[2820] Blood Glucose Levels/Glucose Tolerance Test:

[2821] The male (-/-) mice exhibited impaired glucose tolerance when placed on a high fat diet compared with their gender-matched (+/+) littermates and the historical means.

[2822] These studies indicated that (-/-) mice exhibit a decreased or impaired glucose tolerance in the presence of normal fasting glucose at all 3 intervals tested when compared with their gender-matched (+/+) littermates and the historical means. Thus, knockout mutant mice exhibited the phenotypic pattern of an impaired glucose homeostasis, and therefore PRO9917 polypeptides (or agonists thereof) or its encoding gene would be useful in the treatment of conditions associated with an impaired glucose homeostasis and/or various cardiovascular diseases, including diabetes.

[2823] (d) Diagnostics--Heart Rate

[2824] Description

[2825] Heart rate is measured via a noninvasive tail-cuff method for four days on the Visitech BP-2000 Blood

[2826] Pressure Analysis System. Heart rate is measured ten times each day for four days. The four days are then averaged to obtain a mouse's conscious heart rate.

Results:

[2827] Heart Rate The (-/-) mice exhibited increased mean heart rates (.about.2 SD above the mean) when compared with those of their gender-matched (+/+) littermates and the historical means.

[2828] (e) Phenotypic Analysis: CNS/Neurology

[2829] In the area of neurology, analysis focused herein on identifying in vivo validated targets for the treatment of neurological and psychiatric disorders including depression, generalized anxiety disorders, attention deficit hyperactivity disorder, obsessive compulsive disorder, schizophrenia, cognitive disorders, hyperalgesia and sensory disorders. Neurological disorders include the category defined as "anxiety disorders" which include but are not limited to: mild to moderate anxiety, anxiety disorder due to a general medical condition, anxiety disorder not otherwise specified, generalized anxiety disorder, panic attack, panic disorder with agoraphobia, panic disorder without agoraphobia, posttraumatic stress disorder, social phobia, specific phobia, substance-induced anxiety disorder, acute alcohol withdrawal, obsessive compulsive disorder, agoraphobia, bipolar disorder I or II, bipolar disorder not otherwise specified, cyclothymic disorder, depressive disorder, major depressive disorder, mood disorder, substance-induced mood disorder. In addition, anxiety disorders may apply to personality disorders including but not limited to the following types: paranoid, antisocial, avoidant behavior, borderline personality disorders, dependent, histronic, narcissistic, obsessive-compulsive, schizoid, and schizotypal.

[2830] Procedure:

[2831] Behavioral screens were performed on a cohort of 4 wild type, 4 heterozygous and 8 homozygous mutant mice. All behavioral tests were done between 12 and 16 weeks of age unless reduced viability necessitates earlier testing.

[2832] Functional Observational Battery (FOB) Test--Tail Suspension Testing:

[2833] The FOB is a series of situations applied to the animal to determine gross sensory and motor deficits. A subset of tests from the Irwin neurological screen that evaluates gross neurological function is used. In general, short-duration, tactile, olfactory, and visual stimuli are applied to the animal to determine their ability to detect and respond normally. These simple tests take approximately 10 minutes and the mouse is returned to its home cage at the end of testing.

[2834] Tail Suspension Testing:

[2835] The tail suspension test is a procedure that has been developed as a model for depressive-like behavior in rodents. In this particular setup, a mouse is suspended by its tail for 6 minutes, and in response the mouse will struggle to escape from this position. After a certain period of time the struggling of the mouse decreases and this is interpreted as a type of learned helplessness paradigm. Animals with invalid data (i.e. climbed their tail during the testing period) are excluded from analysis.

[2836] Results:

Tail Suspension2: The (-/-) mice exhibited decreased immobility time when compared with the value for their (+/+) littermates and the historical mean, which is indicative of a decreased depressive-like response in the mutants. Thus, antagonists (inhibitors) of PRO9917 would be expected to mimic this phenotype.

[2837] Functional Observational Battery (FOB) Test--Stress-induced Hyperthermia:

[2838] The FOB is a series of situations applied to the animal to determine gross sensory and motor deficits. A subset of tests from the Irwin neurological screen that evaluates gross neurological function is used. In general, short-duration, tactile, olfactory, and visual stimuli are applied to the animal to determine their ability to detect and respond normally. These simple tests take approximately 10 minutes and the mouse is returned to its home cage at the end of testing.

[2839] Results:

Stress-Induced Hyperthermia: The (-/-) mice exhibited resistance to stress-induced hyperthermia when compared with the value for their gender-matched (+/+) littermates and the historical mean, suggesting a decreased anxiety-like response in the mutants. Thus antagonists or inhibitors of PRO9917 polypeptides would be expected to mimic this phenotype and would be useful in the treatment of anxiety related disorders.

[2840] (f) Bone Metabolism: Radiology Phenotypic Analysis

[2841] In the area of bone metabolism, targets were identified herein for the treatment of arthritis, osteoporosis, osteopenia and osteopetrosis as well as identifying targets that promote bone healing. Tests included: [2842] DEXA for measurement of bone mineral density on femur and vertebra [2843] MicroCT for very high resolution and very high sensitivity measurements of bone mineral density for both trabecular and cortical bone.

[2844] Dexa Analysis--Test Description:

[2845] Procedure: A cohort of 4 wild type, 4 heterozygotes and 8 homozygotes were tested in this assay. Dual Energy X-ray Absorptiometry (DEXA) has been used successfully to identify changes in bone. Anesthetized animals were examined and bone mineral content (BMC), BMC/LBM ratios, volumetric bone mineral density (vBMD), total body BMD, femur BMD and vertebra BMD were measured.

[2846] The mouse was anesthetized by intraperitoneal injection of Avertin (1.25% 2,2,2,-tribromoethanol, 20 ml/kg body weight), body length and weight were measured, and then the mouse was placed in a prone position on the platform of the PIXImus.TM. Densitometer (Lunar Inc.) for a DEXA scan. Using Lunar PIXImus software, the bone mineral density (BMD) and fat composition (% fat) and total tissue mass (TTM) were determined in the regions of interest (ROI) [i.e., whole body, vertebrae, and both femurs].

[2847] Results:

DEXA: The (-/-) mice exhibited increased total tissue mass and mean percent total body fat and total fat mass when compared with that of their gender-matched (+/+) littermates and the historical mean.

[2848] These studies show that mutant (-/-) mice exhibit a negative phenotype that is associated with obesity. Thus, PRO9917 polypeptides or agonists thereof are essential for normal growth and metabolic processes and especially would be useful in the prevention and/or treatment of lipid storage diseases, dyslipidemia and/or obesity.

[2849] 66.62. Generation and Analysis of Mice Comprising DNA226874 (UNQ5291) Gene Disruptions

[2850] In these knockout experiments, the gene encoding PRO37337 polypeptides (designated as DNA226874) (UNQ5291) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: NM.sub.--010128 Mus musculus epithelial membrane protein 1 (Emp1); protein reference: P47801 ACCESSION:P47801 NID: Mus musculus (Mouse). Epithelial membrane protein-1 (EMP-1) (Tumor-associated membrane protein); the human gene sequence reference: NM.sub.--001423 Homo sapiens epithelial membrane protein 1 (EMP1); the human protein sequence corresponds to reference: P54849 ACCESSION:P54849 NID: Homo sapiens (Human). Epithelial membrane protein-1 (EMP-1) (Tumor-associated membrane protein) (CL-20) (B4B protein).

[2851] The mouse gene of interest is Emp1 (epithelial membrane protein 1), ortholog of human EMP1. Aliases include tumor-associated membrane protein, TMP, B4B protein, and CL-20.

[2852] EMP1 is a putative integral plasma membrane glycoprotein, consisting of four transmembrane segments within a single PMP22 family domain (Lobsiger et al, Genomics 36(3):379-87 (1996); Marvin et al, J Biol Chem 270(48):28910-6 (1995); Ruegg et al, J Immunol 157(1):72-80 (1996)). EMP1 is structurally similar to claudins, which function as components of tight junctions, and voltage-dependent calcium channel gamma subunits, which function as regulatory subunits (InterPro accession IPR004031). EMP1 is expressed primarily in neurons during development (Wulf and Suter, Brain Res Dev Brain Res 116(2):169-80 (1999)) but is also expressed in several other tissues, including tumors (Ben-Porath and Benvenisty, Gene 183(1-2):69-75 (1996)), squamous-differentiated bronchial epithelial cells (Chen et al, Genomics 41(1):40-8 (1997)), and a subpopulation of immature B cells (Ruegg et al, J Immunol 157(1):72-80 (1996)). EMP1 may play a role in processes such as cell proliferation, development, differentiation, and cell death (Ruegg et al, J Immunol 157(1):72-80 (1996); Wang et al, World J Gastroenterol 9(3):392-8 (2003); Wulf and Suter, Brain Res Dev Brain Res 116(2):169-80 (1999)).

[2853] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00133 wt het hom Total Observed 10 41 13 64 Expected 16 32 16 64

Chi-Sq.=1.35 Significance=0.5091564 (hom/n)=0.23 Avg. Litter Size=8

Mutation Information

[2854] Mutation Type: Homologous Recombination (standard) Description: Coding exon 1 was targeted (NCBI accession NM.sub.--010128.3). 1. Wild-type Expression Panel: Expression of the target gene was detected in embryonic stem (ES) cells and in all 13 adult tissue samples tested by RT-PCR. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[2855] 66.62.1. Phenotypic Analysis (for Disrupted Gene: DNA226874 (UNQ5291)

[2856] (a) Overall Phenotypic Summary:

[2857] Mutation of the gene encoding the ortholog of human epithelial membrane protein 1 (EMP1) resulted in the mutant (-/-) mice exhibiting increased bone-mineral density measurements. Both the male and female (-/-) mice exhibited increased total tissue mass and total body fat. The female (-/-) mice also exhibited decreased mean systolic blood pressure when compared with their gender-matched (+/+) littermates and the historical mean. Embryonic expression showed a strong signal in the vasculature. Gene disruption was confirmed by Southern blot.

[2858] (b) Bone Metabolism & Radiology Phenotypic Analysis

[2859] In the area of bone metabolism, targets were identified herein for the treatment of arthritis, osteoporosis, osteopenia and osteopetrosis as well as identifying targets that promote bone healing. Tests included: [2860] DEXA for measurement of bone mineral density on femur and vertebra [2861] MicroCT for very high resolution and very high sensitivity measurements of bone mineral density for both trabecular and cortical bone.

[2862] Dexa Analysis--Test Description:

[2863] Procedure: A cohort of 4 wild type, 4 heterozygotes and 8 homozygotes were tested in this assay. Dual Energy X-ray Absorptiometry (DEXA) has been used successfully to identify changes in bone. Anesthetized animals were examined and bone mineral content (BMC), BMC/LBM ratios, volumetric bone mineral density (vBMD), total body BMD, femur BMD and vertebra BMD were measured.

[2864] The mouse was anesthetized by intraperitoneal injection of Avertin (1.25% 2,2,2,-tribromoethanol, 20 ml/kg body weight), body length and weight were measured, and then the mouse was placed in a prone position on the platform of the PIXImus.TM. Densitometer (Lunar Inc.) for a DEXA scan. Using Lunar PIXImus software, the bone mineral density (BMD) and fat composition (% fat) and total tissue mass (TTM) were determined in the regions of interest (ROI) [i.e., whole body, vertebrae, and both femurs].

[2865] Bone microCT Analysis:

[2866] Procedure: MicroCT was also used to get very sensitive measurements of BMD. One vertebra and 1 femur were taken from a cohort of 4 wild type and 8 homozygous mice. Measurements were taken of lumbar 5 vertebra trabecular bone volume, trabecular thickness, connectivity density and midshaft femur total bone area and cortical thickness. The .mu.CT40 scans provided detailed information on bone mass and architecture. Multiple bones were placed into sample holders and scanned automatically. Instrument software was used to select regions of interest for analysis. Trabecular bone parameters were analyzed in the fifth lumbar vertebrae (LV5) at 16 micrometer resolution and cortical bone parameters were analyzed in the femur midshaft at a resolution of 20 micrometers.

[2867] Results:

DEXA: The (-/-) mice exhibited increased total tissue mass and total body fat. In addition, the male (-/-) mice exhibited increased mean volumetric bone mineral density and bone mineral density in total body and femur when compared with their gender-matched (+/+) littermates and the historical means. Micro CT: The male (-/-) mice exhibited increased mean femoral mid-shaft cross-sectional area when compared with their gender-matched (+/+) littermates and the historical mean.

[2868] These results demonstrate that knockout mutant mice exhibit abnormal bone metabolism with increased bone measurements similar to osteopetrosis characterized by increase in bone mass. The knockout (-/-) mice also exhibited signs of an obesity phenotype. Thus, it appears that PRO37337 polypeptides or agonists thereof would be useful in maintaining bone homeostasis and for bone remodeling by balancing osteoclast and osteoblast activity. In addition, antagonists or inhibitors of PRO37337 polypeptides or its encoding gene would be useful in bone healing or for the treatment of other bone related abnormalities associated with increased bone mineralization. PRO37337 polypeptides or agonists thereof would also be useful for maintaining normal lipid metabolism.

[2869] 66.63. Generation and Analysis of Mice Comprising DNA227033 (UNQ5407) Gene Disruptions

[2870] In these knockout experiments, the gene encoding PRO37496 polypeptides (designated as DNA227033) (UNQ5407) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: NM.sub.--010762 Mus musculus myelin and lymphocyte protein, T-cell differentiation protein (Mal); protein reference: O09198 ACCESSION:O09198 NID: Mus musculus (Mouse). Myelin and lymphocyte protein (T-lymphocyte maturation-associated protein); the human gene sequence reference: NM.sub.--002371 ACCESSION:NM.sub.--002371 NID: gi 12408666 ref NM.sub.--002371.2 Homo sapiens mal, T-cell differentiation protein (MAL), transcript variant a; the human protein sequence corresponds to reference: P21145 ACCESSION:P21145 NID: Homo sapiens (Human). Myelin and lymphocyte protein (T-lymphocyte maturation-associated protein).

[2871] The mouse gene of interest is Mal (myelin and lymphocyte protein, T-cell differentiation protein), ortholog of human MAL (mal, T-cell differentiation protein). Aliases include MPV17, VIP17, myelin and lymphocyte protein, and T-cell differentiation protein MAL.

[2872] MAL is a lipophilic integral membrane protein, consisting of four transmembrane segments contained within a MARVEL (membrane-associated) domain (Pfam accession PF01284). MAL is found in glycolipid-enriched microdomains of epithelial cells, mature T-cells, and myelin-forming cells. Moreover, MAL has been detected in several subcellular locations, including endoplasmic reticulum, Golgi apparatus, large vesicles, and plasma membrane. The function of MAL is not clearly known; however, it may play a role in polarized glycolipid and protein transport, vesicle formation, and myelination (Marazuela and Alonso, Histol Histopathol 19(3):925-33 (2004); Puertollano et al, J Biol Chem 272(29):18311-5 (1997); Magyar et al, Gene 189(2):269-75 (1997); Erne et al, J Neurochem 82(3):550-62 (2002); Schaeren-Wiemers et al, J Cell Biol 166(5):731-42 (2004); Saravanan et al, Neurobiol Dis 16(2):396-406 (2004); Frank et al, J Neurochem 73(2):587-97 (1999); Frank, Prog Neurobiol 60(6):531-44 (2000)).

[2873] Schaeren-Wiemers and colleagues (2004) investigated the physiological role of MAL using knockout mice. They showed that myelin formation and paranode-axon interface structure were abnormal in MAL-deficient mice but not in wild-type mice. The authors concluded that MAL is critical for paranode formation in the central nervous system. They proposed that MAL likely controls trafficking or sorting of various membrane components in oligodendrocytes.

[2874] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00134 wt het hom Total Observed 21 37 18 76 Expected 19 38 19 76

Chi-Sq.=2.09 Significance=0.35169184 (hom/n)=0.24 Avg. Litter Size=9

Mutation Information

[2875] Mutation Type: Homologous Recombination (standard) Description: Coding exon 1 was targeted (NCBI accession NM.sub.--010762.2). 1. Wild-type Expression Panel: Expression of the target gene was detected in embryonic stem (ES) cells and in all 13 adult tissue samples tested by RT-PCR, except thymus, lung, liver, skeletal muscle, and bone. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[2876] 66.63.1. Phenotypic Analysis (for Disrupted Gene: DNA227033 (UNQ5407)

[2877] (a) Overall Phenotypic Summary:

[2878] Mutation of the gene encoding the ortholog of human mal, T-cell differentiation protein (MAL) resulted in the homozygous mutant mice exhibiting a decreased mean percentage of CD8 cells in the peripheral blood and decreased naive CD4 and CD8 T cells in the lymph nodes when compared with that of their wild-type littermates and the historical mean. Disruption of the target gene was confirmed by Southern hybridization analysis.

[2879] (b) Immunology Phenotypic Analysis

[2880] Immune related and inflammatory diseases are the manifestation or consequence of fairly complex, often multiple interconnected biological pathways which in normal physiology are critical to respond to insult or injury, initiate repair from insult or injury, and mount innate and acquired defense against foreign organisms. Disease or pathology occurs when these normal physiological pathways cause additional insult or injury either as directly related to the intensity of the response, as a consequence of abnormal regulation or excessive stimulation, as a reaction to self, or as a combination of these.

[2881] Though the genesis of these diseases often involves multistep pathways and often multiple different biological systems/pathways, intervention at critical points in one or more of these pathways can have an ameliorative or therapeutic effect. Therapeutic intervention can occur by either antagonism of a detrimental process/pathway or stimulation of a beneficial process/pathway.

[2882] T lymphocytes (T cells) are an important component of a mammalian immune response. T cells recognize antigens which are associated with a self-molecule encoded by genes within the major histocompatibility complex (MHC). The antigen may be displayed together with MHC molecules on the surface of antigen presenting cells, virus infected cells, cancer cells, grafts, etc. The T cell system eliminates these altered cells which pose a health threat to the host mammal. T cells include helper T cells and cytotoxic T cells. Helper T cells proliferate extensively following recognition of an antigen-MHC complex on an antigen presenting cell. Helper T cells also secrete a variety of cytokines, i.e., lymphokines, which play a central role in the activation of B cells, cytotoxic T cells and a variety of other cells which participate in the immune response.

[2883] In many immune responses, inflammatory cells infiltrate the site of injury or infection. The migrating cells may be neutrophilic, eosinophilic, monocytic or lymphocytic as can be determined by histologic examination of the affected tissues. Current Protocols in Immunology, ed. John E. Coligan, 1994, John Wiley & Sons, Inc.

[2884] Many immune related diseases are known and have been extensively studied. Such diseases include immune-mediated inflammatory diseases (such as rheumatoid arthritis, immune mediated renal disease, hepatobiliary diseases, inflammatory bowel disease (IBD), psoriasis, and asthma), non-immune-mediated inflammatory diseases, infectious diseases, immunodeficiency diseases, neoplasia, and graft rejection, etc. In the area of immunology, targets were identified for the treatment of inflammation and inflammatory disorders.

[2885] In the area of immunology, targets have been identified herein for the treatment of inflammation and inflammatory disorders. Immune related diseases, in one instance, could be treated by suppressing the immune response. Using neutralizing antibodies that inhibit molecules having immune stimulatory activity would be beneficial in the treatment of immune-mediated and inflammatory diseases. Molecules which inhibit the immune response can be utilized (proteins directly or via the use of antibody agonists) to inhibit the immune response and thus ameliorate immune related disease.

[2886] The following tests were performed:

[2887] Flourescence-Activated Cell-Sorting (FACS) Analysis/Tissue Specific FACS

[2888] Procedure:

[2889] FACS analysis of immune cell composition from peripheral blood was performed including CD4, CD8 and T cell receptor to evaluate T lymphocytes, CD19 for B lymphocytes, CD45 as a leukocyte marker and pan NK for natural killer cells. The FACS analysis was carried out on 2 wild type and 6 homozygous mice and included cells derived from thymus, spleen, bone marrow and lymph node.

[2890] In these studies, analyzed cells were isolated from thymus, peripheral blood, spleen, bone marrow and lymph nodes. Flow cytometry was designed to determine the relative proportions of CD4 and CD8 positive T cells, B cells, NK cells and monocytes in the mononuclear cell population. A Becton-Dickinson FACSCalibur 3-laser FACS machine was used to assess immune status. For Phenotypic Assays and Screening, this machine records CD4+/CD8-, CD8+/CD4-, NK, B cell and monocyte numbers in addition to the CD4+/CD8+ ratio.

[2891] The mononuclear cell profile was derived by staining a single sample of lysed peripheral blood from each mouse with a panel of six lineage-specific antibodies: CD45 PerCP, anti-TCRb APC, CD4 PE, CD8 FITC, pan-NK PE, and CD19 FITC. The two FITC and PE labeled antibodies stain mutually exclusive cell types. The samples were analyzed using a Becton Dickinson FACSCalibur flow cytometer with CellQuest software.

[2892] Results:

FACS3: The (-/-) mice exhibited an altered distribution of leukocyte subsets in the peripheral blood, characterized by a decreased mean percentage of CD8 cells and reduced percentages of naive CD4 and CD8 T cells in lymph nodes when compared with that of their (+/+) littermates.

[2893] By knocking out the gene encoding PRO37496 polypeptides, the mutant (-/-) mice exhibited a decreased mean percentage of CD8 cells and CD4 naive T cells. CD8 proteins are the co-receptor molecules which bind/recognize the MHC Class 1 molecules for cooperation with the T cell receptor in antigen recognition. Thus, PRO379496 polypeptides or agonists thereof would stimulate the immune system and would find utility in the cases wherein this effect would be beneficial to the individual such as in the case of leukemia, and other types of cancer, and in immunocompromised patients, such as AIDS sufferers. Accordingly, antagonists or inhibitors of PRO37496 polypeptides would be useful in inhibiting the immune response and would be useful candidates for suppressing harmful immune responses, e.g. in the case of graft rejection or graft-versus-host diseases.

[2894] In addition, the (-/-) mice exhibited decreased mean percentages of naive CD4 cells in the cell population when compared with their (+/+) littermates and the historical means. Thus, knocking out the gene which encodes PRO37496 polypeptides causes a decrease in the T cell population. From these observations, PRO37496 polypeptides or the gene encoding PRO37496 appears to act as a regulator of T cell proliferation. Thus, PRO37496 polypeptides would be beneficial in enhancing T cell proliferation. 66.64. Generation and Analysis of Mice Comprising DNA145841-2868 (UNQ5827) Gene Disruptions

[2895] In these knockout experiments, the gene encoding PRO19646 polypeptides (designated as DNA145841-2868) (UNQ5827) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: NM.sub.--172898 Mus musculus kin of IRRE like 2 (Drosophila) (Kirrel2); protein reference: Q7TSU7 ACCESSION:Q7TSU7 NID: Mus musculus (Mouse). Kin of IRRE-like 2; the human gene sequence reference: NM.sub.--199180 Homo sapiens kin of IRRE like 2 (Drosophila) (KIRREL2), transcript variant 3; the human protein sequence corresponds to reference: Q6UWL6 ACCESSION:Q6UWL6 NID: Homo sapiens (Human). Kin of IRRE-like protein 2 precursor (Kin of irregular chiasm-like protein 2) (Nephrin-like protein 3) (UNQ5827/PRO19646).

[2896] The mouse gene of interest is Kirrel2 (kin of IRRE like 2 [Drosophila]), ortholog of human KIRREL2. Aliases include NLG1, NEPH3, FILTRIN, MGC15718, DKFZP564A1164, C330019F22Rik, kin of irregular chiasm-like 2, X kin of IRRE like 2 (Drosophila), nephrin-like 3, and nephrin-like gene 1.

[2897] KIRREL2 is a type I integral plasma membrane protein that likely functions as a cell adhesion molecule. The protein contains a signal peptide, 5 Ig-like domains, a transmembrane segment, and a cytoplasmic C-terminus containing nine amino acids conserved in family members KIRREL and KIRREL3. The C-terminal domain of KIRREL2, like those of KIRREL and KIRREL3, is capable of interacting with podocin, a component of a structure (slit diaphragm) that functions as a glomerular filtration barrier. KIRREL2 is expressed in many different tissues but appears to be primarily expressed in pancreatic islet beta cells and in lymph nodes. Moreover, expression of KIRREL2 negatively correlates with T-cell invasion of pancreatic islets and development of diabetes in nonobese diabetic (NOD) mice. KIRREL2 may be involved in physiological processes such as glomerular filtration, pancreatic beta cell function, and immunity (Ihalmo et al, Biochem Biophys Res Commun 300(2):364-70 (2003); Sellin et al, FASEB J 17(1):115-7 (2003); Sun et al, Genomics 82(2):130-42 (2003)).

[2898] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00135 wt het hom Total Observed 14 31 13 58 Expected 14.5 29 14.5 58

[2899] Chi-Sq.=0.74 Significance=0.6907343 (hom/n)=0.22 Avg. Litter Size=8 Mutation Information

[2900] Mutation Type Homologous Recombination (standard)

Description: Coding exons 1 through 3 were targeted (NCBI accession NM.sub.--172898.1). 1. Wild-type Expression Panel: Expression of the target gene was detected in embryonic stem (ES) cells and in brain; spinal cord; eye; and stomach, small intestine, and colon among the 13 adult tissue samples tested by RT-PCR. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[2901] 66.64.1. Phenotypic Analysis (for disrupted gene: DNA145841-2868 (UNQ5827)

[2902] (a) Overall Phenotypic Summary:

[2903] Mutation of the gene encoding the ortholog of human kin of IRRE like 2 (Drosophila) (KIRREL2) resulted in the mutant (-/-) mice exhibiting decreased mean body weight and length. In addition, the male (-/-) mice showed degeneration of the seminiferous tubules. Gene disruption was confirmed by Southern blot.

[2904] (b) Pathology

Microscopic: Both of the male (-/-) mice analyzed exhibited vacuolar degeneration of the seminiferous tubules. One (-/-) mouse (M-173) also exhibited a microvesicular fatty change in the centrilobular portion of the liver. Gene Expression: Expression of the target gene was not detected in the panel of tissues by immunohistochemical analysis.

[2905] (c) Bone Metabolism & Body Diagnostics

[2906] (1) Tissue Mass & Lean Body Mass Measurements--Dexa

[2907] Dexa Analysis--Test Description:

[2908] Procedure: A cohort of 4 wild type, 4 heterozygotes and 8 homozygotes were tested in this assay. Dual Energy X-ray Absorptiometry (DEXA) has been used successfully to identify changes in total tissue mass (TTM).

[2909] The mouse was anesthetized by intraperitoneal injection of Avertin (1.25% 2,2,2,-tribromoethanol, 20 ml/kg body weight), body length and weight were measured, and then the mouse was placed in a prone position on the platform of the PIXImus.TM. Densitometer (Lunar Inc.) for a DEXA scan. Using Lunar PIXImus software, the bone mineral density (BMD) and fat composition (% fat) and total tissue mass (TTM) were determined in the regions of interest (ROI, i.e., whole body, vertebrae, and both femurs).

[2910] Body Measurements (Body Length & Weight):

[2911] Body Measurements: A measurement of body length and weight was performed at approximately 16 weeks of age.

[2912] Results:

Body Weight and Length: The male (-/-) mice exhibited decreased mean body weight and mean body length when compared with their gender-matched (+/+) littermates and the historical mean. Thus, the mutant (-/-) mice exhibited a phenotype that could be associated with growth retardation. PRO19646 polypeptides or agonists thereof would be useful in promoting normal growth whereas inhibitors or antagonists of PRO19646 polypeptides would mimic this negative phenotype.

[2913] 66.65. Generation and Analysis of Mice Comprising DNA188342 (UNQ5893) Gene Disruptions

[2914] In these knockout experiments, the gene encoding PRO21718 polypeptides (designated as DNA188342) (UNQ5893) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: BC024587 ACCESSION:BC024587 NID:19354042 Mus musculus Mus musculus, Similar to RIKEN cDNA 5830408F06 gene, clone MGC:37716 IMAGE:5066283; protein reference: Q9D3G2 ACCESSION:Q9D3G2 NID: Mus musculus (Mouse). 5830408F06Rik protein; the human gene sequence reference: NM.sub.--020125 ACCESSION:NM.sub.--020125 NID: gi 9910341 ref NM.sub.--020125.1 Homo sapiens B lymphocyte activator macrophage expressed (BLAME); the human protein sequence corresponds to reference: Q9P0V8 ACCESSION:Q9P0V8 NID: Homo sapiens (Human). BCM-like membrane protein (Hypothetical protein FLJ90188).

[2915] The mouse gene of interest is Slamf8 (SLAM family member 8), ortholog of human SLAMF8. Aliases include Blame, SBBI42, 5830408F06Rik, B lymphocyte activator macrophage expressed, and BCM-like membrane protein precursor.

[2916] SLAMF8 is a type I plasma membrane protein that likely functions as a receptor or B-cell co-receptor. SLAMF8 is expressed in several lymphoid tissues, including lymph node, spleen, thymus, and bone marrow, and in interferon-gamma-activated peripheral blood mononuclear cells, adherence-activated monocytes and dendritic cell subsets. SLAMF8 likely plays a role in B-cell lineage commitment or B-cell receptor signaling (Kingsbury et al, J Immunol 166(9):5675-80 (2001)).

[2917] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00136 wt het hom Total Observed 28 41 20 89 Expected 22.25 44.5 22.25 89

Chi-Sq.=2.35 Significance=0.308819 (hom/n)=0.26 Avg. Litter Size=10

Mutation Information

[2918] Mutation Type: Homologous Recombination (standard)

Description: Coding exons 1 and 2 were targeted (NCBI accession BC024587.1). 1. Wild-type Expression Panel: Expression of the target gene was detected in all 13 adult tissue samples tested by RT-PCR, except skeletal muscle, bone, and adipose. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[2919] 66.65.1. Phenotypic Analysis (for disrupted gene: DNA188342 (UNQ5893)

[2920] (a) Overall Phenotypic Summary:

[2921] Mutation of the gene encoding the ortholog of human SLAM family member 8 (SLAMF8) resulted in the mutant (-/-) mice exhibiting an impaired glucose tolerance. Gene disruption was confirmed by Southern blot.

[2922] (b) Phenotypic Analysis: Metabolism--Blood Chemistry/Glucose Tolerance

[2923] In the area of metabolism, targets may be identified for the treatment of diabetes. Blood chemistry phenotypic analysis includes blood glucose measurements. The COBAS Integra 400 (mfr: Roche) was used for running blood chemistry tests on the mice. In the area of metabolism, targets may be identified for the treatment of diabetes. Blood chemistry phenotypic analysis includes glucose tolerance tests to measure insulin sensitivity and changes in glucose metabolism. Abnormal glucose tolerance test results may indicate but may not be limited to the following disorders or conditions: Diabetes Type 1 and Type 2, Syndrome X, various cardiovascular diseases and/or obesity.

[2924] Procedure: A cohort of 2 wild type and 4 homozygous mice were used in this assay. The glucose tolerance test is the standard for defining impaired glucose homeostasis in mammals. Glucose tolerance tests were performed using a Lifescan glucometer. Animals were injected IP at 2 g/kg with D-glucose delivered as a 20% solution and blood glucose levels were measured at 0, 30, 60 and 90 minutes after injection.

[2925] Results:

[2926] Blood Glucose Levels/Glucose Tolerance Test:

[2927] The (-/-) mice exhibited impaired glucose tolerance when placed on a high fat diet and when compared with their gender-matched (+/+) littermates and the historical means.

[2928] These studies indicated that (-/-) mice exhibit a decreased or impaired glucose tolerance in the presence of normal fasting glucose at all 3 intervals tested when compared with their gender-matched (+/+) littermates and the historical means. Thus, knockout mutant mice exhibited the phenotypic pattern of an impaired glucose homeostasis, and therefor PRO21718 polypeptides (or agonists thereof) or its encoding gene would be useful in the treatment of conditions associated with an impaired glucose homeostasis and/or various cardiovascular diseases, including diabetes.

[2929] 66.66. Generation and Analysis of Mice Comprising DNA149911-2885 (UNQ5926) Gene Disruptions

[2930] In these knockout experiments, the gene encoding PRO19820 polypeptides (designated as DNA149911-2885) (UNQ5926) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: NM.sub.--026516 ACCESSION:NM.sub.--026516 NID: gi 21312655 ref NM.sub.--026516.1 Mus musculus RIKEN cDNA 2810417M05 gene (2810417M05Rik); protein reference: Q9CZ16 ACCESSION:Q9CZ16 NID: Mus musculus (Mouse). 2810417M05Rik protein; the human gene sequence reference: NM.sub.--152390 ACCESSION:NM.sub.--152390 NID: gi 22748834 ref NM.sub.--152390.1 Homo sapiens hypothetical protein MGC33926 (MGC33926); the human protein sequence corresponds to reference: Q8NBL3 ACCESSION:Q8NBL3 NID: Homo sapiens (Human). Hypothetical protein PLACE1004322.

[2931] The mouse gene of interest is RIKEN cDNA 2810417M05 gene, ortholog of human hypothetical protein MGC33926.

[2932] Hypothetical protein MGC33926 is a 297-amino acid polypeptide, containing a signal peptide, three potential transmembrane segments, and a potential glycosylphosphatidylinositol (GPI) anchor site near the C-terminus. The predicted function and cell location of this hypothetical protein is ambiguous. Bioinformatic analyses suggest that the transmembrane domains are similar to those of claudins, integral plasma membrane proteins that typically function as components of tight junctions (TrEMBL accession Q8NBL3; InterPro accession IPRO06187). Other bioinformatic analyses suggest that the human protein is tethered to the extracellular surface of the plasma membrane by a GPI anchor.

[2933] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00137 wt het hom Total Observed 14 40 19 73 Expected 18.25 36.5 18.25 73

Chi-Sq.=2.42 Significance=0.29819727 (hom/n)=0.29 Avg. Litter Size=8

Mutation Information

[2934] Mutation Type Homologous Recombination (standard) Description: Coding exon 1 was targeted (NCBI accession NM.sub.--026516.1). 1. Wild-type Expression Panel: Expression of the target gene was detected in the 13 adult tissue samples tested by RT-PCR, except skeletal muscle; bone; stomach, small intestine, and colon; and adipose. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[2935] 66.66.1. Phenotypic Analysis (for Disrupted Gene: DNA149911-2885 (UNQ5926)

[2936] (a) Overall Phenotypic Summary:

[2937] Mutation of the gene encoding the ortholog of a human hypothetical protein (MGC33926) resulted in the male homozygous mutant mice exhibiting an increased anxiety-like response during stress-induced hyperthermia testing when compared with the level for their gender-matched wild-type littermates and the historical mean. Defecation was absent in 3 of 8 (-/-) mutant mice. Disruption of the target gene was confirmed by Southern hybridization analysis.

[2938] (b) Phenotypic Analysis: CNS/Neurology

[2939] In the area of neurology, analysis focused herein on identifying in vivo validated targets for the treatment of neurological and psychiatric disorders including depression, generalized anxiety disorders, attention deficit hyperactivity disorder, obsessive compulsive disorder, schizophrenia, cognitive disorders, hyperalgesia and sensory disorders. Neurological disorders include the category defined as "anxiety disorders" which include but are not limited to: mild to moderate anxiety, anxiety disorder due to a general medical condition, anxiety disorder not otherwise specified, generalized anxiety disorder, panic attack, panic disorder with agoraphobia, panic disorder without agoraphobia, posttraumatic stress disorder, social phobia, specific phobia, substance-induced anxiety disorder, acute alcohol withdrawal, obsessive compulsive disorder, agoraphobia, bipolar disorder I or II, bipolar disorder not otherwise specified, cyclothymic disorder, depressive disorder, major depressive disorder, mood disorder, substance-induced mood disorder. In addition, anxiety disorders may apply to personality disorders including but not limited to the following types: paranoid, antisocial, avoidant behavior, borderline personality disorders, dependent, histronic, narcissistic, obsessive-compulsive, schizoid, and schizotypal.

[2940] Procedure:

[2941] Behavioral screens were performed on a cohort of 4 wild type, 4 heterozygous and 8 homozygous mutant mice. All behavioral tests were done between 12 and 16 weeks of age unless reduced viability necessitates earlier testing.

Results:

[2942] Stress-Induced Hyperthermia: The male (-/-) mice exhibited increased sensitivity to stress-induced hyperthermia when compared with the level for their gender-matched (+/+) littermates and the historical mean, suggesting an increased anxiety-like response in the mutants.

[2943] In summary, the functional observational testing revealed a phenotype associated with increased anxiety which could be associated with mild to moderate anxiety, anxiety due to a general medical condition, and/or bipolar disorders; hyperactivity; sensory disorders; obsessive-compulsive disorders, schizophrenia or a paranoid personality. Thus, PRO19820 polypeptides or agonists thereof would be useful in the treatment of such neurological disorders.

66.67. Generation and Analysis of Mice Comprising DNA168028-2956 (UNQ6098) Gene Disruptions

[2944] In these knockout experiments, the gene encoding PRO21201 polypeptides (designated as DNA168028-2956) (UNQ6098) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: NM.sub.--172416 ACCESSION:NM.sub.--172416 NID: gi 29293830 ref NM.sub.--172416.2 Mus musculus grey lethal osteopetrosis (G1-pending); protein reference: Q8BGT0 ACCESSION:Q8BGT0 NID: Mus musculus (Mouse). Osteopetrosis associated transmembrane protein 1 precursor (Gray-lethal protein); the human gene sequence reference: NM.sub.--014028 ACCESSION:NM.sub.--014028 NID: gi 30025025 ref NM.sub.--014028.2 Homo sapiens grey-lethal osteopetrosis (GL); the human protein sequence corresponds to reference: Q86WC4 ACCESSION:Q86WC4 NID: Homo sapiens (Human). Osteopetrosis associated transmembrane protein 1 precursor (HSPC019) (UNQ6098/PRO21201).

[2945] The mouse gene of interest is Ostm1 (osteopetrosis associated transmembrane protein 1), ortholog of human OSTM1. Aliases include GL, GIPN, HSPC019, 1200002H13Rik, grey-lethal, grey-lethal osteopetrosis, grey lethal osteopetrosis, and GAIP-interacting protein N terminus.

[2946] OSTM1 is a putative E3 ubiquitin ligase expressed in osteoblasts, melanocytes, kidney, brain, thymus, spleen, and several other tissues. The protein is located in the cytosol and in cytoplasmic membrane compartments, particularly the basolateral membrane of the renal distal tubule. OSTM1 catalyzes the ubiquitination of the G protein alpha subunit i3 (GNAI3); thus, the protein likely regulates G protein-mediated signal transduction by degradation via the proteasome pathway. OSTM1 is also required for osteoclast and melanocyte maturation and function. Loss-of-function mutations in the OSTM1 gene cause osteopetrosis in humans and mice and coat color defect in mice (Chalhoub et al, Nat Med 9(4):395-406 (2003); Fischer et al, Proc Natl Acad Sci USA 100(14):8270-5 (2003)).

[2947] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00138 wt het hom Total Observed 26 39 26 91 Expected 22.75 45.5 22.75 91

Chi-Sq.=3.18 Significance=0.20392561 (hom/n)=0.31 Avg. Litter Size=9

Mutation Information

[2948] Mutation Type Homologous Recombination (standard) Description: Coding exon 1 was targeted (NCBI accession NM.sub.--172416.2). 1. Wild-type Expression Panel: Expression of the target gene was detected in embryonic stem (ES) cells and in all 13 adult tissue samples tested by RT-PCR, except bone. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[2949] 66.67.1. Phenotypic Analysis (for Disrupted Gene: DNA168028-2956 (UNQ6098)

[2950] (a) Overall Phenotypic Summary:

[2951] Mutation of the gene encoding the ortholog of human osteopetrosis associated transmembrane protein 1 (OSTM1) resulted in the homozygous mutant mice being notably smaller than their wild-type littermates. The knockout (-/-) mice exhibited a failure to thrive, showed very reduced mean body weight, had a grey coat color, and possessed no teeth. Microscopic analysis revealed retinal degeneration, neuronal necrosis, and osteopetrosis in the homozygous mutants. The heterozygous mice exhibited an increased mean serum IL-6 response to LPS challenge when compared with their wild-type littermates and the historical mean. Disruption of the target gene was confirmed by Southern hybridization analysis.

[2952] (b) Pathology

Microscopic: The (-/-) mice exhibited diffuse marked osteopetrosis, diffuse moderate retinal degeneration, and multifocal mild neuronal necrosis. The medullary cavities of all long bones, vertebrae, and sternebra were filled with woven trabecular bone. Osteoclasts were increased in number and frequently had large vesicular nuclei (activated). In some areas, there were degenerating and necrotic osteoclasts. Osteoblasts were also numerous, although they tended to be elongated and fibroblastic. Bones in the skull, nasal trabeculae, and epiphyses of long bones contained abundant loosely woven bone and trabeculae. Molar teeth failed to erupt through the bony matrix and there were disorganized dysplastic odontogenic tissues at the base of the impacted incisor teeth. The retinal degeneration affected the receptor and external nuclear layers. Numerous macrophages were present in the photoreceptor layer. In the cerebral cortex, there was laminar degeneration and necrosis/apoptosis of layer IV/V neurons. Similarly affected neurons were also present in the hippocampus and dentate gyrus. All of the mutant (-/-) mice organs were small, but most were proportional to the weight of the mice (1/2 to 1/3 the weight of the (+/+) littermates). However, the thymus tended to be smaller (about 1/10th the weight for (+/+) littermates). Gene Expression LacZ activity was not detected in the panel of tissues by immunohistochemical analysis.

[2953] (c) Bone Metabolism & Body Diagnostics

[2954] (1) Tissue Mass & Lean Body Mass Measurements--Dexa

[2955] Dexa Analysis--Test Description:

[2956] Procedure: A cohort of wild type, heterozygotes and homozygotes were tested in this assay. Dual Energy X-ray Absorptiometry (DEXA) has been used successfully to identify changes in total tissue mass (TTM).

[2957] The mouse was anesthetized by intraperitoneal injection of Avertin (1.25% 2,2,2,-tribromoethanol, 20 ml/kg body weight), body length and weight were measured, and then the mouse was placed in a prone position on the platform of the PIXImus.TM. Densitometer (Lunar Inc.) for a DEXA scan. Using Lunar PIXImus software, the bone mineral density (BMD) and fat composition (% fat) and total tissue mass (TTM) were determined in the regions of interest (ROI, i.e., whole body, vertebrae, and both femurs).

[2958] Body Measurements (Body Length & Weight):

[2959] Body Measurements: A measurement of body length and weight was performed at approximately 16 weeks of age.

[2960] Results:

Obvious General Observations: The (-/-) mice were small with a grey coat color and no teeth. The mutants either died or were sacrificed due to their failure to thrive. Weight: The (-/-) mice exhibited notably decreased mean body weight when compared with their gender-matched (+/+) littermates and the historical means at the 2- and 4-week measurements. Length data was not collected for the (-/-) mice but in the gross photo the (-/-) mice appeared to be shorter than the (+/+) sibling.

[2961] Thus, the mutant (-/-) mice exhibited a phenotype that could be associated with reduced viability and growth retardation. The absence of teeth is consistent with the pathological observations that the molar teeth failed to erupt though the bony matrix. Thus, PRO21201 polypeptides or agonists thereof appear to be essential for normal growth and development, whereas inhibitors or antagonists of PRO21201 polypeptides would mimic this negative phenotype.

[2962] (d) Immunology Phenotypic Analysis

[2963] Immune related and inflammatory diseases are the manifestation or consequence of fairly complex, often multiple interconnected biological pathways which in normal physiology are critical to respond to insult or injury, initiate repair from insult or injury, and mount innate and acquired defense against foreign organisms. Disease or pathology occurs when these normal physiological pathways cause additional insult or injury either as directly related to the intensity of the response, as a consequence of abnormal regulation or excessive stimulation, as a reaction to self, or as a combination of these.

[2964] Though the genesis of these diseases often involves multistep pathways and often multiple different biological systems/pathways, intervention at critical points in one or more of these pathways can have an ameliorative or therapeutic effect. Therapeutic intervention can occur by either antagonism of a detrimental process/pathway or stimulation of a beneficial process/pathway.

[2965] T lymphocytes (T cells) are an important component of a mammalian immune response. T cells recognize antigens which are associated with a self-molecule encoded by genes within the major histocompatibility complex (MHC). The antigen may be displayed together with MHC molecules on the surface of antigen presenting cells, virus infected cells, cancer cells, grafts, etc. The T cell system eliminates these altered cells which pose a health threat to the host mammal. T cells include helper T cells and cytotoxic T cells. Helper T cells proliferate extensively following recognition of an antigen-MHC complex on an antigen presenting cell. Helper T cells also secrete a variety of cytokines, i.e., lymphokines, which play a central role in the activation of B cells, cytotoxic T cells and a variety of other cells which participate in the immune response.

[2966] In many immune responses, inflammatory cells infiltrate the site of injury or infection. The migrating cells may be neutrophilic, eosinophilic, monocytic or lymphocytic as can be determined by histologic examination of the affected tissues. Current Protocols in Immunology, ed. John E. Coligan, 1994, John Wiley & Sons, Inc.

[2967] Many immune related diseases are known and have been extensively studied. Such diseases include immune-mediated inflammatory diseases (such as rheumatoid arthritis, immune mediated renal disease, hepatobiliary diseases, inflammatory bowel disease (IBD), psoriasis, and asthma), non-immune-mediated inflammatory diseases, infectious diseases, immunodeficiency diseases, neoplasia, and graft rejection, etc. In the area of immunology, targets were identified for the treatment of inflammation and inflammatory disorders.

[2968] In the area of immunology, targets have been identified herein for the treatment of inflammation and inflammatory disorders. Immune related diseases, in one instance, could be treated by suppressing the immune response. Using neutralizing antibodies that inhibit molecules having immune stimulatory activity would be beneficial in the treatment of immune-mediated and inflammatory diseases. Molecules which inhibit the immune response can be utilized (proteins directly or via the use of antibody agonists) to inhibit the immune response and thus ameliorate immune related disease.

[2969] The following test was performed:

[2970] Acute Phase Response:

[2971] Test Description Bacterial lipopolysaccharide (LPS) is an endotoxin, and as such is a potent inducer of an acute phase response and systemic inflammation. The Level I LPS mice were injected intraperitoneally (i.p.) with a sub-lethal dose of LPS in 200 .mu.L sterile saline using a 26 gauge needle. The doses were based on the average weight of the mice tested at 1 .mu.g/g body weight 3 hours after injection; a 100 ul blood sample was then taken and analyzed for the presence of TNFa, MCP-1, and IL-6 on the FACS Calibur instrument.

[2972] Results:

[2973] The (+/-) mice exhibited increased mean serum IL-6 responses to LPS challenge when compared with their (+/+) littermates and the historical means.

[2974] In summary, the LPS endotoxin challenge demonstrated that knockout mice deficient in the gene encoding PRO21201 polypeptides exhibit immunological abnormalities when compared with their wild-type littermates. In particular, the mutant mice exhibited an increased ability to elicit an immunological response (IL-6 production) when challenged with the LPS endotoxin indicating a pro-inflammatory response. IL-6 contribute to the later stages of B cell activation. In addition, IL-6 plays a critical role in inducing the acute phase response and systemic inflammation.

[2975] 66.68. Generation and Analysis of Mice Comprising DNA154095-2998 (UNQ6115) Gene Disruptions

[2976] In these knockout experiments, the gene encoding PRO20026 polypeptides (designated as DNA154095-2998) (UNQ6115) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: NM.sub.--134437 ACCESSION:NM.sub.--134437 NID: gi 24025661 ref NM.sub.--134437.1 Mus musculus similar expression to Fgf genes (Sef-pending); protein reference: Q8J71 ACCESSION:Q8JZL1 NID: Mus musculus (Mouse). Transmembrane protein (Interleukin 17 receptor-like protein long form); the human gene sequence reference: AF494208 Homo sapiens interleukin 17 receptor-like protein long form (IL17RLM); the human protein sequence corresponds to reference: Q8NFM7 ACCESSION:Q8NFM7 NID: Homo sapiens (Human). Interleukin 17 receptor-like protein long form.

[2977] The mouse gene of interest is Il17rd (interleukin 17 receptor D), ortholog of human IL17RD. Aliases include Sef, Sef-S, similar expression to Fgf genes, IL17RLM, FLJ35755, DKFZp434N1928, and similar expression to FGF protein.

[2978] IL17RD is a type I plasma membrane protein that likely functions as a receptor or signaling molecule involved in feedback inhibition of fibroblast growth factor (FGF) signaling and in activation of pathways regulating apoptosis. A shorter cytosolic isoform of IL17RD generated by alternative splicing also inhibits FGF signaling. IL17RD inhibits FGF signaling by blocking FGF receptor tyrosine phosphorylation and RAS/ERK MAP kinase pathway. IL17RD stimulates apoptosis by activating TAK1/c-Jun N-terminal kinase pathway. IL17RD is expressed in vascular endothelial cells, in highly vascularized tissues, such as kidney, colon, skeletal muscle, heart, and small intestine, and in ductal epithelial cells of kidney, salivary glands, and seminal vesicles. Expression of the cytosolic form of IL17RD is apparently more limited. IL17RD likely plays a role in processes such as cell proliferation, cell migration, differentiation, apoptosis, and angiogenesis (Yang et al, J Biol Chem 279(37):38099-102 (2004); Torii et al, Dev Cell 7(1):33-44 (2004); Preger et al, Proc Natl Acad Sci USA 101(5):1229-34 (2004); Xiong et al, J Biol Chem 278(50):50273-82 (2003); Yang et al, J Biol Chem 278(35):33232-8 (2003); Kovalenko et al, J Biol Chem 278(16):14087-91 (2003); Furthauer et al, Nat Cell Biol 4(2):170-4 (2002); Tsang et al, Nat Cell Biol 4(2):165-9 (2002)).

[2979] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00139 wt het hom Total Observed 16 25 14 55 Expected 13.75 27.5 13.75 55

Chi-Sq.=0.2 Significance=0.9048374 (hom/n)=0.25 Avg. Litter Size=8

Mutation Information

[2980] Mutation Type: Homologous Recombination (standard) Coding exon 4 was targeted (NCBI accession NM.sub.--134437.1). 1. Wild-type Expression Panel: Expression of the target gene was detected in all 13 adult tissue samples tested by RT-PCR, except thymus; liver; stomach, small intestine, and colon; and adipose. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[2981] 66.68.1. Phenotypic Analysis (for Disrupted Gene: DNA154095-2998 (UNQ6115)

[2982] (a) Overall Phenotypic Summary:

[2983] Mutation of the gene encoding the ortholog of human interleukin 17 receptor D (IL17RD) resulted in the male homozygous mutant mice being larger than their gender-matched wild-type littermates, exhibiting increased body weight and length, increased total tissue mass, and increased lean body mass. The male (-/-) mice showed increased total fat mass with a similar trend in serum triglyceride levels. The male (-/-) mice also showed decreased blood pressure and an atrophic testes. The male mutants exhibited enhanced glucose tolerance. Disruption of the target gene was confirmed by Southern hybridization analysis.

[2984] (b) Cardiology--Blood Pressure

[2985] Test Description: Systolic blood pressure is measured via a noninvasive tail-cuff method for four days on the Visitech BP-2000 Blood Pressure Analysis System. The blood pressure is measured ten times each day for four days. The four days are then averaged to obtain a mouse's conscious systolic blood pressure.

[2986] Results

Blood Pressure: The male (-/-) mice exhibited decreased blood pressure when compared with that of the (+/+) littermates and the historical mean.

[2987] (c) Phenotypic Analysis: Metabolism--Blood Chemistry/Glucose Tolerance

[2988] In the area of metabolism, targets may be identified for the treatment of diabetes. Blood chemistry phenotypic analysis includes blood glucose measurements. The COBAS Integra 400 (mfr: Roche) was used for running blood chemistry tests on the mice. In the area of metabolism, targets may be identified for the treatment of diabetes. Blood chemistry phenotypic analysis includes glucose tolerance tests to measure insulin sensitivity and changes in glucose metabolism. Abnormal glucose tolerance test results may indicate but may not be limited to the following disorders or conditions: Diabetes Type 1 and Type 2, Syndrome X, various cardiovascular diseases and/or obesity.

[2989] Procedure: A cohort of 2 wild type and 4 homozygous mice were used in this assay. The glucose tolerance test is the standard for defining impaired glucose homeostasis in mammals. Glucose tolerance tests were performed using a Lifescan glucometer. Animals were injected IP at 2 g/kg with D-glucose delivered as a 20% solution and blood glucose levels were measured at 0, 30, 60 and 90 minutes after injection.

[2990] Results:

Oral Glucose Tolerance: The male (-/-) mice exhibited enhanced glucose tolerance when compared with that of their gender-matched (+/+) littermates and the historical means.

[2991] In these studies the mutant (-/-) mice showed an increased or enhanced glucose tolerance in the presence of normal fasting glucose at all 3 intervals tested when compared with their gender-matched (+/+) littermates and the historical means. Thus, knockout mice exhibited an increased insulin sensitivity or the opposite phenotypic pattern of an impaired glucose homeostasis, and as such antagonists (inhibitors) to PRO20026 polypeptides or its encoding gene would be useful in the treatment of an impaired glucose homeostasis.

[2992] (d) Phenotypic Analysis: Cardiology

[2993] In the area of cardiovascular biology, targets were identified herein for the treatment of hypertension, atherosclerosis, heart failure, stroke, various coronary artery diseases, dyslipidemias such as high cholesterol (hypercholesterolemia) and elevated serum triglycerides (hypertriglyceridemia), diabetes and/or obesity. The phenotypic tests included the measurement of serum triglycerides.

[2994] Blood Lipids

[2995] Procedure: A cohort of 4 wild type, 4 heterozygotes and 8 homozygotes were tested in this assay. High cholesterol levels and increased triglyceride blood levels are recognized risk factors in the development of cardiovascular disease and/or diabetes. Measuring blood lipids facilitates the finding of biological switches that regulate blood lipid levels. Inhibition of factors which elevate blood lipid levels may be useful for reducing the risk for cardiovascular disease. In these blood chemistry tests, measurements were recorded using the COBAS Integra 400 (mfr: Roche).

[2996] Results:

Blood Chemistry: The (-/-) mice exhibited increased mean serum triglyceride levels when compared with their gender-matched (+/+) littermates and the historical means.

[2997] As summarized above, the (-/-) mice exhibited notably increased mean serum triglyceride levels when compared with their gender-matched (+/+) littermates and the historical means. Thus, mutant mice deficient in the PRO20026 gene can serve as a model for cardiovascular disease. PRO20026 polypeptides or its encoding gene would be useful in regulating blood lipids such as triglycerides. Thus, PRO20026 polypeptides or agonists thereof would be useful in the treatment of such cardiovascular diseases as hypertension, atherosclerosis, heart failure, stroke, various coronary diseases, hypercholesterolemia, hypertriglyceridemia, diabetes and/or obesity.

[2998] (e) Bone Metabolism & Radiology Phenotypic Analysis

[2999] In the area of bone metabolism, targets were identified herein for the treatment of arthritis, osteoporosis, osteopenia and osteopetrosis as well as identifying targets that promote bone healing. Tests included: [3000] DEXA for measurement of bone mineral density on femur and vertebra [3001] MicroCT for very high resolution and very high sensitivity measurements of bone mineral density for both trabecular and cortical bone.

[3002] Dexa Analysis--Test Description:

[3003] Procedure: A cohort of 4 wild type, 4 heterozygotes and 8 homozygotes were tested in this assay. Dual Energy X-ray Absorptiometry (DEXA) has been used successfully to identify changes in bone. Anesthetized animals were examined and bone mineral content (BMC), BMC/LBM ratios, volumetric bone mineral density (vBMD), total body BMD, femur BMD and vertebra BMD were measured.

[3004] The mouse was anesthetized by intraperitoneal injection of Avertin (1.25% 2,2,2-tribromoethanol, 20 ml/kg body weight), body length and weight were measured, and then the mouse was placed in a prone position on the platform of the PIXImus.TM. Densitometer (Lunar Inc.) for a DEXA scan. Using Lunar PIXImus software, the bone mineral density (BMD) and fat composition (% fat) and total tissue mass (TTM) were determined in the regions of interest (ROI) [i.e., whole body, vertebrae, and both femurs].

[3005] CAT-Scan Protocol:

[3006] Mice were injected with a CT contrast agent, Omnipaque 300 (Nycomed Amershan, 300 mg of iodine per nil, 0.25 ml per animal, or 2.50-3.75 g iodine/kg of body weight) intraperitoneally. After resting in the cage for .about.10 minutes, the mouse was then sedated by intraperitoneal injection of Avertin (1.25% 2,2,2,-tribromoethanol, 20 ml/kg body weight). A CAT-scan was performed using a MicroCAT scanner (ImTek, Inc.) with the anesthetized animal lying prone on the test bed. Three dimensional images were reconstructed by the Feldkamp algorithm in a cluster of workstations using an ImTek 3D RECON software.

[3007] Results:

DEXA: The male (-/-) mice exhibited increased mean total tissue mass, lean body mass, and total fat mass when compared with that of their gender-matched (+/+) littermates and the historical means.

[3008] These studies suggest that mutant (-/-) non-human transgenic animals exhibit a negative phenotype that would be associated with obesity. Thus, PRO20026 polypeptides or agonists thereof are essential for normal growth and metabolic processes and especially would be important in the prevention and/or treatment of obesity.

CAT Scan: The two male (-/-) mice analyzed (M-75 and M-100) exhibited atrophic left testes.

[3009] 66.69. Generation and Analysis of Mice Comprising DNA166819-P1381R1C1P1 (UNQ6129) Gene Disruptions

[3010] In these knockout experiments, the gene encoding PRO20110 polypeptides (designated as DNA166819-1381R1C1P1) (UNQ6129) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: NM.sub.--145856 ACCESSION:NM.sub.--145856 NID: gi 22003915 ref NM.sub.--145856.1 Mus musculus interleukin 17F (IL-17F); protein reference: Q8K4C3 ACCESSION:Q8K4C3 NID: Mus musculus (Mouse). IL-17F; the human gene sequence reference: NM.sub.--052872 Homo sapiens interleukin 17F (IL17F), transcript variant 1; the human protein sequence corresponds to reference: Q6NSI0 ACCESSION:Q6NSI0 NID: Homo sapiens (Human). Interleukin 17F, isoform 1.

[3011] The mouse gene of interest is 1117f (interleukin 17F), ortholog of human IL17F. Aliases include ML1, IL24, ML-1, IL-24, IL-26, IL-17F, cytokine ML-1, and interleukin-24.

[3012] IL17F is a cytokine that functions as a signal-transducing ligand, stimulating the production of inflammatory cytokines and chemokines typical of a T-cell helper type 1 (Th1) response. IL17F stimulates production of IL-6, IL-8, granulocyte-macrophage colony stimulating factor (GM-CSF), IL-2, transforming growth factor-beta, and monocyte chemoattractant protein-1 in bronchial epithelial cells or vascular endothelial cells (Kawaguchi et al, J Biol Chem 277(18):15229-32 (2002); Starnes et al, J Immunol 167(8):4137-40 (2001); Numasake et al, Immunol Lett 95(2):175-84 (2004); Kawaguchi et al, J Allergy Clin Immunol 114(2):444-50 (2004)). The signaling pathway for Th17F-induced cytokine or chemokine production likely involves activation of extracellular signal-regulated kinase (ERK) 1/2 (Kawaguchi et al, J Biol Chem 277(18):15229-32 (2002); Kawaguchi et al, J Allergy Clin Immunol 114(2):444-50 (2004)). IL17F plays a role in inhibiting angiogenesis (Starnes et al, J Immunol 167(8):4137-40 (2001), inducing neutrophilia, and amplifying antigen-induced allergic responses (Oda et al, Am J Respir Crit. Care Med 171(1):12-18 (2004)).

[3013] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00140 wt het hom Total Observed 20 40 18 78 Expected 19.5 39 19.5 78

Chi-Sq.=9.65 Significance=0.008026555 (hom/n)=0.18 Avg. Litter Size=8

Mutation Information

[3014] Mutation Type: Homologous Recombination (standard) Description: Coding exons 1 and 2 were targeted (NCBI accession NM.sub.--145856.1). 1. Wild-type Expression Panel: Expression of the target gene was detected in embryonic stem (ES) cells and, in brain, spinal cord, thymus, spleen, and kidney among the 13 adult tissue samples tested by RT-PCR. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[3015] 66.69.1. Phenotypic Analysis (for Disrupted Gene: DNA166819-P1381R1C1P1 (UNQ6129)

[3016] (a) Overall Phenotypic Summary:

[3017] Mutation of the gene encoding the ortholog of human interleukin 17F (IL17F) resulted in an increased anxiety-related response in (-/-) mice. In addition, the mutant (-/-) mice exhibited increased mean serum IgG1, IgG2a and IgG3 levels; increased mean body weight and length as well as increased total tissue mass, lean body mass and total body fat percent and mass with increased bone mineral density measurements. The (-/-) mice exhibited increased mean trabecular bone volume, number and connectivity density. The male (-/-) mice also showed an increasing trend for elevated cholesterol and triglyceride levels. Gene disruption was confirmed by Southern blot.

[3018] (b) Immunology Phenotypic Analysis

[3019] Immune related and inflammatory diseases are the manifestation or consequence of fairly complex, often multiple interconnected biological pathways which in normal physiology are critical to respond to insult or injury, initiate repair from insult or injury, and mount innate and acquired defense against foreign organisms. Disease or pathology occurs when these normal physiological pathways cause additional insult or injury either as directly related to the intensity of the response, as a consequence of abnormal regulation or excessive stimulation, as a reaction to self, or as a combination of these.

[3020] Though the genesis of these diseases often involves multistep pathways and often multiple different biological systems/pathways, intervention at critical points in one or more of these pathways can have an ameliorative or therapeutic effect. Therapeutic intervention can occur by either antagonism of a detrimental process/pathway or stimulation of a beneficial process/pathway.

[3021] T lymphocytes (T cells) are an important component of a mammalian immune response. T cells recognize antigens which are associated with a self-molecule encoded by genes within the major histocompatibility complex (MHC). The antigen may be displayed together with MHC molecules on the surface of antigen presenting cells, virus infected cells, cancer cells, grafts, etc. The T cell system eliminates these altered cells which pose a health threat to the host mammal. T cells include helper T cells and cytotoxic T cells. Helper T cells proliferate extensively following recognition of an antigen-MHC complex on an antigen presenting cell. Helper T cells also secrete a variety of cytokines, i.e., lymphokines, which play a central role in the activation of B cells, cytotoxic T cells and a variety of other cells which participate in the immune response.

[3022] In many immune responses, inflammatory cells infiltrate the site of injury or infection. The migrating cells may be neutrophilic, eosinophilic, monocytic or lymphocytic as can be determined by histologic examination of the affected tissues. Current Protocols in Immunology, ed. John E. Coligan, 1994, John Wiley & Sons, Inc.

[3023] Many immune related diseases are known and have been extensively studied. Such diseases include immune-mediated inflammatory diseases (such as rheumatoid arthritis, immune mediated renal disease, hepatobiliary diseases, inflammatory bowel disease (IBD), psoriasis, and asthma), non-immune-mediated inflammatory diseases, infectious diseases, immunodeficiency diseases, neoplasia, and graft rejection, etc. In the area of immunology, targets were identified for the treatment of inflammation and inflammatory disorders.

[3024] In the area of immunology, targets have been identified herein for the treatment of inflammation and inflammatory disorders. Immune related diseases, in one instance, could be treated by suppressing the immune response. Using neutralizing antibodies that inhibit molecules having immune stimulatory activity would be beneficial in the treatment of immune-mediated and inflammatory diseases. Molecules which inhibit the immune response can be utilized (proteins directly or via the use of antibody agonists) to inhibit the immune response and thus ameliorate immune related disease.

[3025] The following test was performed:

[3026] Serum Immunoglobulin Isotyping Assay:

[3027] The Serum Immunoglobulin Isotyping Assay is performed using a Cytometric Bead Array (CBA) kit. This assay is used to rapidly identify the heavy and light chain isotypes of a mouse monoclonal antibody in a single sample. The values expressed are "relative fluorescence units" and are based on the detection of kappa light chains. Any value <6 is not significant.

[3028] Results:

Serum Imm. 2: The (-/-) mice exhibited increased mean serum IgG1, IgG2a and IgG3 levels when compared with those of their (+/+) littermates, the (+/+) mice within the project run, and the historical medians.

[3029] Mutant (-/-) mice exhibited elevation of IgG1, IgG2a and IgG3 serum immunoglobulins. These immunoglobulins have neutralization effects and to a lesser extent are important for activation of the complement system. The observed phenotype suggests that the PRO20110 polypeptide is a negative regulator of inflammatory responses. These immunological abnormalities suggest that inhibitors (antagonists) of PRO20110 polypeptides would be useful in stimulating the immune system and would find utility in the cases wherein this effect would be beneficial to the individual such as in the case of leukemia, and other types of cancer, and in immunocompromised patients, such as AIDS sufferers. Accordingly, PRO20110 polypeptides or agonists thereof would be useful in inhibiting the immune response and would be useful candidates for suppressing harmful immune responses, e.g. in the case of graft rejection or graft-versus-host diseases.

[3030] (c) Phenotypic Analysis: CNS/Neurology

[3031] In the area of neurology, analysis focused herein on identifying in vivo validated targets for the treatment of neurological and psychiatric disorders including depression, generalized anxiety disorders, attention deficit hyperactivity disorder, obsessive compulsive disorder, schizophrenia, cognitive disorders, hyperalgesia and sensory disorders. Neurological disorders include the category defined as "anxiety disorders" which include but are not limited to: mild to moderate anxiety, anxiety disorder due to a general medical condition, anxiety disorder not otherwise specified, generalized anxiety disorder, panic attack, panic disorder with agoraphobia, panic disorder without agoraphobia, posttraumatic stress disorder, social phobia, specific phobia, substance-induced anxiety disorder, acute alcohol withdrawal, obsessive compulsive disorder, agoraphobia, bipolar disorder I or II, bipolar disorder not otherwise specified, cyclothymic disorder, depressive disorder, major depressive disorder, mood disorder, substance-induced mood disorder. In addition, anxiety disorders may apply to personality disorders including but not limited to the following types: paranoid, antisocial, avoidant behavior, borderline personality disorders, dependent, histronic, narcissistic, obsessive-compulsive, schizoid, and schizotypal.

[3032] Procedure:

[3033] Behavioral screens were performed on a cohort of 4 wild type, 4 heterozygous and 8 homozygous mutant mice. All behavioral tests were done between 12 and 16 weeks of age unless reduced viability necessitates earlier testing.

Results:

[3034] Stress-Induced Hyperthermia: The male (-/-) mice exhibited increased sensitivity to stress-induced hyperthermia when compared with the level for their gender-matched (+/+) littermates and the historical mean, suggesting an increased anxiety-like response in the mutants.

[3035] In summary, the functional observational testing revealed a phenotype associated with increased anxiety which could be associated with mild to moderate anxiety, anxiety due to a general medical condition, and/or bipolar disorders; hyperactivity; sensory disorders; obsessive-compulsive disorders, schizophrenia or a paranoid personality. Thus, PRO20110 polypeptides or agonists thereof would be useful in the treatment of such neurological disorders.

[3036] (d) Phenotypic Analysis: Cardiology

[3037] In the area of cardiovascular biology, targets were identified herein for the treatment of hypertension, atherosclerosis, heart failure, stroke, various coronary artery diseases, dyslipidemias such as high cholesterol (hypercholesterolemia) and elevated serum triglycerides (hypertriglyceridemia), diabetes and/or obesity. The phenotypic tests included the measurement of serum cholesterol and triglycerides.

[3038] Blood Lipids

[3039] Procedure: A cohort of 4 wild type, 4 heterozygotes and 8 homozygotes were tested in this assay. High cholesterol levels and increased triglyceride blood levels are recognized risk factors in the development of cardiovascular disease and/or diabetes. Measuring blood lipids facilitates the finding of biological switches that regulate blood lipid levels. Inhibition of factors which elevate blood lipid levels may be useful for reducing the risk for cardiovascular disease. In these blood chemistry tests, measurements were recorded using the COBAS Integra 400 (mfr: Roche).

[3040] Results:

Blood Chemistry: Both the male and female (-/-) mice exhibited increased mean serum cholesterol and triglyceride levels when compared with those of their gender-matched (+/+) littermates and the historical means.

[3041] As summarized above, the (-/-) mice exhibited notably increased mean serum cholesterol and triglyceride levels when compared with their gender-matched (+/+) littermates and the historical means. Thus, mutant mice deficient in the PRO20110 gene can serve as a model for cardiovascular disease. PRO20110 polypeptides or its encoding gene would be useful in regulating blood lipids such as cholesterol and triglycerides. Thus, PRO20110 polypeptides or agonists thereof would be useful in the treatment of such cardiovascular diseases as hypertension, atherosclerosis, heart failure, stroke, various coronary diseases, hypercholesterolemia, hypertriglyceridemia, diabetes and/or obesity.

[3042] (e) Bone Metabolism & Body Diagnostics

[3043] (1) Tissue Mass & Lean Body Mass Measurements--Dexa

[3044] Dexa Analysis--Test Description:

[3045] Procedure: A cohort of 4 wild type, 4 heterozygotes and 8 homozygotes were tested in this assay. Dual Energy X-ray Absorptiometry (DEXA) has been used successfully to identify changes in total tissue mass (TTM).

[3046] The mouse was anesthetized by intraperitoneal injection of Avertin (1.25% 2,2,2,-tribromoethanol, 20 ml/kg body weight), body length and weight were measured, and then the mouse was placed in a prone position on the platform of the PIXImus.TM. Densitometer (Lunar Inc.) for a DEXA scan. Using Lunar PIXImus software, the bone mineral density (BMD) and fat composition (% fat) and total tissue mass (TTM) were determined in the regions of interest (ROI, i.e., whole body, vertebrae, and both femurs).

[3047] Body Measurements (Body Length & Weight):

[3048] Body Measurements: A measurement of body length and weight was performed at approximately 16 weeks of age.

[3049] Results:

Body Weight and Length: The male (-/-) mice exhibited increased mean body weight and mean body length when compared with their gender-matched (+/+) littermates and the historical mean.

[3050] (2) Bone Metabolism: Radiology Phenotypic Analysis

[3051] In the area of bone metabolism, targets were identified herein for the treatment of arthritis, osteoporosis, osteopenia and osteopetrosis as well as identifying targets that promote bone healing. Tests included: [3052] DEXA for measurement of bone mineral density on femur and vertebra [3053] MicroCT for very high resolution and very high sensitivity measurements of bone mineral density for both trabecular and cortical bone.

[3054] Dexa Analysis--Test Description:

[3055] Procedure: A cohort of 4 wild type, 4 heterozygotes and 8 homozygotes were tested in this assay. Dual Energy X-ray Absorptiometry (DEXA) has been used successfully to identify changes in bone. Anesthetized animals were examined and bone mineral content (BMC), BMC/LBM ratios, volumetric bone mineral density (vBMD), total body BMD, femur BMD and vertebra BMD were measured.

[3056] The mouse was anesthetized by intraperitoneal injection of Avertin (1.25% 2,2,2,-tribromoethanol, 20 ml/kg body weight), body length and weight were measured, and then the mouse was placed in a prone position on the platform of the PIXImus.TM. Densitometer (Lunar Inc.) for a DEXA scan. Using Lunar PIXImus software, the bone mineral density (BMD) and fat composition (% fat) and total tissue mass (TTM) were determined in the regions of interest (ROI) [i.e., whole body, vertebrae, and both femurs].

[3057] Bone microCT Analysis:

[3058] Procedure: MicroCT was also used to get very sensitive measurements of BMD. One vertebra and 1 femur were taken from a cohort of 4 wild type and 8 homozygous mice. Measurements were taken of lumbar 5 vertebra trabecular bone volume, trabecular thickness, connectivity density and midshaft femur total bone area and cortical thickness. The .mu.CT40 scans provided detailed information on bone mass and architecture. Multiple bones were placed into sample holders and scanned automatically. Instrument software was used to select regions of interest for analysis. Trabecular bone parameters were analyzed in the fifth lumbar vertebrae (LV5) at 16 micrometer resolution and cortical bone parameters were analyzed in the femur midshaft at a resolution of 20 micrometers.

[3059] Results:

DEXA: Both the male and female (-/-) mice exhibited increased mean total tissue mass when compared with that of their gender-matched (+/+) littermates. The male mutants also exhibited increased mean lean body mass, percent total body fat, and total fat mass; the female mutants exhibited increased mean percent total body fat and total fat mass. Micro CT: The male (-/-) mice exhibited increased mean vertebral trabecular bone volume, number and connectivity density when compared with their gender-matched (+/+) littermates and the historical means.

[3060] The (-/-) mice analyzed by DEXA and bone micro CT analysis exhibited increased bone measurements when compared with their (+/+) littermates, suggestive of abnormal bone disorders such as osteopetrosis. However, the mutant (-/-) mice also exhibited increased body weight and length and total tissue mass and lean body mass. The female (-/-) mice exhibited an increased mean percentage of body fat and fat mass suggestive of an obesity. These observations suggest that mutant mice deficient in the gene which encodes PRO20110 polypeptides leads to metabolic disorders associated with accumulation of fat but also abnormal bone measurements reflective of osteopetrosis. Thus, PRO20110 polypeptides or agonists thereof would be useful in the treatment of bone related disorders such as osteopetrosis or would be useful in maintaining bone homeostasis. In addition, PRO20110 polypeptides would be useful in maintaining normal lipid metabolism. As well as useful in the treatment of obesity and hypercholesterolemia and hypertriglyceridemia. Antagonists (or inhibitors) of PRO20110 polypeptides or its encoding gene would lead to abnormal or pathological bone disorders including inflammatory diseases associated with abnormal bone metabolism.

[3061] 66.70. Generation and Analysis of Mice Comprising DNA185171-2994 (UNQ6507) Gene Disruptions

[3062] In these knockout experiments, the gene encoding PRO23203 polypeptides (designated as DNA185171-2994) (UNQ6507) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: AK052981 Mus musculus 15 days embryo head cDNA, RIKEN full-length enriched library, clone:D930007L06 product:weakly similar to TUMOR SUPPRESSOR PHYDE [Rattus norvegicus], full insert sequence; protein reference: Q8BWB6 ACCESSION:Q8BWB6 NID: Mus musculus (Mouse). Mus musculus 15 days embryo head cDNA, RIKEN full-length enriched library, clone:D930007L06 product:weakly similar to TUMOR SUPPRESSOR PHYDE; the human gene sequence reference: NM.sub.--152999 ACCESSION:NM.sub.--152999 NID: gi 25092600 ref NM.sub.--152999.2 Homo sapiens six transmembrane epithelial antigen of prostate 2 (STEAP2); the human protein sequence corresponds to reference: Q8NFT2 ACCESSION:Q8NFT2 NID: Homo sapiens (Human). Six-transmembrane epithelial antigen of prostate 2.

[3063] The mouse gene of interest is Steap2 (six transmembrane epithelial antigen of prostate 2), ortholog of human STEAP2. Aliases include STMP, IPCA1, IPCA-1, STAMP1, PCANAP1, 4921538B 17Rik, prostate cancer associated gene 1, six transmembrane prostate protein, prostate cancer associated protein 1, and SixTransMembrane Protein of Prostate 1.

[3064] STEAP2 is an integral membrane protein located primarily in the plasma membrane and trans-Golgi network but also in cytosolic vesicular tubule structures and in endosomes. The protein contains a six transmembrane (6.TM.) domain that is structurally similar to the 6.TM. heme-binding domains of NADPH oxidase family members and TedZ bacterial oxidoreductase family members. Expression of STEAP2 is high in prostate gland epithelium but is detectable in other tissues, such as heart, brain, kidney, pancreas, and ovary. STEAP2 may play a role in vesicle transport from the Golgi apparatus to the plasma membrane or in regulated secretion. Because STEAP2 expression is generally higher in prostate cancer cells than in normal prostate epithelial cells, STEAP2 may also play a role in development or progression of prostate cancer (Korkmaz et al, J Biol Chem 277(39):36689-96 (2002); Porkka et al, Lab Invest 82(11):1573-82 (2002); Sanchez-Pulido et al, BMC Cancer 4(1):98 (2004)).

[3065] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00141 wt het hom Total Observed 20 42 20 82 Expected 20.5 41 20.5 82

Chi-Sq.=0.43 Significance=0.80654144 (hom/n)=0.27 Avg. Litter Size=8

Mutation Information

[3066] Mutation Type: Homologous Recombination (standard)

Description: The exon preceding coding exon 1 and coding exon 1 were targeted (NCBI accession AK052981.1). 1. Wild-type Expression Panel: Expression of the target gene was detected in embryonic stem (ES) cells and in all 13 adult tissue samples tested by RT-PCR. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[3067] 66.70.1. Phenotypic Analysis (for disrupted gene: DNA185171-2994 (UNQ6507)

[3068] (a) Overall Phenotypic Summary:

[3069] Mutation of the gene encoding the ortholog of human six transmembrane epithelial antigen of prostate

2 (STEAP2) resulted in the homozygous mutant mice exhibiting increased mean serum IgG1 and IgG2a responses to ovalbumin challenge when compared with those of their wild-type littermates and the historical means. In addition, the female (-/-) mice exhibited increased anxiety during circadian rhythm testing. Disruption of the target gene was confirmed by Southern hybridization analysis.

[3070] (b) Immunology Phenotypic Analysis

[3071] Immune related and inflammatory diseases are the manifestation or consequence of fairly complex, often multiple interconnected biological pathways which in normal physiology are critical to respond to insult or injury, initiate repair from insult or injury, and mount innate and acquired defense against foreign organisms. Disease or pathology occurs when these normal physiological pathways cause additional insult or injury either as directly related to the intensity of the response, as a consequence of abnormal regulation or excessive stimulation, as a reaction to self, or as a combination of these.

[3072] Though the genesis of these diseases often involves multistep pathways and often multiple different biological systems/pathways, intervention at critical points in one or more of these pathways can have an ameliorative or therapeutic effect. Therapeutic intervention can occur by either antagonism of a detrimental process/pathway or stimulation of a beneficial process/pathway.

[3073] T lymphocytes (T cells) are an important component of a mammalian immune response. T cells recognize antigens which are associated with a self-molecule encoded by genes within the major histocompatibility complex (MHC). The antigen may be displayed together with MHC molecules on the surface of antigen presenting cells, virus infected cells, cancer cells, grafts, etc. The T cell system eliminates these altered cells which pose a health threat to the host mammal. T cells include helper T cells and cytotoxic T cells. Helper T cells proliferate extensively following recognition of an antigen-MHC complex on an antigen presenting cell. Helper T cells also secrete a variety of cytokines, i.e., lymphokines, which play a central role in the activation of B cells, cytotoxic T cells and a variety of other cells which participate in the immune response.

[3074] In many immune responses, inflammatory cells infiltrate the site of injury or infection. The migrating cells may be neutrophilic, eosinophilic, monocytic or lymphocytic as can be determined by histologic examination of the affected tissues. Current Protocols in Immunology, ed. John E. Coligan, 1994, John Wiley & Sons, Inc.

[3075] Many immune related diseases are known and have been extensively studied. Such diseases include immune-mediated inflammatory diseases (such as rheumatoid arthritis, immune mediated renal disease, hepatobiliary diseases, inflammatory bowel disease (IBD), psoriasis, and asthma), non-immune-mediated inflammatory diseases, infectious diseases, immunodeficiency diseases, neoplasia, and graft rejection, etc. In the area of immunology, targets were identified for the treatment of inflammation and inflammatory disorders.

[3076] In the area of immunology, targets have been identified herein for the treatment of inflammation and inflammatory disorders. Immune related diseases, in one instance, could be treated by suppressing the immune response. Using neutralizing antibodies that inhibit molecules having immune stimulatory activity would be beneficial in the treatment of immune-mediated and inflammatory diseases. Molecules which inhibit the immune response can be utilized (proteins directly or via the use of antibody agonists) to inhibit the immune response and thus ameliorate immune related disease.

[3077] The following test was performed:

[3078] Ovalbumin Challenge

[3079] Procedure: This assay was carried out on 7 wild types and 8 homozygotes. Chicken ovalbumin (OVA) is a T-cell dependent antigen, which is commonly used as a model protein for studying antigen-specific immune responses in mice. OVA is non-toxic and inert and therefore will not cause harm to the animals even if no immune response is induced. The murine immune response to OVA has been well characterized, to the extent that the immunodominant peptides for eliciting T cell responses have been identified. Anti-OVA antibodies are detectable 8 to 10 days after immunization using enzyme-linked immunosorbent assay (ELIZA), and determination of different isotypes of antibodies gives further information on the complex processes that may lead to a deficient response in genetically engineered mice.

[3080] As noted above, this protocol assesses the ability of mice to raise an antigen-specific immune response. Animals were injected IP with 50 mg of chicken ovalbumin emulsified in Complete Feund's Adjuvant and 14 days later the serum titer of anti-ovalbumin antibodies (IgM, IgG1 and IgG2 subclasses) was measured. The amount of OVA-specific antibody in the serum sample is proportional to the Optical Density (OD) value generated by an instrument that scans a 96-well sample plate. Data was collected for a set of serial dilutions of each serum sample.

[3081] Results of this Challenge:

Ovalbumin: The (-/-) mice exhibited increased mean serum IgG1 and IgG2a responses to ovalbumin challenge when compared with those of their (+/+) littermates and the historical means.

[3082] In summary, the ovalbumin challenge studies indicate that knockout mice deficient in the gene encoding PRO23203 polypeptides exhibit immunological abnormalities when compared with their wild-type littermates. In particular, the mutant mice exhibited an increased ability to elicit an immunological response when challenged with the T-cell dependent OVA antigen. Thus, antagonists (inhibitors) of PRO23203 polypeptides would be useful for stimulating the immune system and would find utility in the cases wherein this effect would be beneficial to the individual such as in the case of leukemia, and other types of cancer, and in immunocompromised patients, such as AIDS sufferers. Accordingly, PRO23203 polypeptides or agonists thereof, would be useful for inhibiting the immune response and thus would be useful candidates for suppressing harmful immune responses, e.g. in the case of graft rejection or graft-versus-host diseases.

[3083] (c) Phenotypic Analysis: CNS/Neurology

[3084] In the area of neurology, analysis focused herein on identifying in vivo validated targets for the treatment of neurological and psychiatric disorders including depression, generalized anxiety disorders, attention deficit hyperactivity disorder, obsessive compulsive disorder, schizophrenia, cognitive disorders, hyperalgesia and sensory disorders. Neurological disorders include the category defined as "anxiety disorders" which include but are not limited to: mild to moderate anxiety, anxiety disorder due to a general medical condition, anxiety disorder not otherwise specified, generalized anxiety disorder, panic attack, panic disorder with agoraphobia, panic disorder without agoraphobia, posttraumatic stress disorder, social phobia, specific phobia, substance-induced anxiety disorder, acute alcohol withdrawal, obsessive compulsive disorder, agoraphobia, bipolar disorder I or II, bipolar disorder not otherwise specified, cyclothymic disorder, depressive disorder, major depressive disorder, mood disorder, substance-induced mood disorder. In addition, anxiety disorders may apply to personality disorders including but not limited to the following types: paranoid, antisocial, avoidant behavior, borderline personality disorders, dependent, histronic, narcissistic, obsessive-compulsive, schizoid, and schizotypal.

[3085] Procedure:

[3086] Behavioral screens were performed on a cohort of 4 wild type, 4 heterozygous and 8 homozygous mutant mice. All behavioral tests were done between 12 and 16 weeks of age unless reduced viability necessitates earlier testing.

[3087] Circadian Test Description:

[3088] Female mice are individually housed at 4 pm on the first day of testing in 48.2 cm.times.26.5 cm home cages and administered food and water ad libitum. Animals are exposed to a 12-hour light/dark cycle with lights turning on at 7 am and turning off at 7 pm. The system software records the number of beam interruptions caused by the animal's movements, with beam breaks automatically divided into ambulations. Activity is recorded in 60, one-hour intervals during the three-day test. Data generated are displayed by median activity levels recorded for each hour (circadian rhythm) and median total activity during each light/dark cycle (locomotor activity) over the three-day testing period.

[3089] Results:

Circadian: The female (-/-) mice exhibited increased median ambulatory counts during the 12-hour habituation and both dark periods when compared with the number for their gender-matched (+/+) littermates and the historical means.

[3090] These observations during home-cage activity testing is indicative of hyperactivity and increased anxiety which is consistent with neurological disorders such as generalized anxiety disorders, attention deficit hyperactivity disorder, obsessive compulsive disorder, schizophrenia, cognitive disorders generalized anxiety disorder.

66.71. Generation and Analysis of Mice Comprising DNA171732-3100 (UNQ9574) Gene Disruptions

[3091] In these knockout experiments, the gene encoding PRO35250 polypeptides (designated as DNA171732-3100) (UNQ9574) was disrupted. The gene specific information for these studies is as follows: the mutated mouse gene corresponds to nucleotide reference: XM.sub.--128001 PREDICTED: Mus musculus GPI-anchored HDL-binding protein 1 (Gpihbp1); protein reference: Q9D1N2 ACCESSION:Q9D1N2 NID: Mus musculus (Mouse). 1110002J19RIK PROTEIN; the human gene sequence reference: NM.sub.--178172 Homo sapiens high density lipoprotein-binding protein (LOC338328); the human protein sequence corresponds to reference: Q6P3T2 ACCESSION:Q6P3T2 NID: Homo sapiens (Human). High density lipoprotein-binding protein.

[3092] The mouse gene of interest is Gpihbp1 (GPI-anchored HDL-binding protein 1), ortholog of human "high density lipoprotein-binding protein." Aliases include GPI-HBP1 and 1110002119Rik.

[3093] Gpihbp1 is a glycosylphosphatidylinositol (GPI)-anchored extracellular membrane protein that functions as a high-density lipoprotein-binding protein. The protein contains a signal peptide, an acidic region, an Ly-6 domain highly conserved among the lymphocyte antigen family, and a hydrophobic C-terminal region. Gpihbp1 is capable of mediating selective lipid uptake but not cholesterol efflux. Gpihbp1 is expressed in liver Kupfer cells, liver sinusoidal epithelium, cardiac muscle cells, bronchial epithelial cells, and alveolar macrophages and is likely to play a role in initial uptake of HDL cholesterol (Ioka et al, J Biol Chem 278(9):7344-9 (2003)).

[3094] Targeted or gene trap mutations are generated in strain 129SvEv.sup.Brd-derived embryonic stem (ES) cells. The chimeric mice are bred to C57BL/6J albino mice to generate F1 heterozygous animals. These progeny are intercrossed to generate F2 wild type, heterozygous, and homozygous mutant progeny. On rare occasions, for example when very few F1 mice are obtained from the chimera, F1 heterozygous mice are crossed to 129SvEv.sup.Brd/C57 hybrid mice to yield additional heterozygous animals for the intercross to generate the F2 mice. Level I phenotypic analysis is performed on mice from this generation

TABLE-US-00142 wt het hom Total Observed 14 58 14 86 Expected 21.5 43 21.5 86

Chi-Sq.=13.97 Significance=9.2566316E-4 (hom/n)=0.18 Avg. Litter Size=9

Mutation Information

[3095] Mutation Type Homologous Recombination (standard) Description: Coding exons 1 through 4 were targeted (NCBI accession BC061225). 1. Wild-type Expression Panel: Expression of the target gene was detected in all 13 adult tissue samples tested by RT-PCR, except brain, eye, skeletal muscle, and bone. 2. QC Expression: Disruption of the target gene was confirmed by Southern hybridization analysis.

[3096] 66.71.1. Phenotypic Analysis (for disrupted gene: DNA171732-3100 (UNQ9574)

[3097] (a) Overall Phenotypic Summary:

[3098] Mutation of the gene encoding the ortholog of human "high density lipoprotein-binding protein" resulted in lipemia in (-/-) mice. Blood chemistry measurements and microscopic analysis revealed that the homozygous mutant mice were notably lipemic. The greatly increased concentration of serum lipids in the mutants affected several other Level 1 parameters, including the total bilirubin measurement and the fundus and angiogram analyses. In addition, the homozygous mutant mice exhibited signs of anemia and immunological abnormalities when compared with the measurements for their wild-type littermates and the historical means. Disruption of the target gene was confirmed by Southern hybridization analysis.

[3099] (b) Pathology

Microscopic: Among the 6 (-/-) mice examined, 4 exhibited markedly hyperlipidemic blood at necropsy. Histopathology revealed increased amounts of pale-staining acellular material in scattered blood vessels. In the 4 (-/-) mice with lipemia, the only notable histopathologic alteration was in the cytoplasm of all cells in the zona fasciculata of the adrenal gland which is consistent with the altered lipid/cholesterol uptake or metabolism in these cells. Instead of the normal microvacuolated cytoplasm typical of these cells in normal tissue, the cytoplasm of these cells lacked microvacuoles in the hyperlipidemic mice. Instead, the cytoplasm of the zona fasciculata cells in the mutants was uniformly finely granular and eosinophilic, which would be consistent with altered lipid/cholesterol uptake or metabolism in these cells. Gene Expression LacZ activity was not detected in the panel of tissues by immunohistochemical analysis.

[3100] (c) Cardiovascular Phenotypic Analysis:

[3101] In the area of cardiovascular biology, phenotypic testing was performed to identify potential targets for the treatment of cardiovascular, endothelial or angiogenic disorders. One such phenotypic test included optic fundus photography and angiography to determine the retinal arteriovenous ratio (A/V ratio) in order to flag various eye abnormalities. An abnormal A/V ratio signals such systemic diseases or disorders that may be related to the vascular disease of hypertension (and any disease that causes hypertension, e.g. atherosclerosis), diabetes or other ocular diseases corresponding to ophthalmological disorders. Such eye abnormalities may include but are not limited to the following: retinal abnormality is retinal dysplasia, various retinopathies, restenosis, retinal artery obstruction or occlusion; retinal degeneration causing secondary atrophy of the retinal vasculature, retinitis pigmentosa, macular dystrophies, Stargardt's disease, congenital stationary night blindness, choroideremia, gyrate atrophy, Leber's congenital amaurosis, retinoschisis disorders, Wagner's syndrome, Usher syndromes, Zellweger syndrome, Saldino-Mainzer syndrome, Senior-Loken syndrome, Bardet-Biedl syndrome, Alport's syndrome, Alstom's syndrome, Cockayne's syndrome, dysplaisa spondyloepiphysaria congentia, Flynn-Aird syndrome, Friedreich ataxia, Hallgren syndrome, Marshall syndrome, Albers-Schnoberg disease, Refsum's disease, Kearns-Sayre syndrome, Waardenburg's syndrome, Alagile syndrome, myotonic dystrophy, olivopontocerebellar atrophy, Pierre-Marie dunsdrome, Stickler syndrome, carotinemeia, cystinosis, Wolfram syndrome, Bassen-Kornzweig syndrome, abetalipoproteinemia, incontinentia pigmenti, Batten's disease, mucopolysaccharidoses, homocystinuria, or mannosidosis.

[3102] Procedure: A cohort of 4 wild type, 4 heterozygotes and 8 homozygotes were tested in this assay. Optic fundus photography was performed on conscious animals using a Kowa Genesis small animal fundus camera modified according to Hawes and coauthors (Hawes et al., 1999 Molecular Vision 1999; 5:22). Intra-peritoneal injection of fluorescein permitted the acquisition of direct light fundus images and fluorescent angiograms for each examination. In addition to direct ophthalmological changes, this test can detect retinal changes associated with systemic diseases such as diabetes and atherosclerosis or other retinal abnormalities. Pictures were provided of the optic fundus under normal light. The angiographic pictures allowed examination of the arteries and veins of the eye. In addition an artery to vein (A/V) ratio was determined for the eye.

[3103] Ophthalmology analysis was performed on generated F2 wild type, heterozygous, and homozygous mutant progeny using the protocol described above. Specifically, the A/V ratio was measured and calculated according to the fundus images with Kowa COMIT+ software. This test takes color photographs through a dilated pupil: the images help in detecting and classifying many diseases. The artery to vein ratio (A/V) is the ratio of the artery diameter to the vein diameter (measured before the bifurcation of the vessels). Many diseases will influence the ratio, i.e., diabetes, cardiovascular disorders, papilledema, optic atrophy or other eye abnormalities such as retinal degeneration (known as retinitis pigmentosa) or retinal dysplasia, vision problems or blindness. Thus, phenotypic observations which result in an increased artery-to-vein ratio in homozygous (-/-) and heterozygous (+/-) mutant progeny compared to wildtype (+/+) littermates would be indicative of such pathological conditions.

[3104] Results:

Fundus: The (-/-) mice all exhibited semi-transparent retinal vessels that appeared pink in color. The bloodstream could be observed under the fundus microscope, suggesting anomalies of the retinal vasculature in the mutants. Angiogram: The main retinal vasculature of the (-/-) mice could be clearly visualized with blue light illumination before administration of the fluorescein dye, suggesting increased fluorescent material was already present in the blood of the mutant mice. After administration of the fluorescein dye, no notable difference was observed between the (-/-) mice and their (+/+) littermates.

[3105] (d) Immunology Phenotypic Analysis

[3106] Immune related and inflammatory diseases are the manifestation or consequence of fairly complex, often multiple interconnected biological pathways which in normal physiology are critical to respond to insult or injury, initiate repair from insult or injury, and mount innate and acquired defense against foreign organisms. Disease or pathology occurs when these normal physiological pathways cause additional insult or injury either as directly related to the intensity of the response, as a consequence of abnormal regulation or excessive stimulation, as a reaction to self, or as a combination of these.

[3107] Though the genesis of these diseases often involves multistep pathways and often multiple different biological systems/pathways, intervention at critical points in one or more of these pathways can have an ameliorative or therapeutic effect. Therapeutic intervention can occur by either antagonism of a detrimental process/pathway or stimulation of a beneficial process/pathway.

[3108] T lymphocytes (T cells) are an important component of a mammalian immune response. T cells recognize antigens which are associated with a self-molecule encoded by genes within the major histocompatibility complex (MHC). The antigen may be displayed together with MHC molecules on the surface of antigen presenting cells, virus infected cells, cancer cells, grafts, etc. The T cell system eliminates these altered cells which pose a health threat to the host mammal. T cells include helper T cells and cytotoxic T cells. Helper T cells proliferate extensively following recognition of an antigen-MHC complex on an antigen presenting cell. Helper T cells also secrete a variety of cytokines, i.e., lymphokines, which play a central role in the activation of B cells, cytotoxic T cells and a variety of other cells which participate in the immune response.

[3109] In many immune responses, inflammatory cells infiltrate the site of injury or infection. The migrating cells may be neutrophilic, eosinophilic, monocytic or lymphocytic as can be determined by histologic examination of the affected tissues. Current Protocols in Immunology, ed. John E. Coligan, 1994, John Wiley & Sons, Inc.

[3110] Many immune related diseases are known and have been extensively studied. Such diseases include immune-mediated inflammatory diseases (such as rheumatoid arthritis, immune mediated renal disease, hepatobiliary diseases, inflammatory bowel disease (IBD), psoriasis, and asthma), non-immune-mediated inflammatory diseases, infectious diseases, immunodeficiency diseases, neoplasia, and graft rejection, etc. In the area of immunology, targets were identified for the treatment of inflammation and inflammatory disorders.

[3111] In the area of immunology, targets have been identified herein for the treatment of inflammation and inflammatory disorders. Immune related diseases, in one instance, could be treated by suppressing the immune response. Using neutralizing antibodies that inhibit molecules having immune stimulatory activity would be beneficial in the treatment of immune-mediated and inflammatory diseases. Molecules which inhibit the immune response can be utilized (proteins directly or via the use of antibody agonists) to inhibit the immune response and thus ameliorate immune related disease.

[3112] The following tests were performed:

[3113] (1) Hematology

[3114] Test Description Blood tests are carried out by Abbott's Cell-Dyn 3500R, an automated hematology analyzer. Some of its features include a five-part WBC differential. `Patient` reports can cover over 22 parameters in all.

[3115] Results:

Hematology: The (-/-) mice exhibited a notably increased mean absolute neutrophil count and a decreased mean absolute lymphocyte count when compared with those of their (+/+) littermates and the historical means. The (-/-) mice also exhibited a decreased mean red blood cell count and a decreased mean hematocrit level. In addition, the (-/-) mice exhibited increased mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, and red blood cell distribution width, suggesting that the red blood cells in the mutant mice are a little larger than normal with increased variation in size.

[3116] These results are related to a phenotype associated with anemia. Thus, PRO35250 polypeptides, agonists thereof or the encoding gene for PRO35350 polypeptides must be essential for normal red blood cell production and as such would be useful in the treatment of blood disorders associated with anemia or a low hematocrit.

[3117] (2) Acute Phase Response:

[3118] Test Description: Bacterial lipopolysaccharide (LPS) is an endotoxin, and as such is a potent inducer of an acute phase response and systemic inflammation. The Level I LPS mice were injected intraperitoneally (i.p.) with a sublethal dose of LPS in 200 .mu.L sterile saline using a 26 gauge needle. The doses were based on the average weight of the mice tested at 1 .mu.g/g body weight 3 hours after injection; a 100 ul blood sample was then taken and analyzed for the presence of TNFa, MCP-1, and IL-6 on the FACS Calibur instrument.

[3119] Results:

Acute Phase Response: The (-/-) mice exhibited a notably increased mean serum IL-6 response to LPS challenge when compared with that of their (+/+) littermates and the historical mean.

[3120] In summary, the LPS endotoxin challenge demonstrated that knockout mice deficient in the gene encoding PRO35250 polypeptides exhibit immunological abnormalities when compared with their wild-type littermates. In particular, the mutant mice exhibited an increased ability to elicit an immunological response (IL-6 production) when challenged with the LPS endotoxin indicating a pro-inflammatory response. 11-6 contributes to the later stages of B cell activation. In addition, 11-6 plays a critical role in inducing the acute phase response and systemic inflammation. Thus, PRO35250 polypeptides function as a negative regulator of the immune response.

[3121] (3) Serum Immunoglobulin. Isotyping Assay:

[3122] The Serum Immunoglobulin Isotyping Assay is performed using a Cytometric Bead Array (CBA) kit. This assay is used to rapidly identify the heavy and light chain isotypes of a mouse monoclonal antibody in a single sample. The values expressed are "relative fluorescence units" and are based on the detection of kappa light chains. Any value <6 is not significant.

[3123] Results:

Serum Imm. 2: The (-/-) mice exhibited an increased mean serum IgM level and an increased mean serum IgG3 level when compared with that of their (+/+) littermates, the (+/+) mice within the project run, and the historical medians.

[3124] Mutant (-/-) mice exhibited elevation of IgM serum immunoglobulins compared to their gender-matched (+/+) littermates. IgM immunoglobulins are the first to be produced in a humoral immune response for neutralization of bacterial toxins and are particularly important in activating the complement system. The mutant (-/-) mice also exhibited elevation of IgG3 serum immunoglobulins compared to their gender-matched (+/+) littermates. These immunoglobulins have neutralization effects and to a lesser extent are important for activation of the complement system. The observed phenotype suggests that the PRO35250 polypeptide is a negative regulator of inflammatory responses. These immunological abnormalities suggest that inhibitors (antagonists) of PRO35250 polypeptides would be important agents which could stimulate the immune system (such as T cell proliferation) and would find utility in the cases wherein this effect would be beneficial to the individual such as in the case of leukemia, and other types of cancer, and in immunocompromised patients, such as AIDS sufferers. Accordingly, PRO35250 polypeptides or agonists thereof would be useful in inhibiting the immune response and would be useful candidates for suppressing harmful immune responses, e.g. in the case of graft rejection or graft-versus-host diseases.

[3125] (e) Phenotypic Analysis: Cardiology

[3126] In the area of cardiovascular biology, targets were identified herein for the treatment of hypertension, atherosclerosis, heart failure, stroke, various coronary artery diseases, dyslipidemias such as high cholesterol (hypercholesterolemia) and elevated serum triglycerides (hypertriglyceridemia), diabetes and/or obesity. The phenotypic tests included the measurement of serum cholesterol and triglycerides. In addition to measuring blood lipid levels the following blood chemistry tests are also routinely performed: Alkaline Phosphatase; Alanine Amino-Transferase; Albumin; Bilirubin; Phosphorous; Creatinine; BUN=Blood Urea Nitrogen; Calcium; Uric Acid; Sodium; Potassium; and Chloride.

[3127] Blood Lipids & Blood Chemistry Results

[3128] Procedure: A cohort of 4 wild type, 4 heterozygotes and 8 homozygotes were tested in this assay. High cholesterol levels and increased triglyceride blood levels are recognized risk factors in the development of cardiovascular disease and/or diabetes. Measuring blood lipids facilitates the finding of biological switches that regulate blood lipid levels. Inhibition of factors which elevate blood lipid levels may be useful for reducing the risk for cardiovascular disease. In these blood chemistry tests, measurements were recorded using the COBAS Integra 400 (mfr: Roche).

[3129] Results:

Blood Chemistry: Both the male and female (-/-) mice exhibited enormously elevated mean serum cholesterol (>11 SD above the mean) and triglyceride (.about.214 SD above the mean) levels. Alkaline phosphatase levels were also elevated as well as total bilirubin (.about.29 times the normal) and decreased calcium levels (8 SD below the mean) when compared with those of their gender-matched (+/+) littermates and the historical means.

[3130] As summarized above, the (-/-) mice exhibited notably increased mean serum cholesterol and triglyceride levels when compared with their gender-matched (+/+) littermates and the historical means. Thus, mutant mice deficient in the PRO35250 gene can serve as a model for cardiovascular disease. PRO35250 polypeptides or its encoding gene would be useful in regulating blood lipids such as cholesterol and triglycerides. Thus, PRO35250 polypeptides or agonists thereof would be useful in the treatment of such cardiovascular diseases as hypertension, atherosclerosis, heart failure, stroke, various coronary diseases, hypercholesterolemia, hypertriglyceridemia, diabetes and/or obesity.

[3131] The (-/-) mice exhibited notably decreased mean serum calcium, sodium, and chloride levels. The (-/-) mice also exhibited an increased mean serum bilirubin level; however, the notable lipemia in the mutant samples could have skewed this reading, since the presence of even slight lipemia is known to affect the reliability of bilirubin measurements. The depressed levels of sodium and chloride are an indication of an electrolyte imbalance. The decreased mean serum calcium levels could be indicative of the increased alkaline phosphatase activity noted above.

[3132] Bone Metabolism: Radiology Phenotypic Analysis

[3133] In the area of bone metabolism, targets were identified herein for the treatment of arthritis, osteoporosis, osteopenia and osteopetrosis as well as identifying targets that promote bone healing. Tests included: [3134] DEXA for measurement of bone mineral density on femur and vertebra [3135] MicroCT for very high resolution and very high sensitivity measurements of bone mineral density for both trabecular and cortical bone.

[3136] Dexa Analysis--Test Description:

[3137] Procedure: A cohort of 4 wild type, 4 heterozygotes and 8 homozygotes were tested in this assay. Dual Energy X-ray Absorptiometry (DEXA) has been used successfully to identify changes in bone. Anesthetized animals were examined and bone mineral content (BMC), BMC/LBM ratios, volumetric bone mineral density (vBMD), total body BMD, femur BMD and vertebra BMD were measured.

[3138] The mouse was anesthetized by intraperitoneal injection of Avertin (1.25% 2,2,2,-tribromoethanol, 20 ml/kg body weight), body length and weight were measured, and then the mouse was placed in a prone position on the platform of the PIXImus.TM. Densitometer (Lunar Inc.) for a DEXA scan. Using Lunar PIXImus software, the bone mineral density (BMD) and fat composition (% fat) and total tissue mass (TTM) were determined in the regions of interest (ROI) [i.e., whole body, vertebrae, and both femurs].

[3139] Bone MicroCT Analysis:

[3140] Procedure: MicroCT was also used to get very sensitive measurements of BMD. One vertebra and 1 femur were taken from a cohort of 4 wild type and 8 homozygous mice. Measurements were taken of lumbar 5 veterbra traebecular bone volume, traebecular thickness, connectivity density and midshaft femur total bone area and cortical thickness. The .mu.CT40 scans provided detailed information on bone mass and architecture. Multiple bones were placed into sample holders and scanned automatically. Instrument software was used to select regions of interest for analysis. Trabecular bone parameters were analyzed in the fifth lumbar vertebrae (LV5) at 16 micrometer resolution and cortical bone parameters were analyzed in the femur midshaft at a resolution of 20 micrometers.

[3141] Results:

Micro CT: The male (-/-) mice exhibited increased mean vertebral trabecular number and connectivity density when compared with that of their gender-matched (+/+) littermates and the historical means.

[3142] The (-/-) mice analyzed by bone micro CT analysis exhibited increased bone measurements when compared with their (+/+) littermates, suggestive of abnormal bone disorders such as osteopetrosis. These observations suggest that mutant mice deficient in the gene which encodes PRO35250 polypeptides leads to metabolic disorders abnormal bone measurements reflective of osteopetrosis. Thus, PRO35250 polypeptides or agonists thereof would be useful in the treatment of bone related disorders such as osteopetrosis or would be useful in maintaining bone homeostasis. Antagonists (or inhibitors) of PRO35250 polypeptides or its encoding gene would lead to abnormal or pathological bone disorders including inflammatory diseases associated with abnormal bone metabolism.

Example 67

Use of PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 as a Hybridization Probe

[3143] The following method describes use of a nucleotide sequence encoding a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide as a hybridization probe.

[3144] DNA comprising the coding sequence of full-length or mature PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides as disclosed herein is employed as a probe to screen for homologous DNAs (such as those encoding naturally-occurring variants of PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides) in human tissue cDNA libraries or human tissue genomic libraries.

[3145] Hybridization and washing of filters containing either library DNAs is performed under the following high stringency conditions. Hybridization of radiolabeled PRO69122-, PRO204-, PRO214-, PRO222-, PRO234-, PRO265-, PRO309-, PRO332-, PRO342-, PRO356-, PRO540-, PRO618-, PRO944-, PRO994-, PRO1079-, PRO1110-, PRO1122-, PRO1138-, PRO1190-, PRO1272-, PRO1286-, PRO1295-, PRO1309-, PRO1316-, PRO1383-, PRO1384-, PRO1431-, PRO1434-, PRO1475-, PRO1481-, PRO1568-, PRO1573-, PRO1599-, PRO1604-, PRO1605-, PRO1693-, PRO1753-, PRO1755-, PRO1777-, PRO1788-, PRO1864-, PRO1925-, PRO1926-, PRO3566-, PRO4330-, PRO4423-, PRO36935-, PRO4977-, PRO4979-, PRO4980-, PRO4981-, PRO5801-, PRO5995-, PRO6001-, PRO6095-, PRO6182-, PRO7170-, PRO7171-, PRO7436-, PRO9912-, PRO9917-, PRO37337-, PRO37496-, PRO19646-, PRO21718-, PRO19820-, PRO21201-, PRO20026-, PRO20110-, PRO23203- or PRO35250-derived probe to the filters is performed in a solution of 50% formamide, 5.times.SSC, 0.1% SDS, 0.1% sodium pyrophosphate, 50 mM sodium phosphate, pH 6.8, 2.times.Denhardt's solution, and 10% dextran sulfate at 42.degree. C. for 20 hours. Washing of the filters is performed in an aqueous solution of 0.1.times.SSC and 0.1% SDS at 42.degree. C.

[3146] DNAs having a desired sequence identity with the DNA encoding full-length native sequence PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides can then be identified using standard techniques known in the art.

Example 68

Expression of PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 in E. coli

[3147] This example illustrates preparation of an unglycosylated form of PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides by recombinant expression in E. coli.

[3148] The DNA sequence encoding a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide is initially amplified using selected PCR primers. The primers should contain restriction enzyme sites which correspond to the restriction enzyme sites on the selected expression vector. A variety of expression vectors may be employed. An example of a suitable vector is pBR322 (derived from E. coli; see Bolivar et al., Gene, 2:95 (1977)) which contains genes for ampicillin and tetracycline resistance. The vector is digested with restriction enzyme and dephosphorylated. The PCR amplified sequences are then ligated into the vector. The vector will preferably include sequences which encode for an antibiotic resistance gene, a trp promoter, a polyhis leader (including the first six STII codons, polyhis sequence, and enterokinase cleavage site), the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 coding region, lambda transcriptional terminator, and an argU gene.

[3149] The ligation mixture is then used to transform a selected E. coli strain using the methods described in Sambrook et al., supra. Transformants are identified by their ability to grow on LB plates and antibiotic resistant colonies are then selected. Plasmid DNA can be isolated and confirmed by restriction analysis and DNA sequencing.

[3150] Selected clones can be grown overnight in liquid culture medium such as LB broth supplemented with antibiotics. The overnight culture may subsequently be used to inoculate a larger scale culture. The cells are then grown to a desired optical density, during which the expression promoter is turned on.

[3151] After culturing the cells for several more hours, the cells can be harvested by centrifugation. The cell pellet obtained by the centrifugation can be solubilized using various agents known in the art, and the solubilized PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 protein can then be purified using a metal chelating column under conditions that allow tight binding of the protein.

[3152] PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 may be expressed in E. coli in a poly-His tagged form, using the following procedure. The DNA encoding PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 is initially amplified using selected PCR primers. The primers will contain restriction enzyme sites which correspond to the restriction enzyme sites on the selected expression vector, and other useful sequences providing for efficient and reliable translation initiation, rapid purification on a metal chelation column, and proteolytic removal with enterokinase. The PCR-amplified, poly-His tagged sequences are then ligated into an expression vector, which is used to transform an E. coli host based on strain 52 (W3110 fuhA(tonA) lon galE rpoHts(htpRts) c1pP(lacIq). Transformants are first grown in LB containing 50 mg/ml carbenicillin at 30.degree. C. with shaking until an O.D.600 of 3-5 is reached. Cultures are then diluted 50-100 fold into CRAP media (prepared by mixing 3.57 g (NH.sub.4).sub.2SO.sub.4, 0.71 g sodium citrate.2H2O, 1.07 g KCl, 5.36 g Difco yeast extract, 5.36 g Sheffield hycase SF in 500 mL water, as well as 110 mM MPOS, pH 7.3, 0.55% (w/v) glucose and 7 mM MgSO.sub.4) and grown for approximately 20-30 hours at 30.degree. C. with shaking. Samples are removed to verify expression by SDS-PAGE analysis, and the bulk culture is centrifuged to pellet the cells. Cell pellets are frozen until purification and refolding.

[3153] E. coli paste from 0.5 to 1 L fermentations (6-10 g pellets) is resuspended in 10 volumes (w/v) in 7 M guanidine, 20 mM Tris, pH 8 buffer. Solid sodium sulfite and sodium tetrathionate is added to make final concentrations of 0.1M and 0.02 M, respectively, and the solution is stirred overnight at 4.degree. C. This step results in a denatured protein with all cysteine residues blocked by sulfitolization. The solution is centrifuged at 40,000 rpm in a Beckman Ultracentifuge for 30 min. The supernatant is diluted with 3-5 volumes of metal chelate column buffer (6 M guanidine, 20 mM Tris, pH 7.4) and filtered through 0.22 micron filters to clarify. The clarified extract is loaded onto a 5 ml Qiagen Ni-NTA metal chelate column equilibrated in the metal chelate column buffer. The column is washed with additional buffer containing 50 mM imidazole (Calbiochem, Utrol grade), pH 7.4. The protein is eluted with buffer containing 250 mM imidazole. Fractions containing the desired protein are pooled and stored at 4.degree. C. Protein concentration is estimated by its absorbance at 280 nm using the calculated extinction coefficient based on its amino acid sequence.

[3154] The proteins are refolded by diluting the sample slowly into freshly prepared refolding buffer consisting of: 20 mM Tris, pH 8.6, 0.3 M NaCl, 2.5 M urea, 5 mM cysteine, 20 mM glycine and 1 mM EDTA. Refolding volumes are chosen so that the final protein concentration is between 50 to 100 micrograms/ml. The refolding solution is stirred gently at 4.degree. C. for 12-36 hours. The refolding reaction is quenched by the addition of TFA to a final concentration of 0.4% (pH of approximately 3). Before further purification of the protein, the solution is filtered through a 0.22 micron filter and acetonitrile is added to 2-10% final concentration. The refolded protein is chromatographed on a Paras R1/H reversed phase column using a mobile buffer of 0.1% TFA with elution with a gradient of acetonitrile from 10 to 80%. Aliquots of fractions with A280 absorbance are analyzed on SDS polyacrylamide gels and fractions containing homogeneous refolded protein are pooled. Generally, the properly refolded species of most proteins are eluted at the lowest concentrations of acetonitrile since those species are the most compact with their hydrophobic interiors shielded from interaction with the reversed phase resin. Aggregated species are usually eluted at higher acetonitrile concentrations. In addition to resolving misfolded forms of proteins from the desired form, the reversed phase step also removes endotoxin from the samples.

[3155] Fractions containing the desired folded PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide are pooled and the acetonitrile removed using a gentle stream of nitrogen directed at the solution. Proteins are formulated into 20 mM Hepes, pH 6.8 with 0.14 M sodium chloride and 4% mannitol by dialysis or by gel filtration using G25 Superfine (Pharmacia) resins equilibrated in the formulation buffer and sterile filtered.

Example 69

Expression of PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 in mammalian cells

[3156] This example illustrates preparation of a potentially glycosylated form of a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide by recombinant expression in mammalian cells.

[3157] The vector, pRK5 (see EP 307,247, published Mar. 15, 1989), is employed as the expression vector. Optionally, the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 DNA is ligated into pRK5 with selected restriction enzymes to allow insertion of the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 DNA using ligation methods such as described in Sambrook et al., supra. The resulting vector is called pRK5-PRO69122, pRK5-PRO204, pRK5-PRO214, pRK5-PRO222, pRK5-PRO234, pRK5-PRO265, pRK5-PRO309, pRK5-PRO332, pRK5-PRO342, pRK5-PRO356, pRK5-PRO540, pRK5-PRO618, pRK5-PRO944, pRK5-PRO994, pRK5-PRO1079, pRK5-PRO1110, pRK5-PRO1122, pRK5-PRO1138, pRK5-PRO1190, pRK5-PRO1272, pRK5-PRO1286, pRK5-PRO1295, pRK5-PRO1309, pRK5-PRO1316, pRK5-pRK5-PRO1383, pRK5-PRO1384, pRK5-PRO1431, pRK5-PRO1434, pRK5-PRO1475, pRK5-PRO1481, pRK5-PRO1568, pRK5-PRO1573, pRK5-PRO1599, pRK5-PRO1604, pRK5-PRO1605, pRK5-PRO1693, pRK5-PRO1753, pRK5-PRO1755, pRK5-PRO1777, pRK5-PRO1788, pRK5-PRO1864, pRK5-PRO1925, pRK5-PRO1926, pRK5-PRO3566, pRK5-PRO4330, pRK5-PRO4423, pRK5-PRO36935, pRK5-PRO4977, pRK5-PRO4979, pRK5-PRO4980, pRK5-PRO4981, pRK5-PRO5801, pRK5-PRO5995, pRK5-PRO6001, pRK5-PRO6095, pRK5-PRO6182, pRK5-PRO7170, pRK5-PRO7171, pRK5-PRO7436, pRK5-PRO9912, pRK5-PRO9917, pRK5-PRO37337, pRK5-PRO37496, pRK5-PRO19646, pRK5-PRO21718, pRK5-PRO19820, pRK5-PRO21201, pRK5-PRO20026, pRK5-PRO20110, pRK5-PRO23203 or pRK5-PRO35250.

[3158] The selected host cells may be 293 cells. Human 293 cells (ATCC CCL 1573) are grown to confluence in tissue culture plates in medium such as DMEM supplemented with fetal calf serum and optionally, nutrient components and/or antibiotics. About 10 .mu.g pRK5-PRO69122, pRK5-PRO204, pRK5-PRO214, pRK5-PRO222, pRK5-PRO234, pRK5-PRO265, pRK5-PRO309, pRK5-PRO332, pRK5-PRO342, pRK5-PRO356, pRK5-PRO540, pRK5-PRO618, pRK5-PRO944, pRK5-PRO994, pRK5-PRO1079, pRK5-PRO1110, pRK5-PRO1122, pRK5-PRO1138, pRK5-PRO1190, pRK5-PRO1272, pRK5-PRO1286, pRK5-PRO1295, pRK5-PRO1309, pRK5-PRO1316, pRK5-pRK5-PRO1383, pRK5-PRO1384, pRK5-PRO1431, pRK5-PRO1434, pRK5-PRO1475, pRK5-PRO1481, pRK5-PRO1568, pRK5-PRO1573, pRK5-PRO1599, pRK5-PRO1604, pRK5-PRO1605, pRK5-PRO1693, pRK5-PRO1753, pRK5-PRO1755, pRK5-PRO1777, pRK5-PRO1788, pRK5-PRO1864, pRK5-PRO1925, pRK5-PRO1926, pRK5-PRO3566, pRK5-PRO4330, pRK5-PRO4423, pRK5-PRO36935, pRK5-PRO4977, pRK5-PRO4979, pRK5-PRO4980, pRK5-PRO4981, pRK5-PRO5801, pRK5-PRO5995, pRK5-PRO6001, pRK5-PRO6095, pRK5-PRO6182, pRK5-PRO7170, pRK5-PRO7171, pRK5-PRO7436, pRK5-PRO9912, pRK5-PRO9917, pRK5-PRO37337, pRK5-PRO37496, pRK5-PRO19646, pRK5-PRO21718, pRK5-PRO19820, pRK5-PRO21201, pRK5-PRO20026, pRK5-PRO20110, pRK5-PRO23203 or pRK5-PRO35250 DNA is mixed with about 1 .mu.g DNA encoding the VA RNA gene [Thimmappaya et al., Cell, 31:543 (1982)] and dissolved in 500 .mu.l of 1 mM Tris-HCl, 0.1 mM EDTA, 0.227 M CaCl.sub.2. To this mixture is added, dropwise, 500 .mu.l of 50 mM HEPES (pH 7.35), 280 mM NaCl, 1.5 mM NaPO.sub.4, and a precipitate is allowed to form for 10 minutes at 25.degree. C. The precipitate is suspended and added to the 293 cells and allowed to settle for about four hours at 37.degree. C. The culture medium is aspirated off and 2 ml of 20% glycerol in PBS is added for 30 seconds. The 293 cells are then washed with serum free medium, fresh medium is added and the cells are incubated for about 5 days.

[3159] Approximately 24 hours after the transfections, the culture medium is removed and replaced with culture medium (alone) or culture medium containing 200 .mu.Ci/ml .sup.35S-cysteine and 200 .mu.Ci/ml .sup.35S-methionine. After a 12 hour incubation, the conditioned medium is collected, concentrated on a spin filter, and loaded onto a 15% SDS gel. The processed gel may be dried and exposed to film for a selected period of time to reveal the presence of PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides. The cultures containing transfected cells may undergo further incubation (in serum free medium) and the medium is tested in selected bioassays.

[3160] In an alternative technique, PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 may be introduced into 293 cells transiently using the dextran sulfate method described by Somparyrac et al., Proc. Natl. Acad. Sci., 12:7575 (1981). 293 cells are grown to maximal density in a spinner flask and 700 .mu.g, pRK5-PRO69122, pRK5-PRO204, pRK5-PRO214, pRK5-PRO222, pRK5-PRO234, pRK5-PRO265, pRK5-PRO309, pRK5-PRO332, pRK5-PRO342, pRK5-PRO356, pRK5-PRO540, pRK5-PRO618, pRK5-PRO944, pRK5-PRO994, pRK5-PRO1079, pRK5-PRO1110, pRK5-PRO1122, pRK5-PRO1138, pRK5-PRO1190, pRK5-PRO1272, pRK5-PRO1286, pRK5-PRO1295, pRK5-PRO1309, pRK5-PRO1316, pRK5-pRK5-PRO1383, pRK5-PRO1384, pRK5-PRO1431, pRK5-PRO1434, pRK5-PRO1475, pRK5-PRO1481, pRK5-PRO1568, pRK5-PRO1573, pRK5-PRO1599, pRK5-PRO1604, pRK5-PRO1605, pRK5-PRO1693, pRK5-PRO1753, pRK5-PRO1755, pRK5-PRO1777, pRK5-PRO1788, pRK5-PRO1864, pRK5-PRO1925, pRK5-PRO1926, pRK5-PRO3566, pRK5-PRO4330, pRK5-PRO4423, pRK5-PRO36935, pRK5-PRO4977, pRK5-PRO4979, pRK5-PRO4980, pRK5-PRO4981, pRK5-PRO5801, pRK5-PRO5995, pRK5-PRO6001, pRK5-PRO6095, pRK5-PRO6182, pRK5-PRO7170, pRK5-PRO7171, pRK5-PRO7436, pRK5-PRO9912, pRK5-PRO9917, pRK5-PRO37337, pRK5-PRO37496, pRK5-PRO19646, pRK5-PRO21718, pRK5-PRO19820, pRK5-PRO21201, pRK5-PRO20026, pRK5-PRO20110, pRK5-PRO23203 or pRK5-PRO35250 DNA is added. The cells are first concentrated from the spinner flask by centrifugation and washed with PBS. The DNA-dextran precipitate is incubated on the cell pellet for four hours. The cells are treated with 20% glycerol for 90 seconds, washed with tissue culture medium, and re-introduced into the spinner flask containing tissue culture medium, 5 .mu.g/ml bovine insulin and 0.1 .mu.g/ml bovine transferrin. After about four days, the conditioned media is centrifuged and filtered to remove cells and debris. The sample containing expressed PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 can then be concentrated and purified by any selected method, such as dialysis and/or column chromatography.

[3161] PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 can be expressed in CHO cells. The pRK5-PRO69122, pRK5-PRO204, pRK5-PRO214, pRK5-PRO222, pRK5-PRO234, pRK5-PRO265, pRK5-PRO309, pRK5-PRO332, pRK5-PRO342, pRK5-PRO356, pRK5-PRO540, pRK5-PRO618, pRK5-PRO944, pRK5-PRO994, pRK5-PRO1079, pRK5-PRO1110, pRK5-PRO1122, pRK5-PRO1138, pRK5-PRO1190, pRK5-PRO1272, pRK5-PRO1286, pRK5-PRO1295, pRK5-PRO1309, pRK5-PRO1316, pRK5-pRK5-PRO1383, pRK5-PRO1384, pRK5-PRO1431, pRK5-PRO1434, pRK5-PRO1475, pRK5-PRO1481, pRK5-PRO1568, pRK5-PRO1573, pRK5-PRO1599, pRK5-PRO1604, pRK5-PRO1605, pRK5-PRO1693, pRK5-PRO1753, pRK5-PRO1755, pRK5-PRO1777, pRK5-PRO1788, pRK5-PRO1864, pRK5-PRO1925, pRK5-PRO1926, pRK5-PRO3566, pRK5-PRO4330, pRK5-PRO4423, pRK5-PRO36935, pRK5-PRO4977, pRK5-PRO4979, pRK5-PRO4980, pRK5-PRO4981, pRK5-PRO5801, pRK5-PRO5995, pRK5-PRO6001, pRK5-PRO6095, pRK5-PRO6182, pRK5-PRO7170, pRK5-PRO7171, pRK5-PRO7436, pRK5-PRO9912, pRK5-PRO9917, pRK5-PRO37337, pRK5-PRO37496, pRK5-PRO19646, pRK5-PRO21718, pRK5-PRO19820, pRK5-PRO21201, pRK5-PRO20026, pRK5-PRO20110, pRK5-PRO23203 or pRK5-PRO35250 can be transfected into CHO cells using known reagents such as CaPO.sub.4 or DEAE-dextran. As described above, the cell cultures can be incubated, and the medium replaced with culture medium (alone) or medium containing a radiolabel such as .sup.35S-methionine. After determining the presence of PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, the culture medium may be replaced with serum free medium. Preferably, the cultures are incubated for about 6 days, and then the conditioned medium is harvested. The medium containing the expressed PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 can then be concentrated and purified by any selected method.

[3162] Epitope-tagged PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 may also be expressed in host CHO cells. The PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 may be subcloned out of the pRK5 vector. The subclone insert can undergo PCR to fuse in frame with a selected epitope tag such as a poly-his tag into a Baculovirus expression vector. The poly-his tagged PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 insert can then be subcloned into a SV40 driven vector containing a selection marker such as DHFR for selection of stable clones. Finally, the CHO cells can be transfected (as described above) with the SV40 driven vector. Labeling may be performed, as described above, to verify expression. The culture medium containing the expressed poly-His tagged PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 can then be concentrated and purified by any selected method, such as by Ni.sup.2+-chelate affinity chromatography.

[3163] PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 may also be expressed in CHO and/or COS cells by a transient expression procedure or in CHO cells by another stable expression procedure.

[3164] Stable expression in CHO cells is performed using the following procedure. The proteins are expressed as an IgG construct (immunoadhesin), in which the coding sequences for the soluble forms (e.g. extracellular domains) of the respective proteins are fused to an IgG1 constant region sequence containing the hinge, CH2 and CH2 domains and/or is a poly-His tagged form.

[3165] Following PCR amplification, the respective DNAs are subcloned in a CHO expression vector using standard techniques as described in Ausubel et al., Current Protocols of Molecular Biology, Unit 3.16, John Wiley and Sons (1997). CHO expression vectors are constructed to have compatible restriction sites 5' and 3' of the DNA of interest to allow the convenient shuttling of cDNA's. The vector used expression in CHO cells is as described in Lucas et al., Nucl. Acids Res. 24:9 (1774-1779 (1996), and uses the SV40 early promoter/enhancer to drive expression of the cDNA of interest and dihydrofolate reductase (DHFR). DHFR expression permits selection for stable maintenance of the plasmid following transfection.

[3166] Twelve micrograms of the desired plasmid DNA is introduced into approximately 10 million CHO cells using commercially available transfection reagents Superfect.RTM. (Qiagen), Dosper.RTM. or Fugene.RTM. (Boehringer Mannheim). The cells are grown as described in Lucas et al., supra. Approximately 3.times.10.sup.7 cells are frozen in an ampule for further growth and production as described below.

[3167] The ampules containing the plasmid DNA are thawed by placement into water bath and mixed by vortexing. The contents are pipetted into a centrifuge tube containing 10 mLs of media and centrifuged at 1000 rpm for 5 minutes. The supernatant is aspirated and the cells are resuspended in 10 mL of selective media (0.2 .mu.m filtered PS20 with 5% 0.2 .mu.m diafiltered fetal bovine serum). The cells are then aliquoted into a 100 mL spinner containing 90 mL of selective media. After 1-2 days, the cells are transferred into a 250 mL spinner filled with 150 mL selective growth medium and incubated at 37.degree. C. After another 2-3 days, 250 mL, 500 mL and 2000 mL spinners are seeded with 3.times.10.sup.5 cells/mL. The cell media is exchanged with fresh media by centrifugation and resuspension in production medium. Although any suitable CHO media may be employed, a production medium described in U.S. Pat. No. 5,122,469, issued Jun. 16, 1992 may actually be used. A 3L production spinner is seeded at 1.2.times.10.sup.6 cells/mL. On day 0, the cell number pH ie determined. On day 1, the spinner is sampled and sparging with filtered air is commenced. On day 2, the spinner is sampled, the temperature shifted to 33.degree. C., and 30 mL of 500 g/L glucose and 0.6 mL of 10% antifoam (e.g., 35% polydimethylsiloxane emulsion, Dow Corning 365 Medical Grade Emulsion) taken. Throughout the production, the pH is adjusted as necessary to keep it at around 7.2. After 10 days, or until the viability dropped below 70%, the cell culture is harvested by centrifugation and filtering through a 0.22 .mu.m filter. The filtrate was either stored at 4.degree. C. or immediately loaded onto columns for purification.

[3168] For the poly-His tagged constructs, the proteins are purified using a Ni-NTA column (Qiagen). Before purification, imidazole is added to the conditioned media to a concentration of 5 mM. The conditioned media is pumped onto a 6 ml Ni-NTA column equilibrated in 20 mM Hepes, pH 7.4, buffer containing 0.3 M NaCl and 5 mM imidazole at a flow rate of 4-5 ml/min. at 4.degree. C. After loading, the column is washed with additional equilibration buffer and the protein eluted with equilibration buffer containing 0.25 M imidazole. The highly purified protein is subsequently desalted into a storage buffer containing 10 mM Hepes, 0.14 M NaCl and 4% mannitol, pH 6.8, with a 25 ml G25 Superfine (Pharmacia) column and stored at -80.degree. C.

[3169] Immunoadhesin (Fc-containing) constructs are purified from the conditioned media as follows. The conditioned medium is pumped onto a 5 ml Protein A column (Pharmacia) which had been equilibrated in 20 mM Na phosphate buffer, pH 6.8. After loading, the column is washed extensively with equilibration buffer before elution with 100 mM citric acid, pH 3.5. The eluted protein is immediately neutralized by collecting 1 ml fractions into tubes containing 275 .mu.l of 1 M Tris buffer, pH 9. The highly purified protein is subsequently desalted into storage buffer as described above for the poly-His tagged proteins. The homogeneity is assessed by SDS polyacrylamide gels and by N-terminal amino acid sequencing by Edman degradation.

Example 70

Expression of PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO1110, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 in Yeast

[3170] The following method describes recombinant expression of PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 in yeast.

[3171] First, yeast expression vectors are constructed for intracellular production or secretion of PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 from the ADH2/GAPDH promoter. DNA encoding PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO1110, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 and the promoter is inserted into suitable restriction enzyme sites in the selected plasmid to direct intracellular expression of PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250. For secretion, DNA encoding PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 can be cloned into the selected plasmid, together with DNA encoding the ADH2/GAPDH promoter, a native PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 signal peptide or other mammalian signal peptide, or, for example, a yeast alpha-factor or invertase secretory signal/leader sequence, and linker sequences (if needed) for expression of PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250.

[3172] Yeast cells, such as yeast strain AB 110, can then be transformed with the expression plasmids described above and cultured in selected fermentation media. The transformed yeast supernatants can be analyzed by precipitation with 10% trichloroacetic acid and separation by SDS-PAGE, followed by staining of the gels with Coomassie Blue stain.

[3173] Recombinant PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 can subsequently be isolated and purified by removing the yeast cells from the fermentation medium by centrifugation and then concentrating the medium using selected cartridge filters. The concentrate containing PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 may further be purified using selected column chromatography resins.

Example 71

Expression of PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 in Baculovirus-Infected Insect Cells

[3174] The following method describes recombinant expression of PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 in Baculovirus-infected insect cells.

[3175] The sequence coding for PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 is fused upstream of an epitope tag contained within a baculovirus expression vector. Such epitope tags include poly-his tags and immunoglobulin tags (like Fc regions of IgG). A variety of plasmids may be employed, including plasmids derived from commercially available plasmids such as pVL1393 (Novagen). Briefly, the sequence encoding PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 or the desired portion of the coding sequence of PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 such as the sequence encoding the extracellular domain of a transmembrane protein or the sequence encoding the mature protein if the protein is extracellular is amplified by PCR with primers complementary to the 5' and 3' regions. The 5' primer may incorporate flanking (selected) restriction enzyme sites. The product is then digested with those selected restriction enzymes and subcloned into the expression vector.

[3176] Recombinant baculovirus is generated by co-transfecting the above plasmid and BaculoGold.TM. virus DNA (Pharmingen) into Spodoptera frugiperda ("Sf9") cells (ATCC CRL 1711) using lipofectin (commercially available from GIBCO-BRL). After 4-5 days of incubation at 28.degree. C., the released viruses are harvested and used for further amplifications. Viral infection and protein expression are performed as described by O'Reilley et al., Baculovirus expression vectors: A Laboratory Manual, Oxford: Oxford University Press (1994).

[3177] Expressed poly-his tagged PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 can then be purified, for example, by Ni.sup.2+-chelate affinity chromatography as follows. Extracts are prepared from recombinant virus-infected Sf9 cells as described by Rupert et al., Nature, 362:175-179 (1993). Briefly, Sf9 cells are washed, resuspended in sonication buffer (25 mL Hepes, pH 7.9; 12.5 mM MgCl.sub.2; 0.1 mM EDTA; 10% glycerol; 0.1% NP-40; 0.4 M KCl), and sonicated twice for 20 seconds on ice. The sonicates are cleared by centrifugation, and the supernatant is diluted 50-fold in loading buffer (50 mM phosphate, 300 mM NaCl, 10% glycerol, pH 7.8) and filtered through a 0.45 .mu.m filter. A Ni.sup.2+-NTA agarose column (commercially available from Qiagen) is prepared with a bed volume of 5 mL, washed with 25 mL of water and equilibrated with 25 mL of loading buffer. The filtered cell extract is loaded onto the column at 0.5 mL per minute. The column is washed to baseline A.sub.280 with loading buffer, at which point fraction collection is started. Next, the column is washed with a secondary wash buffer (50 mM phosphate; 300 mM NaCl, 10% glycerol, pH 6.0), which elutes nonspecifically bound protein. After reaching A.sub.280 baseline again, the column is developed with a 0 to 500 mM Imidazole gradient in the secondary wash buffer. One mL fractions are collected and analyzed by SDS-PAGE and silver staining or Western blot with Ni.sup.2+-NTA-conjugated to alkaline phosphatase (Qiagen). Fractions containing the eluted His.sub.10-tagged PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 are pooled and dialyzed against loading buffer.

[3178] Alternatively, purification of the IgG tagged (or Fc tagged) PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 can be performed using known chromatography techniques, including for instance, Protein A or protein G column chromatography.

Example 72

Preparation of Antibodies that Bind PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475. PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250

[3179] This example illustrates preparation of monoclonal antibodies which can specifically bind PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250.

[3180] Techniques for producing the monoclonal antibodies are known in the art and are described, for instance, in Goding, supra. Immunogens that may be employed include purified PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides, fusion proteins containing PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides, and cells expressing recombinant PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides on the cell surface. Selection of the immunogen can be made by the skilled artisan without undue experimentation.

[3181] Mice, such as Balb/c, are immunized with the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 immunogen emulsified in complete Freund's adjuvant and injected subcutaneously or intraperitoneally in an amount from 1-100 micrograms. Alternatively, the immunogen is emulsified in MPL-TDM adjuvant (Ribi Immunochemical Research, Hamilton, Mont.) and injected into the animal's hind foot pads. The immunized mice are then boosted 10 to 12 days later with additional immunogen emulsified in the selected adjuvant. Thereafter, for several weeks, the mice may also be boosted with additional immunization injections. Serum samples may be periodically obtained from the mice by retro-orbital bleeding for testing in ELISA assays to detect anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 antibodies.

[3182] After a suitable antibody titer has been detected, the animals "positive" for antibodies can be injected with a final intravenous injection of PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250. Three to four days later, the mice are sacrificed and the spleen cells are harvested. The spleen cells are then fused (using 35% polyethylene glycol) to a selected murine myeloma cell line such as P3X63AgU.1, available from ATCC, No. CRL 1597. The fusions generate hybridoma cells which can then be plated in 96 well tissue culture plates containing HAT (hypoxanthine, aminopterin, and thymidine) medium to inhibit proliferation of non-fused cells, myeloma hybrids, and spleen cell hybrids.

[3183] The hybridoma cells will be screened in an ELISA for reactivity against PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250. Determination of "positive" hybridoma cells secreting the desired monoclonal antibodies against PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 is within the skill in the art.

[3184] The positive hybridoma cells can be injected intraperitoneally into syngeneic Balb/c mice to produce ascites containing the anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 monoclonal antibodies. Alternatively, the hybridoma cells can be grown in tissue culture flasks or roller bottles. Purification of the monoclonal antibodies produced in the ascites can be accomplished using ammonium sulfate precipitation, followed by gel exclusion chromatography. Alternatively, affinity chromatography based upon binding of antibody to protein A or protein G can be employed.

Example 73

Purification of PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 Polypeptides Using Specific Antibodies

[3185] Native or recombinant PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides may be purified by a variety of standard techniques in the art of protein purification. For example, pro-PRO69122, pro-PRO204, pro-PRO214, pro-PRO222, pro-PRO234, pro-PRO265, pro-PRO309, pro-PRO332, pro-PRO342, pro-PRO356, pro-PRO540, pro-PRO618, pro-PRO944, pro-PRO994, pro-PRO1079, pro-PRO1110, pro-PRO1122, pro-PRO1138, pro-PRO1190, pro-PRO1272, pro-PRO1286, pro-PRO1295, pro-PRO1309, pro-PRO1316, pro-PRO1383, pro-PRO1384, pro-PRO1431, pro-PRO1434, pro-PRO1475, pro-PRO1481, pro-PRO1568, pro-PRO1573, pro-PRO1599, pro-PRO1604, pro-PRO1605, pro-PRO1693, pro-PRO1753, pro-PRO1755, pro-PRO1777, pro-PRO1788, pro-PRO1864, pro-PRO1925, pro-PRO1926, pro-PRO3566, pro-PRO4330, pro-PRO4423, pro-PRO36935, pro-PRO4977, pro-PRO4979, pro-PRO4980, pro-PRO4981, pro-PRO5801, pro-PRO5995, pro-PRO6001, pro-PRO6095, pro-PRO6182, pro-PRO7170, pro-PRO7171, pro-PRO7436, pro-PRO9912, pro-PRO9917, pro-PRO37337, pro-PRO37496, pro-PRO19646, pro-PRO21718, pro-PRO19820, pro-PRO21201, pro-PRO20026, pro-PRO20110, pro-PRO23203 or pro-PRO35250 polypeptide, mature PRO69122, mature PRO204, mature PRO214, mature PRO222, mature PRO234, mature PRO265, mature PRO309, mature PRO332, mature PRO342, mature PRO356, mature PRO540, mature PRO618, mature PRO944, mature PRO994, mature PRO1079, mature PRO1110, mature PRO1122, mature PRO1138, mature PRO1190, mature PRO1272, mature PRO1286, mature PRO1295, mature PRO1309, mature PRO1316, mature PRO1383, mature PRO1384, mature PRO1431, mature PRO1434, mature PRO1475, mature PRO1481, mature PRO1568, mature PRO1573, mature PRO1599, mature PRO1604, mature PRO1605, mature PRO1693, mature PRO1753, mature PRO1755, mature PRO1777, mature PRO1788, mature PRO1864, mature PRO1925, mature PRO1926, mature PRO3566, mature PRO4330, mature PRO4423, mature PRO36935, mature PRO4977, mature PRO4979, mature PRO4980, mature PRO4981, mature PRO5801, mature PRO5995, mature PRO6001, mature PRO6095, mature PRO6182, mature PRO7170, mature PRO7171, mature PRO7436, mature PRO9912, mature PRO9917, mature PRO37337, mature PRO37496, mature PRO19646, mature PRO21718, mature PRO19820, mature PRO21201, mature PRO20026, mature PRO20110, mature PRO23203 or mature PRO35250 polypeptide, or pre-PRO69122, pre-PRO204, pre-PRO214, pre-PRO222, pre-PRO234, pre-PRO265, pre-PRO309, pre-PRO332, pre-PRO342, pre-PRO356, pre-PRO540, pre-PRO618, pre-PRO944, pre-PRO994, pre-PRO1079, pre-PRO1110, pre-PRO1122, pre-PRO1138, pre-PRO1190, pre-PRO1272, pre-PRO1286, pre-PRO1295, pre-PRO1309, pre-PRO1316, per-PRO1383, pre-PRO1384, pre-PRO1431, pre-PRO1434, pre-PRO1475, pre-PRO1481, pre-PRO1568, pre-PRO1573, pre-PRO1599, pre-PRO1604, pre-PRO1605, pre-PRO1693, pre-PRO1753, pre-PRO1755, pre-PRO1777, pre-PRO1788, pre-PRO1864, pre-PRO1925, pre-PRO1926, pre-PRO3566, pre-PRO4330, pre-PRO4423, pre-PRO36935, pre-PRO4977, pre-PRO4979, pre-PRO4980, pre-PRO4981, pre-PRO5801, pre-PRO5995, pre-PRO6001, pre-PRO6095, pre-PRO6182, pre-PRO7170, pre-PRO7171, pre-PRO7436, pre-PRO9912, pre-PRO9917, pre-PRO37337, pre-PRO37496, pre-PRO19646, pre-PRO21718, pre-PRO19820, pre-PRO21201, pre-PRO20026, pre-PRO20110, pre-PRO23203 or pre-PRO35250 polypeptide is purified by immunoaffinity chromatography using antibodies specific for the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide of interest. In general, an immunoaffinity column is constructed by covalently coupling the anti-PRO69122, anti-PRO204, anti-PRO214, anti-PRO222, anti-PRO234, anti-PRO265, anti-PRO309, anti-PRO332, anti-PRO342, anti-PRO356, anti-PRO540, anti-PRO618, anti-PRO944, anti-PRO994, anti-PRO1079, anti-PRO1110, anti-PRO1122, anti-PRO1138, anti-PRO1190, anti-PRO1272, anti-PRO1286, anti-PRO1295, anti-PRO1309, anti-PRO1316, anti-PRO1383, anti-PRO1384, anti-PRO1431, anti-PRO1434, anti-PRO1475, anti-PRO1481, anti-PRO1568, anti-PRO1573, anti-PRO1599, anti-PRO1604, anti-PRO1605, anti-PRO1693, anti-PRO1753, anti-PRO1755, anti-PRO1777, anti-PRO1788, anti-PRO1864, anti-PRO1925, anti-PRO1926, anti-PRO3566, anti-PRO4330, anti-PRO4423, anti-PRO36935, anti-PRO4977, anti-PRO4979, anti-PRO4980, anti-PRO4981, anti-PRO5801, anti-PRO5995, anti-PRO6001, anti-PRO6095, anti-PRO6182, anti-PRO7170, anti-PRO7171, anti-PRO7436, anti-PRO9912, anti-PRO9917, anti-PRO37337, anti-PRO37496, anti-PRO19646, anti-PRO21718, anti-PRO19820, anti-PRO21201, anti-PRO20026, anti-PRO20110, anti-PRO23203 or anti-PRO35250 polypeptide antibody to an activated chromatographic resin.

[3186] Polyclonal immunoglobulins are prepared from immune sera either by precipitation with ammonium sulfate or by purification on immobilized Protein A (Pharmacia LKB Biotechnology, Piscataway, N.J.). Likewise, monoclonal antibodies are prepared from mouse ascites fluid by ammonium sulfate precipitation or chromatography on immobilized Protein A. Partially purified immunoglobulin is covalently attached to a chromatographic resin such as CnBr-activated SEPHAROSE.TM. (Pharmacia LKB Biotechnology). The antibody is coupled to the resin, the resin is blocked, and the derivative resin is washed according to the manufacturer's instructions.

[3187] Such an immunoaffinity column is utilized in the purification of PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide by preparing a fraction from cells containing PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide in a soluble form. This preparation is derived by solubilization of the whole cell or of a subcellular fraction obtained via differential centrifugation by the addition of detergent or by other methods well known in the art. Alternatively, soluble polypeptide containing a signal sequence may be secreted in useful quantity into the medium in which the cells are grown.

[3188] A soluble PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide-containing preparation is passed over the immunoaffinity column, and the column is washed under conditions that allow the preferential absorbance of PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide (e.g., high ionic strength buffers in the presence of detergent). Then, the column is eluted under conditions that disrupt antibody/PRO69122, antibody/PRO204, antibody/PRO214, antibody/PRO222, antibody/PRO234, antibody/PRO265, antibody/PRO309, antibody/PRO332, antibody/PRO342, antibody/PRO356, antibody/PRO540, antibody/PRO618, antibody/PRO944, antibody/PRO994, antibody/PRO1079, antibody/PRO1110, antibody/PRO1122, antibody/PRO1138, antibody/PRO1190, antibody/PRO1272, antibody/PRO1286, antibody/PRO1295, antibody/PRO1309, antibody/PRO1316, antibody/PRO1383, antibody/PRO1384, antibody/PRO1431, antibody/PRO1434, antibody/PRO1475, antibody/PRO1481, antibody/PRO1568, antibody/PRO1573, antibody/PRO1599, antibody/PRO1604, antibody/PRO1605, antibody/PRO1693, antibody/PRO1753, antibody/PRO1755, antibody/PRO1777, antibody/PRO1788, antibody/PRO1864, antibody/PRO1925, antibody/PRO1926, antibody/PRO3566, antibody/PRO4330, antibody/PRO4423, antibody/PRO36935, antibody/PRO4977, antibody/PRO4979, antibody/PRO4980, antibody/PRO4981, antibody/PRO5801, antibody/PRO5995, antibody/PRO6001, antibody/PRO6095, antibody/PRO6182, antibody/PRO7170, antibody/PRO7171, antibody/PRO7436, antibody/PRO9912, antibody/PRO9917, antibody/PRO37337, antibody/PRO37496, antibody/PRO19646, antibody/PRO21718, antibody/PRO19820, antibody/PRO21201, antibody/PRO20026, antibody/PRO20110, antibody/PRO23203 or antibody/PRO35250 polypeptide binding (e.g., a low pH buffer such as approximately pH 2-3, or a high concentration of a chaotrope such as urea or thiocyanate ion), and PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide is collected.

Example 74

Drug Screening

[3189] This invention is particularly useful for screening compounds by using PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptides or binding fragment thereof in any of a variety of drug screening techniques. The PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide or fragment employed in such a test may either be free in solution, affixed to a solid support, borne on a cell surface, or located intracellularly. One method of drug screening utilizes eukaryotic or prokaryotic host cells which are stably transformed with recombinant nucleic acids expressing the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide or fragment. Drugs are screened against such transformed cells in competitive binding assays. Such cells, either in viable or fixed form, can be used for standard binding assays. One may measure, for example, the formation of complexes between PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide or a fragment and the agent being tested. Alternatively, one can examine the diminution in complex formation between the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide and its target cell or target receptors caused by the agent being tested.

[3190] Thus, the present invention provides methods of screening for drugs or any other agents which can affect a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide-associated disease or disorder. These methods comprise contacting such an agent with an PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026; PRO20110, PRO23203 or PRO35250 polypeptide or fragment thereof and assaying (I) for the presence of a complex between the agent and the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide or fragment, or (ii) for the presence of a complex between the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide or fragment and the cell, by methods well known in the art. In such competitive binding assays, the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide or fragment is typically labeled. After suitable incubation, free PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide or fragment is separated from that present in bound form, and the amount of free or uncomplexed label is a measure of the ability of the particular agent to bind to PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide or to interfere with the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide/cell complex.

[3191] Another technique for drug screening provides high throughput screening for compounds having suitable binding affinity to a polypeptide and is described in detail in WO 84/03564, published on Sep. 13, 1984. Briefly stated, large numbers of different small peptide test compounds are synthesized on a solid substrate, such as plastic pins or some other surface. As applied to a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, the peptide test compounds are reacted with PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide and washed. Bound PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide is detected by methods well known in the art. Purified PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide can also be coated directly onto plates for use in the aforementioned drug screening techniques. In addition, non-neutralizing antibodies can be used to capture the peptide and immobilize it on the solid support.

[3192] This invention also contemplates the use of competitive drug screening assays in which neutralizing antibodies capable of binding PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide specifically compete with a test compound for binding to PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide or fragments thereof. In this manner, the antibodies can be used to detect the presence of any peptide which shares one or more antigenic determinants with PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide.

Example 75

Rational Drug Design

[3193] The goal of rational drug design is to produce structural analogs of biologically active polypeptide of interest (i.e., a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide) or of small molecules with which they interact, e.g., agonists, antagonists, or inhibitors. Any of these examples can be used to fashion drugs which are more active or stable forms of the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide or which enhance or interfere with the function of the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide in vivo (c.f., Hodgson, Bio/Technology, 9: 19-21 (1991)).

[3194] In one approach, the three-dimensional structure of the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide, or of a PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide-inhibitor complex, is determined by x-ray crystallography, by computer modeling or, most typically, by a combination of the two approaches. Both the shape and charges of the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide must be ascertained to elucidate the structure and to determine active site(s) of the molecule. Less often, useful information regarding the structure of the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide may be gained by modeling based on the structure of homologous proteins. In both cases, relevant structural information is used to design analogous PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide-like molecules or to identify efficient inhibitors. Useful examples of rational drug design may include molecules which have improved activity or stability as shown by Braxton and Wells, Biochemistry, 31:7796-7801 (1992) or which act as inhibitors, agonists, or antagonists of native peptides as shown by Athauda et al., J. Biochem., 113:742-746 (1993).

[3195] It is also possible to isolate a target-specific antibody, selected by functional assay, as described above, and then to solve its crystal structure. This approach, in principle, yields a pharmacore upon which subsequent drug design can be based. It is possible to bypass protein crystallography altogether by generating anti-idiotypic antibodies (anti-ids) to a functional, pharmacologically active antibody. As a mirror image of a mirror image, the binding site of the anti-ids would be expected to be an analog of the original receptor. The anti-id could then be used to identify and isolate peptides from banks of chemically or biologically produced peptides. The isolated peptides would then act as the pharmacore.

[3196] By virtue of the present invention, sufficient amounts of the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO540, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide may be made available to perform such analytical studies as X-ray crystallography. In addition, knowledge of the PRO69122, PRO204, PRO214, PRO222, PRO234, PRO265, PRO309, PRO332, PRO342, PRO356, PRO1110, PRO618, PRO944, PRO994, PRO1079, PRO1110, PRO1122, PRO1138, PRO1190, PRO1272, PRO1286, PRO1295, PRO1309, PRO1316, PRO1383, PRO1384, PRO1431, PRO1434, PRO1475, PRO1481, PRO1568, PRO1573, PRO1599, PRO1604, PRO1605, PRO1693, PRO1753, PRO1755, PRO1777, PRO1788, PRO1864, PRO1925, PRO1926, PRO3566, PRO4330, PRO4423, PRO36935, PRO4977, PRO4979, PRO4980, PRO4981, PRO5801, PRO5995, PRO6001, PRO6095, PRO6182, PRO7170, PRO7171, PRO7436, PRO9912, PRO9917, PRO37337, PRO37496, PRO19646, PRO21718, PRO19820, PRO21201, PRO20026, PRO20110, PRO23203 or PRO35250 polypeptide amino acid sequence provided herein will provide guidance to those employing computer modeling techniques in place of or in addition to x-ray crystallography.

Sequence CWU 1

1

25113473DNAHomo sapiens 1aagagcagcg gcgaggcggc ggtggtggct gagtccgtgg tggcagaggc 50gaaggcgaca gctctagggg ttggcaccgg ccccgagagg aggatgcggg 100tccggatagg gctgacgctg ctgctgtgtg cggtgctgct gagcttggcc 150tcggcgtcct cggatgaaga aggcagccag gatgaatcct tagattccaa 200gactactttg acatcagatg agtcagtaaa ggaccacact actgcaggca 250gagtagttgc tggtcaaata tttcttgatt cagaagaatc tgaattagaa 300tcctctattc aagaagagga agacagcctc aagagccaag agggggagag 350tgtcacagaa gatatcagct ttctagagtc tccaaatcca gaaaacaagg 400actatgaaga gccaaagaaa gtacggaaac cagctttgac cgccattgaa 450ggcacagcac atggggagcc ctgccacttc ccttttcttt tcctagataa 500ggagtatgat gaatgtacat cagatgggag ggaagatggc agactgtggt 550gtgctacaac ctatgactac aaagcagatg aaaagtgggg cttttgtgaa 600actgaagaag aggctgctaa gagacggcag atgcaggaag cagaaatggt 650gtatcaaact ggaatgaaaa tccttaatgg aagcaataag aaaagccaaa 700aaagagaagc atatcggtat ctccaaaagg cagcaagcat gaaccatacc 750aaagccctgg agagagtgtc atatgctctt ttatttggtg attacttgcc 800acagaatatc caggcagcga gagagatgtt tgagaagctg actgaggaag 850gctctcccaa gggacagact gctcttggct ttctgtatgc ctctggactt 900ggtgttaatt caagtcaggc aaaggctctt gtatattata catttggagc 950tcttgggggc aatctaatag cccacatggt tttgggttac agatactggg 1000ctggcatcgg cgtcctccag agttgtgaat ctgccctgac tcactatcgt 1050cttgttgcca atcatgttgc tagtgatatc tcgctaacag gaggctcagt 1100agtacagaga atacggctgc ctgatgaagt ggaaaatcca ggaatgaaca 1150gtggaatgct agaagaagat ttgattcaat attaccagtt cctagctgaa 1200aaaggtgatg tacaagcaca ggttggtctt ggacaactgc acctgcacgg 1250agggcgtgga gtagaacaga atcatcagag agcatttgac tacttcaatt 1300tagcagcaaa tgctggcaat tcacatgcca tggccttttt gggaaagatg 1350tattcggaag gaagtgacat tgtacctcag agtaatgaga cagctctcca 1400ctactttaag aaagctgctg acatgggcaa cccagttgga cagagtgggc 1450ttggaatggc ctacctctat gggagaggag ttcaagttaa ttatgatcta 1500gcccttaagt atttccagaa agctgctgaa caaggctggg tggatgggca 1550gctacagctt ggttccatgt actataatgg cattggagtc aagagagatt 1600ataaacaggc cttgaagtat tttaatttag cttctcaggg aggccatatc 1650ttggctttct ataacctagc tcagatgcat gccagtggca ccggcgtgat 1700gcgatcatgt cacactgcag tggagttgtt taagaatgta tgtgaacgag 1750gccgttggtc tgaaaggctt atgactgcct ataacagcta taaagatggc 1800gattacaatg ctgcagtgat ccagtacctc ctcctggctg aacagggcta 1850tgaagtggca caaagcaatg cagcctttat tcttgatcag agagaagcaa 1900gcattgtagg tgagaatgaa acttatccca gagctttgct acattggaac 1950agggccgcct ctcaaggcta tactgtggct agaattaagc tcggagacta 2000ccatttctat gggtttggca ccgatgtaga ttatgaaact gcatttattc 2050attaccgtct ggcttctgag cagcaacaca gtgcacaagc tatgtttaat 2100ctgggatata tgcatgagaa aggactgggc attaaacagg atattcacct 2150tgcgaaacgt ttttatgaca tggcagctga agccagccca gatgcacaag 2200ttccagtctt cctagccctc tgcaaattgg gcgtcgtcta tttcttgcag 2250tacatacggg aaacaaacat tcgagatatg ttcacccaac ttgatatgga 2300ccagcttttg ggacctgagt gggaccttta cctcatgacc atcattgcgc 2350tgctgttggg aacagtcata gcttacaggc aaaggcagca ccaagacatg 2400cctgcaccca ggcctccagg gccacggcca gctccacccc agcaggaggg 2450gccaccagag cagcagccac cacagtaata ggcactgggt ccagccttga 2500tcagtgacag cgaaggaagt tatctgctgg gaacacttgc atttgattta 2550ggaccttgga tcagtggtca cctcccagaa gaggcacggc acaaggaagc 2600attgaattcc taaagctgct tagaatctga tgcctttatt ttcagggata 2650agtaactctt acctaaactg agctgaatgt ttgtttcagt gccatatgga 2700ataacaactt tcagtggctt ttttttttct tttctggaaa catatgtgag 2750acactcagag taatgtctac tgtatccagc tatctttctt ggatcctttt 2800ggtcattatt tcagtgtgca taagttctta atgtcaacca tctttaaggt 2850attgtgcatc gacactaaaa actgatcagt gtaaaaagga aaacccagtt 2900gcaagtttaa acgtgttcga aagtctgaaa atagaacttg ccttttaagt 2950taaaaaaaaa aaaagctatc ttgaaaatgt tttggaactg cgataactga 3000gaaactctta ccagtccaca tgcaattaga catattcagc atatttgtta 3050ttttaaaagg gagggttggg aggtttctta ttggtgattg tcacacggta 3100taccatactc ctctccttca aagaatgaaa ggccttgtta aggagttttt 3150tgtgagcttt acttctttgg aatggaatat acttatgcaa aaccttgtga 3200actgactcct tgcactaacg cgagtttgcc ccacctactc tgtaatttgc 3250ttgtttgttt tgaatataca gagccttgat ccagaagcca gaggatggac 3300taagtgggag aaattagaaa acaaaacgaa ctctggttgg ggtactacga 3350tcacagacac agacatactt ttcctaaagt tgaagcattt gttcccagga 3400tttattttac tttgcatttc cttttgcaca aagaacacat caccatttcc 3450ttttgcacaa agaacacatc acc 34732794PRTHomo sapiens 2Met Arg Val Arg Ile Gly Leu Thr Leu Leu Leu Cys Ala Val Leu1 5 10 15Leu Ser Leu Ala Ser Ala Ser Ser Asp Glu Glu Gly Ser Gln Asp 20 25 30Glu Ser Leu Asp Ser Lys Thr Thr Leu Thr Ser Asp Glu Ser Val 35 40 45Lys Asp His Thr Thr Ala Gly Arg Val Val Ala Gly Gln Ile Phe 50 55 60Leu Asp Ser Glu Glu Ser Glu Leu Glu Ser Ser Ile Gln Glu Glu 65 70 75Glu Asp Ser Leu Lys Ser Gln Glu Gly Glu Ser Val Thr Glu Asp 80 85 90Ile Ser Phe Leu Glu Ser Pro Asn Pro Glu Asn Lys Asp Tyr Glu 95 100 105Glu Pro Lys Lys Val Arg Lys Pro Ala Leu Thr Ala Ile Glu Gly 110 115 120Thr Ala His Gly Glu Pro Cys His Phe Pro Phe Leu Phe Leu Asp 125 130 135Lys Glu Tyr Asp Glu Cys Thr Ser Asp Gly Arg Glu Asp Gly Arg 140 145 150Leu Trp Cys Ala Thr Thr Tyr Asp Tyr Lys Ala Asp Glu Lys Trp 155 160 165Gly Phe Cys Glu Thr Glu Glu Glu Ala Ala Lys Arg Arg Gln Met 170 175 180Gln Glu Ala Glu Met Val Tyr Gln Thr Gly Met Lys Ile Leu Asn 185 190 195Gly Ser Asn Lys Lys Ser Gln Lys Arg Glu Ala Tyr Arg Tyr Leu 200 205 210Gln Lys Ala Ala Ser Met Asn His Thr Lys Ala Leu Glu Arg Val 215 220 225Ser Tyr Ala Leu Leu Phe Gly Asp Tyr Leu Pro Gln Asn Ile Gln 230 235 240Ala Ala Arg Glu Met Phe Glu Lys Leu Thr Glu Glu Gly Ser Pro 245 250 255Lys Gly Gln Thr Ala Leu Gly Phe Leu Tyr Ala Ser Gly Leu Gly 260 265 270Val Asn Ser Ser Gln Ala Lys Ala Leu Val Tyr Tyr Thr Phe Gly 275 280 285Ala Leu Gly Gly Asn Leu Ile Ala His Met Val Leu Gly Tyr Arg 290 295 300Tyr Trp Ala Gly Ile Gly Val Leu Gln Ser Cys Glu Ser Ala Leu 305 310 315Thr His Tyr Arg Leu Val Ala Asn His Val Ala Ser Asp Ile Ser 320 325 330Leu Thr Gly Gly Ser Val Val Gln Arg Ile Arg Leu Pro Asp Glu 335 340 345Val Glu Asn Pro Gly Met Asn Ser Gly Met Leu Glu Glu Asp Leu 350 355 360Ile Gln Tyr Tyr Gln Phe Leu Ala Glu Lys Gly Asp Val Gln Ala 365 370 375Gln Val Gly Leu Gly Gln Leu His Leu His Gly Gly Arg Gly Val 380 385 390Glu Gln Asn His Gln Arg Ala Phe Asp Tyr Phe Asn Leu Ala Ala 395 400 405Asn Ala Gly Asn Ser His Ala Met Ala Phe Leu Gly Lys Met Tyr 410 415 420Ser Glu Gly Ser Asp Ile Val Pro Gln Ser Asn Glu Thr Ala Leu 425 430 435His Tyr Phe Lys Lys Ala Ala Asp Met Gly Asn Pro Val Gly Gln 440 445 450Ser Gly Leu Gly Met Ala Tyr Leu Tyr Gly Arg Gly Val Gln Val 455 460 465Asn Tyr Asp Leu Ala Leu Lys Tyr Phe Gln Lys Ala Ala Glu Gln 470 475 480Gly Trp Val Asp Gly Gln Leu Gln Leu Gly Ser Met Tyr Tyr Asn 485 490 495Gly Ile Gly Val Lys Arg Asp Tyr Lys Gln Ala Leu Lys Tyr Phe 500 505 510Asn Leu Ala Ser Gln Gly Gly His Ile Leu Ala Phe Tyr Asn Leu 515 520 525Ala Gln Met His Ala Ser Gly Thr Gly Val Met Arg Ser Cys His 530 535 540Thr Ala Val Glu Leu Phe Lys Asn Val Cys Glu Arg Gly Arg Trp 545 550 555Ser Glu Arg Leu Met Thr Ala Tyr Asn Ser Tyr Lys Asp Gly Asp 560 565 570Tyr Asn Ala Ala Val Ile Gln Tyr Leu Leu Leu Ala Glu Gln Gly 575 580 585Tyr Glu Val Ala Gln Ser Asn Ala Ala Phe Ile Leu Asp Gln Arg 590 595 600Glu Ala Ser Ile Val Gly Glu Asn Glu Thr Tyr Pro Arg Ala Leu 605 610 615Leu His Trp Asn Arg Ala Ala Ser Gln Gly Tyr Thr Val Ala Arg 620 625 630Ile Lys Leu Gly Asp Tyr His Phe Tyr Gly Phe Gly Thr Asp Val 635 640 645Asp Tyr Glu Thr Ala Phe Ile His Tyr Arg Leu Ala Ser Glu Gln 650 655 660Gln His Ser Ala Gln Ala Met Phe Asn Leu Gly Tyr Met His Glu 665 670 675Lys Gly Leu Gly Ile Lys Gln Asp Ile His Leu Ala Lys Arg Phe 680 685 690Tyr Asp Met Ala Ala Glu Ala Ser Pro Asp Ala Gln Val Pro Val 695 700 705Phe Leu Ala Leu Cys Lys Leu Gly Val Val Tyr Phe Leu Gln Tyr 710 715 720Ile Arg Glu Thr Asn Ile Arg Asp Met Phe Thr Gln Leu Asp Met 725 730 735Asp Gln Leu Leu Gly Pro Glu Trp Asp Leu Tyr Leu Met Thr Ile 740 745 750Ile Ala Leu Leu Leu Gly Thr Val Ile Ala Tyr Arg Gln Arg Gln 755 760 765His Gln Asp Met Pro Ala Pro Arg Pro Pro Gly Pro Arg Pro Ala 770 775 780Pro Pro Gln Gln Glu Gly Pro Pro Glu Gln Gln Pro Pro Gln 785 79031788DNAHomo sapiens 3tgccgggctg cggggcgcct tgactctccc tccaccctgc ctcctcgggc 50tccactcgtc tgcccctgga ctcccgtctc ctcctgtcct ccggcttccc 100agagctccct ccttatggca gcagcttccc gcgtctccgg cgcagcttct 150cagcggacga ccctctcgct ccggggctga gcccagtccc tggatgttgc 200tgaaactctc gagatcatgc gcgggtttgg ctgctgcttc cccgccgggt 250gccactgcca ccgccgccgc ctctgctgcc gccgtccgcg ggatgctcag 300tagcccgctg cccggccccc gcgatcctgt gttcctcgga agccgtttgc 350tgctgcagag ttgcacgaac tagtcatggt gctgtgggag tccccgcggc 400agtgcagcag ctggacactt tgcgagggct tttgctggct gctgctgctg 450cccgtcatgc tactcatcgt agcccgcccg gtgaagctcg ctgctttccc 500tacctcctta agtgactgcc aaacgcccac cggctggaat tgctctggtt 550atgatgacag agaaaatgat ctcttcctct gtgacaccaa cacctgtaaa 600tttgatgggg aatgtttaag aattggagac actgtgactt gcgtctgtca 650gttcaagtgc aacaatgact atgtgcctgt gtgtggctcc aatggggaga 700gctaccagaa tgagtgttac ctgcgacagg ctgcatgcaa acagcagagt 750gagatacttg tggtgtcaga aggatcatgt gccacagatg caggatcagg 800atctggagat ggagtccatg aaggctctgg agaaactagt caaaaggaga 850catccacctg tgatatttgc cagtttggtg cagaatgtga cgaagatgcc 900gaggatgtct ggtgtgtgtg taatattgac tgttctcaaa ccaacttcaa 950tcccctctgc gcttctgatg ggaaatctta tgataatgca tgccaaatca 1000aagaagcatc gtgtcagaaa caggagaaaa ttgaagtcat gtctttgggt 1050cgatgtcaag ataacacaac tacaactact aagtctgaag atgggcatta 1100tgcaagaaca gattatgcag agaatgctaa caaattagaa gaaagtgcca 1150gagaacacca cataccttgt ccggaacatt acaatggctt ctgcatgcat 1200gggaagtgtg agcattctat caatatgcag gagccatctt gcaggtgtga 1250tgctggttat actggacaac actgtgaaaa aaaggactac agtgttctat 1300acgttgttcc cggtcctgta cgatttcagt atgtcttaat cgcagctgtg 1350attggaacaa ttcagattgc tgtcatctgt gtggtggtcc tctgcatcac 1400aaggaaatgc cccagaagca acagaattca cagacagaag caaaatacag 1450ggcactacag ttcagacaat acaacaagag cgtccacgag gttaatctaa 1500agggagcatg tttcacagtg gctggactac cgagagcttg gactacacaa 1550tacagtatta tagacaaaag aataagacaa gagatctaca catgttgcct 1600tgcatttgtg gtaatctaca ccaatgaaaa catgtactac agctatattt 1650gattatgtat ggatatattt gaaatagtat acattgtctt gatgtttttt 1700ctgtaatgta aataaactat ttatatcaca caatatagtt ttttctttcc 1750catgtatttg ttatatataa taaatactca gtgatgag 17884374PRTHomo sapiens 4Met Val Leu Trp Glu Ser Pro Arg Gln Cys Ser Ser Trp Thr Leu1 5 10 15Cys Glu Gly Phe Cys Trp Leu Leu Leu Leu Pro Val Met Leu Leu 20 25 30Ile Val Ala Arg Pro Val Lys Leu Ala Ala Phe Pro Thr Ser Leu 35 40 45Ser Asp Cys Gln Thr Pro Thr Gly Trp Asn Cys Ser Gly Tyr Asp 50 55 60Asp Arg Glu Asn Asp Leu Phe Leu Cys Asp Thr Asn Thr Cys Lys 65 70 75Phe Asp Gly Glu Cys Leu Arg Ile Gly Asp Thr Val Thr Cys Val 80 85 90Cys Gln Phe Lys Cys Asn Asn Asp Tyr Val Pro Val Cys Gly Ser 95 100 105Asn Gly Glu Ser Tyr Gln Asn Glu Cys Tyr Leu Arg Gln Ala Ala 110 115 120Cys Lys Gln Gln Ser Glu Ile Leu Val Val Ser Glu Gly Ser Cys 125 130 135Ala Thr Asp Ala Gly Ser Gly Ser Gly Asp Gly Val His Glu Gly 140 145 150Ser Gly Glu Thr Ser Gln Lys Glu Thr Ser Thr Cys Asp Ile Cys 155 160 165Gln Phe Gly Ala Glu Cys Asp Glu Asp Ala Glu Asp Val Trp Cys 170 175 180Val Cys Asn Ile Asp Cys Ser Gln Thr Asn Phe Asn Pro Leu Cys 185 190 195Ala Ser Asp Gly Lys Ser Tyr Asp Asn Ala Cys Gln Ile Lys Glu 200 205 210Ala Ser Cys Gln Lys Gln Glu Lys Ile Glu Val Met Ser Leu Gly 215 220 225Arg Cys Gln Asp Asn Thr Thr Thr Thr Thr Lys Ser Glu Asp Gly 230 235 240His Tyr Ala Arg Thr Asp Tyr Ala Glu Asn Ala Asn Lys Leu Glu 245 250 255Glu Ser Ala Arg Glu His His Ile Pro Cys Pro Glu His Tyr Asn 260 265 270Gly Phe Cys Met His Gly Lys Cys Glu His Ser Ile Asn Met Gln 275 280 285Glu Pro Ser Cys Arg Cys Asp Ala Gly Tyr Thr Gly Gln His Cys 290 295 300Glu Lys Lys Asp Tyr Ser Val Leu Tyr Val Val Pro Gly Pro Val 305 310 315Arg Phe Gln Tyr Val Leu Ile Ala Ala Val Ile Gly Thr Ile Gln 320 325 330Ile Ala Val Ile Cys Val Val Val Leu Cys Ile Thr Arg Lys Cys 335 340 345Pro Arg Ser Asn Arg Ile His Arg Gln Lys Gln Asn Thr Gly His 350 355 360Tyr Ser Ser Asp Asn Thr Thr Arg Ala Ser Thr Arg Leu Ile 365 37051838DNAHomo sapiens 5cggacgcgtg ggcggacgcg tgggcggccc acggcgcccg cgggctgggg 50cggtcgcttc ttccttctcc gtggcctacg agggtcccca gcctgggtaa 100agatggcccc atggcccccg aagggcctag tcccagctgt gctctggggc 150ctcagcctct tcctcaacct cccaggacct atctggctcc agccctctcc 200acctccccag tcttctcccc cgcctcagcc ccatccgtgt catacctgcc 250ggggactggt tgacagcttt aacaagggcc tggagagaac catccgggac 300aactttggag gtggaaacac tgcctgggag gaagagaatt tgtccaaata 350caaagacagt gagacccgcc tggtagaggt gctggagggt gtgtgcagca 400agtcagactt cgagtgccac cgcctgctgg agctgagtga ggagctggtg 450gagagctggt ggtttcacaa gcagcaggag gccccggacc tcttccagtg 500gctgtgctca gattccctga agctctgctg ccccgcaggc accttcgggc 550cctcctgcct tccctgtcct gggggaacag agaggccctg cggtggctac 600gggcagtgtg aaggagaagg gacacgaggg ggcagcgggc actgtgactg 650ccaagccggc tacgggggtg aggcctgtgg ccagtgtggc cttggctact 700ttgaggcaga acgcaacgcc agccatctgg tatgttcggc ttgttttggc 750ccctgtgccc gatgctcagg acctgaggaa tcaaactgtt tgcaatgcaa 800gaagggctgg gccctgcatc acctcaagtg tgtagacatt gatgagtgtg 850gcacagaggg agccaactgt ggagctgacc aattctgcgt

gaacactgag 900ggctcctatg agtgccgaga ctgtgccaag gcctgcctag gctgcatggg 950ggcagggcca ggtcgctgta agaagtgtag ccctggctat cagcaggtgg 1000gctccaagtg tctcgatgtg gatgagtgtg agacagaggt gtgtccggga 1050gagaacaagc agtgtgaaaa caccgagggc ggttatcgct gcatctgtgc 1100cgagggctac aagcagatgg aaggcatctg tgtgaaggag cagatcccag 1150agtcagcagg cttcttctca gagatgacag aagacgagtt ggtggtgctg 1200cagcagatgt tctttggcat catcatctgt gcactggcca cgctggctgc 1250taagggcgac ttggtgttca ccgccatctt cattggggct gtggcggcca 1300tgactggcta ctggttgtca gagcgcagtg accgtgtgct ggagggcttc 1350atcaagggca gataatcgcg gccaccacct gtaggacctc ctcccaccca 1400cgctgccccc agagcttggg ctgccctcct gctggacact caggacagct 1450tggtttattt ttgagagtgg ggtaagcacc cctacctgcc ttacagagca 1500gcccaggtac ccaggcccgg gcagacaagg cccctggggt aaaaagtagc 1550cctgaaggtg gataccatga gctcttcacc tggcggggac tggcaggctt 1600cacaatgtgt gaatttcaaa agtttttcct taatggtggc tgctagagct 1650ttggcccctg cttaggatta ggtggtcctc acaggggtgg ggccatcaca 1700gctccctcct gccagctgca tgctgccagt tcctgttctg tgttcaccac 1750atccccacac cccattgcca cttatttatt catctcagga aataaagaaa 1800ggtcttggaa agttaaaaaa aaaaaaaaaa aaaaaaaa 18386420PRTHomo sapiens 6Met Ala Pro Trp Pro Pro Lys Gly Leu Val Pro Ala Val Leu Trp1 5 10 15Gly Leu Ser Leu Phe Leu Asn Leu Pro Gly Pro Ile Trp Leu Gln 20 25 30Pro Ser Pro Pro Pro Gln Ser Ser Pro Pro Pro Gln Pro His Pro 35 40 45Cys His Thr Cys Arg Gly Leu Val Asp Ser Phe Asn Lys Gly Leu 50 55 60Glu Arg Thr Ile Arg Asp Asn Phe Gly Gly Gly Asn Thr Ala Trp 65 70 75Glu Glu Glu Asn Leu Ser Lys Tyr Lys Asp Ser Glu Thr Arg Leu 80 85 90Val Glu Val Leu Glu Gly Val Cys Ser Lys Ser Asp Phe Glu Cys 95 100 105His Arg Leu Leu Glu Leu Ser Glu Glu Leu Val Glu Ser Trp Trp 110 115 120Phe His Lys Gln Gln Glu Ala Pro Asp Leu Phe Gln Trp Leu Cys 125 130 135Ser Asp Ser Leu Lys Leu Cys Cys Pro Ala Gly Thr Phe Gly Pro 140 145 150Ser Cys Leu Pro Cys Pro Gly Gly Thr Glu Arg Pro Cys Gly Gly 155 160 165Tyr Gly Gln Cys Glu Gly Glu Gly Thr Arg Gly Gly Ser Gly His 170 175 180Cys Asp Cys Gln Ala Gly Tyr Gly Gly Glu Ala Cys Gly Gln Cys 185 190 195Gly Leu Gly Tyr Phe Glu Ala Glu Arg Asn Ala Ser His Leu Val 200 205 210Cys Ser Ala Cys Phe Gly Pro Cys Ala Arg Cys Ser Gly Pro Glu 215 220 225Glu Ser Asn Cys Leu Gln Cys Lys Lys Gly Trp Ala Leu His His 230 235 240Leu Lys Cys Val Asp Ile Asp Glu Cys Gly Thr Glu Gly Ala Asn 245 250 255Cys Gly Ala Asp Gln Phe Cys Val Asn Thr Glu Gly Ser Tyr Glu 260 265 270Cys Arg Asp Cys Ala Lys Ala Cys Leu Gly Cys Met Gly Ala Gly 275 280 285Pro Gly Arg Cys Lys Lys Cys Ser Pro Gly Tyr Gln Gln Val Gly 290 295 300Ser Lys Cys Leu Asp Val Asp Glu Cys Glu Thr Glu Val Cys Pro 305 310 315Gly Glu Asn Lys Gln Cys Glu Asn Thr Glu Gly Gly Tyr Arg Cys 320 325 330Ile Cys Ala Glu Gly Tyr Lys Gln Met Glu Gly Ile Cys Val Lys 335 340 345Glu Gln Ile Pro Glu Ser Ala Gly Phe Phe Ser Glu Met Thr Glu 350 355 360Asp Glu Leu Val Val Leu Gln Gln Met Phe Phe Gly Ile Ile Ile 365 370 375Cys Ala Leu Ala Thr Leu Ala Ala Lys Gly Asp Leu Val Phe Thr 380 385 390Ala Ile Phe Ile Gly Ala Val Ala Ala Met Thr Gly Tyr Trp Leu 395 400 405Ser Glu Arg Ser Asp Arg Val Leu Glu Gly Phe Ile Lys Gly Arg 410 415 42071843DNAHomo sapiensUnsure1837Unknown base 7cccacgcgtc cggtctcgct cgctcgcgca gcggcggcag cagaggtcgc 50gcacagatgc gggttagact ggcgggggga ggaggcggag gagggaagga 100agctgcatgc atgagaccca cagactcttg caagctggat gccctctgtg 150gatgaaagat gtatcatgga atgaacccga gcaatggaga tggatttcta 200gagcagcagc agcagcagca gcaacctcag tccccccaga gactcttggc 250cgtgatcctg tggtttcagc tggcgctgtg cttcggccct gcacagctca 300cgggcgggtt cgatgacctt caagtgtgtg ctgaccccgg cattcccgag 350aatggcttca ggacccccag cggaggggtt ttctttgaag gctctgtagc 400ccgatttcac tgccaagacg gattcaagct gaagggcgct acaaagagac 450tgtgtttgaa gcattttaat ggaaccctag gctggatccc aagtgataat 500tccatctgtg tgcaagaaga ttgccgtatc cctcaaatcg aagatgctga 550gattcataac aagacatata gacatggaga gaagctaatc atcacttgtc 600atgaaggatt caagatccgg taccccgacc tacacaatat ggtttcatta 650tgtcgcgatg atggaacgtg gaataatctg cccatctgtc aaggctgcct 700gagacctcta gcctcttcta atggctatgt aaacatctct gagctccaga 750cctccttccc ggtggggact gtgatctcct atcgctgctt tcccggattt 800aaacttgatg ggtctgcgta tcttgagtgc ttacaaaacc ttatctggtc 850gtccagccca ccccggtgcc ttgctctgga agcccaagtc tgtccactac 900ctccaatggt gagtcacgga gatttcgtct gccacccgcg gccttgtgag 950cgctacaacc acggaactgt ggtggagttt tactgcgatc ctggctacag 1000cctcaccagc gactacaagt acatcacctg ccagtatgga gagtggtttc 1050cttcttatca agtctactgc atcaaatcag agcaaacgtg gcccagcacc 1100catgagaccc tcctgaccac gtggaagatt gtggcgttca cggcaaccag 1150tgtgctgctg gtgctgctgc tcgtcatcct ggccaggatg ttccagacca 1200agttcaaggc ccactttccc cccagggggc ctccccggag ttccagcagt 1250gaccctgact ttgtggtggt agacggcgtg cccgtcatgc tcccgtccta 1300tgacgaagct gtgagtggcg gcttgagtgc cttaggcccc gggtacatgg 1350cctctgtggg ccagggctgc cccttacccg tggacgacca gagcccccca 1400gcataccccg gctcagggga cacggacaca ggcccagggg agtcagaaac 1450ctgtgacagc gtctcaggct cttctgagct gctccaaagt ctgtattcac 1500ctcccaggtg ccaagagagc acccaccctg cttcggacaa ccctgacata 1550attgccagca cggcagagga ggtggcatcc accagcccag gcatccatca 1600tgcccactgg gtgttgttcc taagaaactg attgattaaa aaatttccca 1650aagtgtcctg aagtgtctct tcaaatacat gttgatctgt ggagttgatt 1700cctttccttc tcttggtttt agacaaatgt aaacaaagct ctgatcctta 1750aaattgctat gctgatagag tggtgagggc tggaagcttg atcaagtcct 1800gtttcttctt gacacagact gattaaaaat taaaagnaaa aaa 18438490PRTHomo sapiens 8Met Tyr His Gly Met Asn Pro Ser Asn Gly Asp Gly Phe Leu Glu1 5 10 15Gln Gln Gln Gln Gln Gln Gln Pro Gln Ser Pro Gln Arg Leu Leu 20 25 30Ala Val Ile Leu Trp Phe Gln Leu Ala Leu Cys Phe Gly Pro Ala 35 40 45Gln Leu Thr Gly Gly Phe Asp Asp Leu Gln Val Cys Ala Asp Pro 50 55 60Gly Ile Pro Glu Asn Gly Phe Arg Thr Pro Ser Gly Gly Val Phe 65 70 75Phe Glu Gly Ser Val Ala Arg Phe His Cys Gln Asp Gly Phe Lys 80 85 90Leu Lys Gly Ala Thr Lys Arg Leu Cys Leu Lys His Phe Asn Gly 95 100 105Thr Leu Gly Trp Ile Pro Ser Asp Asn Ser Ile Cys Val Gln Glu 110 115 120Asp Cys Arg Ile Pro Gln Ile Glu Asp Ala Glu Ile His Asn Lys 125 130 135Thr Tyr Arg His Gly Glu Lys Leu Ile Ile Thr Cys His Glu Gly 140 145 150Phe Lys Ile Arg Tyr Pro Asp Leu His Asn Met Val Ser Leu Cys 155 160 165Arg Asp Asp Gly Thr Trp Asn Asn Leu Pro Ile Cys Gln Gly Cys 170 175 180Leu Arg Pro Leu Ala Ser Ser Asn Gly Tyr Val Asn Ile Ser Glu 185 190 195Leu Gln Thr Ser Phe Pro Val Gly Thr Val Ile Ser Tyr Arg Cys 200 205 210Phe Pro Gly Phe Lys Leu Asp Gly Ser Ala Tyr Leu Glu Cys Leu 215 220 225Gln Asn Leu Ile Trp Ser Ser Ser Pro Pro Arg Cys Leu Ala Leu 230 235 240Glu Ala Gln Val Cys Pro Leu Pro Pro Met Val Ser His Gly Asp 245 250 255Phe Val Cys His Pro Arg Pro Cys Glu Arg Tyr Asn His Gly Thr 260 265 270Val Val Glu Phe Tyr Cys Asp Pro Gly Tyr Ser Leu Thr Ser Asp 275 280 285Tyr Lys Tyr Ile Thr Cys Gln Tyr Gly Glu Trp Phe Pro Ser Tyr 290 295 300Gln Val Tyr Cys Ile Lys Ser Glu Gln Thr Trp Pro Ser Thr His 305 310 315Glu Thr Leu Leu Thr Thr Trp Lys Ile Val Ala Phe Thr Ala Thr 320 325 330Ser Val Leu Leu Val Leu Leu Leu Val Ile Leu Ala Arg Met Phe 335 340 345Gln Thr Lys Phe Lys Ala His Phe Pro Pro Arg Gly Pro Pro Arg 350 355 360Ser Ser Ser Ser Asp Pro Asp Phe Val Val Val Asp Gly Val Pro 365 370 375Val Met Leu Pro Ser Tyr Asp Glu Ala Val Ser Gly Gly Leu Ser 380 385 390Ala Leu Gly Pro Gly Tyr Met Ala Ser Val Gly Gln Gly Cys Pro 395 400 405Leu Pro Val Asp Asp Gln Ser Pro Pro Ala Tyr Pro Gly Ser Gly 410 415 420Asp Thr Asp Thr Gly Pro Gly Glu Ser Glu Thr Cys Asp Ser Val 425 430 435Ser Gly Ser Ser Glu Leu Leu Gln Ser Leu Tyr Ser Pro Pro Arg 440 445 450Cys Gln Glu Ser Thr His Pro Ala Ser Asp Asn Pro Asp Ile Ile 455 460 465Ala Ser Thr Ala Glu Glu Val Ala Ser Thr Ser Pro Gly Ile His 470 475 480His Ala His Trp Val Leu Phe Leu Arg Asn 485 49091815DNAHomo sapiens 9cccacgcgtc cgctccgcgc cctccccccc gcctcccgtg cggtccgtcg 50gtggcctaga gatgctgctg ccgcggttgc agttgtcgcg cacgcctctg 100cccgccagcc cgctccaccg ccgtagcgcc cgagtgtcgg ggggcgcacc 150cgagtcgggc catgaggccg ggaaccgcgc tacaggccgt gctgctggcc 200gtgctgctgg tggggctgcg ggccgcgacg ggtcgcctgc tgagtgcctc 250ggatttggac ctcagaggag ggcagccagt ctgccgggga gggacacaga 300ggccttgtta taaagtcatt tacttccatg atacttctcg aagactgaac 350tttgaggaag ccaaagaagc ctgcaggagg gatggaggcc agctagtcag 400catcgagtct gaagatgaac agaaactgat agaaaagttc attgaaaacc 450tcttgccatc tgatggtgac ttctggattg ggctcaggag gcgtgaggag 500aaacaaagca atagcacagc ctgccaggac ctttatgctt ggactgatgg 550cagcatatca caatttagga actggtatgt ggatgagccg tcctgcggca 600gcgaggtctg cgtggtcatg taccatcagc catcggcacc cgctggcatc 650ggaggcccct acatgttcca gtggaatgat gaccggtgca acatgaagaa 700caatttcatt tgcaaatatt ctgatgagaa accagcagtt ccttctagag 750aagctgaagg tgaggaaaca gagctgacaa cacctgtact tccagaagaa 800acacaggaag aagatgccaa aaaaacattt aaagaaagta gagaagctgc 850cttgaatctg gcctacatcc taatccccag cattcccctt ctcctcctcc 900ttgtggtcac cacagttgta tgttgggttt ggatctgtag aaaaagaaaa 950cgggagcagc cagaccctag cacaaagaag caacacacca tctggccctc 1000tcctcaccag ggaaacagcc cggacctaga ggtctacaat gtcataagaa 1050aacaaagcga agctgactta gctgagaccc ggccagacct gaagaatatt 1100tcattccgag tgtgttcggg agaagccact cccgatgaca tgtcttgtga 1150ctatgacaac atggctgtga acccatcaga aagtgggttt gtgactctgg 1200tgagcgtgga gagtggattt gtgaccaatg acatttatga gttctcccca 1250gaccaaatgg ggaggagtaa ggagtctgga tgggtggaaa atgaaatata 1300tggttattag gacatataaa aaactgaaac tgacaacaat ggaaaagaaa 1350tgataagcaa aatcctctta ttttctataa ggaaaataca cagaaggtct 1400atgaacaagc ttagatcagg tcctgtggat gagcatgtgg tccccacgac 1450ctcctgttgg acccccacgt tttggctgta tcctttatcc cagccagtca 1500tccagctcga ccttatgaga aggtaccttg cccaggtctg gcacatagta 1550gagtctcaat aaatgtcact tggttggttg tatctaactt ttaagggaca 1600gagctttacc tggcagtgat aaagatgggc tgtggagctt ggaaaaccac 1650ctctgttttc cttgctctat acagcagcac atattatcat acagacagaa 1700aatccagaat cttttcaaag cccacatatg gtagcacagg ttggcctgtg 1750catcggcaat tctcatatct gtttttttca aagaataaaa tcaaataaag 1800agcaggaaaa aaaaa 181510382PRTHomo sapiens 10Met Arg Pro Gly Thr Ala Leu Gln Ala Val Leu Leu Ala Val Leu1 5 10 15Leu Val Gly Leu Arg Ala Ala Thr Gly Arg Leu Leu Ser Ala Ser 20 25 30Asp Leu Asp Leu Arg Gly Gly Gln Pro Val Cys Arg Gly Gly Thr 35 40 45Gln Arg Pro Cys Tyr Lys Val Ile Tyr Phe His Asp Thr Ser Arg 50 55 60Arg Leu Asn Phe Glu Glu Ala Lys Glu Ala Cys Arg Arg Asp Gly 65 70 75Gly Gln Leu Val Ser Ile Glu Ser Glu Asp Glu Gln Lys Leu Ile 80 85 90Glu Lys Phe Ile Glu Asn Leu Leu Pro Ser Asp Gly Asp Phe Trp 95 100 105Ile Gly Leu Arg Arg Arg Glu Glu Lys Gln Ser Asn Ser Thr Ala 110 115 120Cys Gln Asp Leu Tyr Ala Trp Thr Asp Gly Ser Ile Ser Gln Phe 125 130 135Arg Asn Trp Tyr Val Asp Glu Pro Ser Cys Gly Ser Glu Val Cys 140 145 150Val Val Met Tyr His Gln Pro Ser Ala Pro Ala Gly Ile Gly Gly 155 160 165Pro Tyr Met Phe Gln Trp Asn Asp Asp Arg Cys Asn Met Lys Asn 170 175 180Asn Phe Ile Cys Lys Tyr Ser Asp Glu Lys Pro Ala Val Pro Ser 185 190 195Arg Glu Ala Glu Gly Glu Glu Thr Glu Leu Thr Thr Pro Val Leu 200 205 210Pro Glu Glu Thr Gln Glu Glu Asp Ala Lys Lys Thr Phe Lys Glu 215 220 225Ser Arg Glu Ala Ala Leu Asn Leu Ala Tyr Ile Leu Ile Pro Ser 230 235 240Ile Pro Leu Leu Leu Leu Leu Val Val Thr Thr Val Val Cys Trp 245 250 255Val Trp Ile Cys Arg Lys Arg Lys Arg Glu Gln Pro Asp Pro Ser 260 265 270Thr Lys Lys Gln His Thr Ile Trp Pro Ser Pro His Gln Gly Asn 275 280 285Ser Pro Asp Leu Glu Val Tyr Asn Val Ile Arg Lys Gln Ser Glu 290 295 300Ala Asp Leu Ala Glu Thr Arg Pro Asp Leu Lys Asn Ile Ser Phe 305 310 315Arg Val Cys Ser Gly Glu Ala Thr Pro Asp Asp Met Ser Cys Asp 320 325 330Tyr Asp Asn Met Ala Val Asn Pro Ser Glu Ser Gly Phe Val Thr 335 340 345Leu Val Ser Val Glu Ser Gly Phe Val Thr Asn Asp Ile Tyr Glu 350 355 360Phe Ser Pro Asp Gln Met Gly Arg Ser Lys Glu Ser Gly Trp Val 365 370 375Glu Asn Glu Ile Tyr Gly Tyr 380112479DNAHomo sapiens 11acttgccatc acctgttgcc agtgtggaaa aattctccct gttgaatttt 50ttgcacatgg aggacagcag caaagagggc aacacaggct gataagacca 100gagacagcag ggagattatt ttaccatacg ccctcaggac gttccctcta 150gctggagttc tggacttcaa cagaacccca tccagtcatt ttgattttgc 200tgtttatttt ttttttcttt ttctttttcc caccacattg tattttattt 250ccgtacttca gaaatgggcc tacagaccac aaagtggccc agccatgggg 300cttttttcct gaagtcttgg cttatcattt ccctggggct ctactcacag 350gtgtccaaac tcctggcctg ccctagtgtg tgccgctgcg acaggaactt 400tgtctactgt aatgagcgaa gcttgacctc agtgcctctt gggatcccgg 450agggcgtaac cgtactctac ctccacaaca accaaattaa taatgctgga 500tttcctgcag aactgcacaa tgtacagtcg gtgcacacgg tctacctgta 550tggcaaccaa ctggacgaat tccccatgaa ccttcccaag aatgtcagag 600ttctccattt gcaggaaaac aatattcaga ccatttcacg ggctgctctt 650gcccagctct tgaagcttga agagctgcac ctggatgaca actccatatc 700cacagtgggg gtggaagacg gggccttccg ggaggctatt agcctcaaat 750tgttgttttt gtctaagaat cacctgagca gtgtgcctgt tgggcttcct

800gtggacttgc aagagctgag agtggatgaa aatcgaattg ctgtcatatc 850cgacatggcc ttccagaatc tcacgagctt ggagcgtctt attgtggacg 900ggaacctcct gaccaacaag ggtatcgccg agggcacctt cagccatctc 950accaagctca aggaattttc aattgtacgt aattcgctgt cccaccctcc 1000tcccgatctc ccaggtacgc atctgatcag gctctatttg caggacaacc 1050agataaacca cattcctttg acagccttct caaatctgcg taagctggaa 1100cggctggata tatccaacaa ccaactgcgg atgctgactc aaggggtttt 1150tgataatctc tccaacctga agcagctcac tgctcggaat aacccttggt 1200tttgtgactg cagtattaaa tgggtcacag aatggctcaa atatatccct 1250tcatctctca acgtgcgggg tttcatgtgc caaggtcctg aacaagtccg 1300ggggatggcc gtcagggaat taaatatgaa tcttttgtcc tgtcccacca 1350cgacccccgg cctgcctctc ttcaccccag ccccaagtac agcttctccg 1400accactcagc ctcccaccct ctctattcca aaccctagca gaagctacac 1450gcctccaact cctaccacat cgaaacttcc cacgattcct gactgggatg 1500gcagagaaag agtgacccca cctatttctg aacggatcca gctctctatc 1550cattttgtga atgatacttc cattcaagtc agctggctct ctctcttcac 1600cgtgatggca tacaaactca catgggtgaa aatgggccac agtttagtag 1650ggggcatcgt tcaggagcgc atagtcagcg gtgagaagca acacctgagc 1700ctggttaact tagagccccg atccacctat cggatttgtt tagtgccact 1750ggatgctttt aactaccgcg cggtagaaga caccatttgt tcagaggcca 1800ccacccatgc ctcctatctg aacaacggca gcaacacagc gtccagccat 1850gagcagacga cgtcccacag catgggctcc ccctttctgc tggcgggctt 1900gatcgggggc gcggtgatat ttgtgctggt ggtcttgctc agcgtctttt 1950gctggcatat gcacaaaaag gggcgctaca cctcccagaa gtggaaatac 2000aaccggggcc ggcggaaaga tgattattgc gaggcaggca ccaagaagga 2050caactccatc ctggagatga cagaaaccag ttttcagatc gtctccttaa 2100ataacgatca actccttaaa ggagatttca gactgcagcc catttacacc 2150ccaaatgggg gcattaatta cacagactgc catatcccca acaacatgcg 2200atactgcaac agcagcgtgc cagacctgga gcactgccat acgtgacagc 2250cagaggccca gcgttatcaa ggcggacaat tagactcttg agaacacact 2300cgtgtgtgca cataaagaca cgcagattac atttgataaa tgttacacag 2350atgcatttgt gcatttgaat actctgtaat ttatacggtg tactatataa 2400tgggatttaa aaaaagtgct atcttttcta tttcaagtta attacaaaca 2450gttttgtaac tctttgcttt ttaaatctt 247912660PRTHomo sapiens 12Met Gly Leu Gln Thr Thr Lys Trp Pro Ser His Gly Ala Phe Phe1 5 10 15Leu Lys Ser Trp Leu Ile Ile Ser Leu Gly Leu Tyr Ser Gln Val 20 25 30Ser Lys Leu Leu Ala Cys Pro Ser Val Cys Arg Cys Asp Arg Asn 35 40 45Phe Val Tyr Cys Asn Glu Arg Ser Leu Thr Ser Val Pro Leu Gly 50 55 60Ile Pro Glu Gly Val Thr Val Leu Tyr Leu His Asn Asn Gln Ile 65 70 75Asn Asn Ala Gly Phe Pro Ala Glu Leu His Asn Val Gln Ser Val 80 85 90His Thr Val Tyr Leu Tyr Gly Asn Gln Leu Asp Glu Phe Pro Met 95 100 105Asn Leu Pro Lys Asn Val Arg Val Leu His Leu Gln Glu Asn Asn 110 115 120Ile Gln Thr Ile Ser Arg Ala Ala Leu Ala Gln Leu Leu Lys Leu 125 130 135Glu Glu Leu His Leu Asp Asp Asn Ser Ile Ser Thr Val Gly Val 140 145 150Glu Asp Gly Ala Phe Arg Glu Ala Ile Ser Leu Lys Leu Leu Phe 155 160 165Leu Ser Lys Asn His Leu Ser Ser Val Pro Val Gly Leu Pro Val 170 175 180Asp Leu Gln Glu Leu Arg Val Asp Glu Asn Arg Ile Ala Val Ile 185 190 195Ser Asp Met Ala Phe Gln Asn Leu Thr Ser Leu Glu Arg Leu Ile 200 205 210Val Asp Gly Asn Leu Leu Thr Asn Lys Gly Ile Ala Glu Gly Thr 215 220 225Phe Ser His Leu Thr Lys Leu Lys Glu Phe Ser Ile Val Arg Asn 230 235 240Ser Leu Ser His Pro Pro Pro Asp Leu Pro Gly Thr His Leu Ile 245 250 255Arg Leu Tyr Leu Gln Asp Asn Gln Ile Asn His Ile Pro Leu Thr 260 265 270Ala Phe Ser Asn Leu Arg Lys Leu Glu Arg Leu Asp Ile Ser Asn 275 280 285Asn Gln Leu Arg Met Leu Thr Gln Gly Val Phe Asp Asn Leu Ser 290 295 300Asn Leu Lys Gln Leu Thr Ala Arg Asn Asn Pro Trp Phe Cys Asp 305 310 315Cys Ser Ile Lys Trp Val Thr Glu Trp Leu Lys Tyr Ile Pro Ser 320 325 330Ser Leu Asn Val Arg Gly Phe Met Cys Gln Gly Pro Glu Gln Val 335 340 345Arg Gly Met Ala Val Arg Glu Leu Asn Met Asn Leu Leu Ser Cys 350 355 360Pro Thr Thr Thr Pro Gly Leu Pro Leu Phe Thr Pro Ala Pro Ser 365 370 375Thr Ala Ser Pro Thr Thr Gln Pro Pro Thr Leu Ser Ile Pro Asn 380 385 390Pro Ser Arg Ser Tyr Thr Pro Pro Thr Pro Thr Thr Ser Lys Leu 395 400 405Pro Thr Ile Pro Asp Trp Asp Gly Arg Glu Arg Val Thr Pro Pro 410 415 420Ile Ser Glu Arg Ile Gln Leu Ser Ile His Phe Val Asn Asp Thr 425 430 435Ser Ile Gln Val Ser Trp Leu Ser Leu Phe Thr Val Met Ala Tyr 440 445 450Lys Leu Thr Trp Val Lys Met Gly His Ser Leu Val Gly Gly Ile 455 460 465Val Gln Glu Arg Ile Val Ser Gly Glu Lys Gln His Leu Ser Leu 470 475 480Val Asn Leu Glu Pro Arg Ser Thr Tyr Arg Ile Cys Leu Val Pro 485 490 495Leu Asp Ala Phe Asn Tyr Arg Ala Val Glu Asp Thr Ile Cys Ser 500 505 510Glu Ala Thr Thr His Ala Ser Tyr Leu Asn Asn Gly Ser Asn Thr 515 520 525Ala Ser Ser His Glu Gln Thr Thr Ser His Ser Met Gly Ser Pro 530 535 540Phe Leu Leu Ala Gly Leu Ile Gly Gly Ala Val Ile Phe Val Leu 545 550 555Val Val Leu Leu Ser Val Phe Cys Trp His Met His Lys Lys Gly 560 565 570Arg Tyr Thr Ser Gln Lys Trp Lys Tyr Asn Arg Gly Arg Arg Lys 575 580 585Asp Asp Tyr Cys Glu Ala Gly Thr Lys Lys Asp Asn Ser Ile Leu 590 595 600Glu Met Thr Glu Thr Ser Phe Gln Ile Val Ser Leu Asn Asn Asp 605 610 615Gln Leu Leu Lys Gly Asp Phe Arg Leu Gln Pro Ile Tyr Thr Pro 620 625 630Asn Gly Gly Ile Asn Tyr Thr Asp Cys His Ile Pro Asn Asn Met 635 640 645Arg Tyr Cys Asn Ser Ser Val Pro Asp Leu Glu His Cys His Thr 650 655 660132153DNAHomo sapiens 13taggaggtcc ccgggttgcc ggcggcgaca gcgggggaag catgactgct 50gtgggccgaa ggtgccccgc gctggggtcc cgaggggctg ctggagagcc 100agaggctggc agcgactatg tgaagttctc caaggagaag tacatcctgg 150actcatcgcc agagaaactc cacaaggaat tggaggagga gctcaaactc 200agcagcacgg atctccgcag ccatgcctgg taccatggcc gcatcccccg 250agaggtctcg gagaccttgg tacaacgcaa cggcgacttc ctcatccggg 300actcgctcac cagcctgggc gactatgtgc tcacgtgccg ctggcgcaac 350caggccttgc acttcaagat caacaaggtg gtggtgaagg caggcgagag 400ctacacacac atccagtacc tgtttgagca ggagagcttt gaccacgtgc 450ccgccctcgt gcgctatcat gtgggcagcc gcaaggctgt gtcagagcag 500agtggtgcca tcatctactg cccggtgaac cgcaccttcc cactgcgcta 550cctcgaggcc agctatggcc tgggacaggg gagtagcaag cctgctagcc 600ccgtcagccc ctcaggcccc aagggcagcc acatgaagcg gcgcagcgtc 650accatgaccg atgggctcac tgctgacaag gtcacccgca gcgatggctg 700ccccaccagt acgtcgctgc cccgccctcg ggactccatc cgcagctgtg 750ccctcagcat ggaccagatc ccagacctgc actcacccat gtcgcccatc 800tccgagagcc ctagctcccc tgcctacagc actgtaaccc gtgtccatgc 850cgcccctgca gccccttctg ccacagcatt gcctgcctcc cctgtcgccc 900gctgttccag tgagccccag ctgtgtcccg gaagtgcccc aaagacccat 950ggggagtcag acaagggccc ccacaccagc ccctcccaca cccttggcaa 1000ggcctccccg tcaccatcac tcagcagcta cagtgacccg gactctggcc 1050actactgcca gctccagcct cccgtgcgtg gcagccgaga gtgggcagcg 1100actgagacct ccagccagca ggccaggagc tatggggaga ggctaaagga 1150actgtcagaa aatggggccc ctgaagggga ctggggcaag accttcacag 1200tccccatcgt ggaagtcact tcttccttca acccggccac cttccagtca 1250ctactgatcc ccagggataa ccggccactg gaggtgggcc ttctgcgcaa 1300ggtcaaggag ctgctggcag aagtggatgc ccggacgctg gcccggcatg 1350tcaccaaggt ggactgcctg gttgctagga tactgggcgt taccaaggag 1400atgcagaccc taatgggagt ccgctggggc atggaactgc tcaccctccc 1450ccatggccgg cagctacgcc tagacctgct ggaaaggttc cacaccatgt 1500ccatcatgct ggccgtggac atcctgggct gcaccggctc tgcggaggag 1550cgggcagcgc tgctgcacaa gaccattcag ctggcggccg agctacgggg 1600gactatgggc aacatgttca gcttcgcggc ggtcatgggt gccctggaca 1650tggctcagat ttctcggctg gagcagacat gggtgaccct gcggcagcga 1700cacacagagg gtgccatcct gtacgagaag aagctcaagc cttttctcaa 1750gagcctcaac gagggcaaag aaggcccgcc gctgagcaac accacgtttc 1800ctcatgtgct gcccctcatc accctgctgg agtgtgactc ggccccacca 1850gagggccctg agccctgggg cagcacggag cacggcgtgg aggtggtgct 1900ggctcacctg gaggccgccc gcacagtggc acaccacgga ggcctgtacc 1950acaccaatgc tgaagtcaag ctgcaggggt tccaggcccg gccggagctc 2000ctggaggtgt tcagcacgga gttccagatg cgccttctct ggggcagtca 2050gggtgccagc agcagccagg cccggcgcta tgagaagttc gacaaggtcc 2100tcactgccct gtcccacaag ctggaacctg ctgtccgctc cagcgagctg 2150tga 215314703PRTHomo sapiens 14Met Thr Ala Val Gly Arg Arg Cys Pro Ala Leu Gly Ser Arg Gly1 5 10 15Ala Ala Gly Glu Pro Glu Ala Gly Ser Asp Tyr Val Lys Phe Ser 20 25 30Lys Glu Lys Tyr Ile Leu Asp Ser Ser Pro Glu Lys Leu His Lys 35 40 45Glu Leu Glu Glu Glu Leu Lys Leu Ser Ser Thr Asp Leu Arg Ser 50 55 60His Ala Trp Tyr His Gly Arg Ile Pro Arg Glu Val Ser Glu Thr 65 70 75Leu Val Gln Arg Asn Gly Asp Phe Leu Ile Arg Asp Ser Leu Thr 80 85 90Ser Leu Gly Asp Tyr Val Leu Thr Cys Arg Trp Arg Asn Gln Ala 95 100 105Leu His Phe Lys Ile Asn Lys Val Val Val Lys Ala Gly Glu Ser 110 115 120Tyr Thr His Ile Gln Tyr Leu Phe Glu Gln Glu Ser Phe Asp His 125 130 135Val Pro Ala Leu Val Arg Tyr His Val Gly Ser Arg Lys Ala Val 140 145 150Ser Glu Gln Ser Gly Ala Ile Ile Tyr Cys Pro Val Asn Arg Thr 155 160 165Phe Pro Leu Arg Tyr Leu Glu Ala Ser Tyr Gly Leu Gly Gln Gly 170 175 180Ser Ser Lys Pro Ala Ser Pro Val Ser Pro Ser Gly Pro Lys Gly 185 190 195Ser His Met Lys Arg Arg Ser Val Thr Met Thr Asp Gly Leu Thr 200 205 210Ala Asp Lys Val Thr Arg Ser Asp Gly Cys Pro Thr Ser Thr Ser 215 220 225Leu Pro Arg Pro Arg Asp Ser Ile Arg Ser Cys Ala Leu Ser Met 230 235 240Asp Gln Ile Pro Asp Leu His Ser Pro Met Ser Pro Ile Ser Glu 245 250 255Ser Pro Ser Ser Pro Ala Tyr Ser Thr Val Thr Arg Val His Ala 260 265 270Ala Pro Ala Ala Pro Ser Ala Thr Ala Leu Pro Ala Ser Pro Val 275 280 285Ala Arg Cys Ser Ser Glu Pro Gln Leu Cys Pro Gly Ser Ala Pro 290 295 300Lys Thr His Gly Glu Ser Asp Lys Gly Pro His Thr Ser Pro Ser 305 310 315His Thr Leu Gly Lys Ala Ser Pro Ser Pro Ser Leu Ser Ser Tyr 320 325 330Ser Asp Pro Asp Ser Gly His Tyr Cys Gln Leu Gln Pro Pro Val 335 340 345Arg Gly Ser Arg Glu Trp Ala Ala Thr Glu Thr Ser Ser Gln Gln 350 355 360Ala Arg Ser Tyr Gly Glu Arg Leu Lys Glu Leu Ser Glu Asn Gly 365 370 375Ala Pro Glu Gly Asp Trp Gly Lys Thr Phe Thr Val Pro Ile Val 380 385 390Glu Val Thr Ser Ser Phe Asn Pro Ala Thr Phe Gln Ser Leu Leu 395 400 405Ile Pro Arg Asp Asn Arg Pro Leu Glu Val Gly Leu Leu Arg Lys 410 415 420Val Lys Glu Leu Leu Ala Glu Val Asp Ala Arg Thr Leu Ala Arg 425 430 435His Val Thr Lys Val Asp Cys Leu Val Ala Arg Ile Leu Gly Val 440 445 450Thr Lys Glu Met Gln Thr Leu Met Gly Val Arg Trp Gly Met Glu 455 460 465Leu Leu Thr Leu Pro His Gly Arg Gln Leu Arg Leu Asp Leu Leu 470 475 480Glu Arg Phe His Thr Met Ser Ile Met Leu Ala Val Asp Ile Leu 485 490 495Gly Cys Thr Gly Ser Ala Glu Glu Arg Ala Ala Leu Leu His Lys 500 505 510Thr Ile Gln Leu Ala Ala Glu Leu Arg Gly Thr Met Gly Asn Met 515 520 525Phe Ser Phe Ala Ala Val Met Gly Ala Leu Asp Met Ala Gln Ile 530 535 540Ser Arg Leu Glu Gln Thr Trp Val Thr Leu Arg Gln Arg His Thr 545 550 555Glu Gly Ala Ile Leu Tyr Glu Lys Lys Leu Lys Pro Phe Leu Lys 560 565 570Ser Leu Asn Glu Gly Lys Glu Gly Pro Pro Leu Ser Asn Thr Thr 575 580 585Phe Pro His Val Leu Pro Leu Ile Thr Leu Leu Glu Cys Asp Ser 590 595 600Ala Pro Pro Glu Gly Pro Glu Pro Trp Gly Ser Thr Glu His Gly 605 610 615Val Glu Val Val Leu Ala His Leu Glu Ala Ala Arg Thr Val Ala 620 625 630His His Gly Gly Leu Tyr His Thr Asn Ala Glu Val Lys Leu Gln 635 640 645Gly Phe Gln Ala Arg Pro Glu Leu Leu Glu Val Phe Ser Thr Glu 650 655 660Phe Gln Met Arg Leu Leu Trp Gly Ser Gln Gly Ala Ser Ser Ser 665 670 675Gln Ala Arg Arg Tyr Glu Lys Phe Asp Lys Val Leu Thr Ala Leu 680 685 690Ser His Lys Leu Glu Pro Ala Val Arg Ser Ser Glu Leu 695 700153296DNAHomo sapiens 15caaaacttgc gtcgcggaga gcgcccagct tgacttgaat ggaaggagcc 50cgagcccgcg gagcgcagct gagactgggg gagcgcgttc ggcctgtggg 100gcgccgctcg gcgccggggc gcagcaggga aggggaagct gtggtctgcc 150ctgctccacg aggcgccact ggtgtgaacc gggagagccc ctgggtggtc 200ccgtccccta tccctccttt atatagaaac cttccacact gggaaggcag 250cggcgaggca ggagggctca tggtgagcaa ggaggccggc tgatctgcag 300gcgcacagca ttccgagttt acagattttt acagatacca aatggaaggc 350gaggaggcag aacagcctgc ctggttccat cagccctggc gcccaggcgc 400atctgactcg gcaccccctg caggcaccat ggcccagagc cgggtgctgc 450tgctcctgct gctgctgccg ccacagctgc acctgggacc tgtgcttgcc 500gtgagggccc caggatttgg ccgaagtggc ggccacagcc tgagccccga 550agagaacgaa tttgcggagg aggagccggt gctggtactg agccctgagg 600agcccgggcc tggcccagcc gcggtcagct gcccccgaga ctgtgcctgt 650tcccaggagg gcgtcgtgga ctgtggcggt attgacctgc gtgagttccc 700gggggacctg cctgagcaca ccaaccacct atctctgcag aacaaccagc 750tggaaaagat ctaccctgag gagctctccc ggctgcaccg gctggagaca 800ctgaacctgc aaaacaaccg cctgacttcc cgagggctcc cagagaaggc 850gtttgagcat ctgaccaacc tcaattacct gtacttggcc aataacaagc 900tgaccttggc accccgcttc ctgccaaacg ccctgatcag tgtggacttt 950gctgccaact atctcaccaa gatctatggg ctcacctttg gccagaagcc 1000aaacttgagg tctgtgtacc tgcacaacaa caagctggca gacgccgggc 1050tgccggacaa catgttcaac ggctccagca acgtcgaggt cctcatcctg 1100tccagcaact tcctgcgcca cgtgcccaag cacctgccgc ctgccctgta 1150caagctgcac ctcaagaaca acaagctgga gaagatcccc ccgggggcct 1200tcagcgagct gagcagcctg cgcgagctat acctgcagaa caactacctg

1250actgacgagg gcctggacaa cgagaccttc tggaagctct ccagcctgga 1300gtacctggat ctgtccagca acaacctgtc tcgggtccca gctgggctgc 1350cgcgcagcct ggtgctgctg cacttggaga agaacgccat ccggagcgtg 1400gacgcgaatg tgctgacccc catccgcagc ctggagtacc tgctgctgca 1450cagcaaccag ctgcgggagc agggcatcca cccactggcc ttccagggcc 1500tcaagcggtt gcacacggtg cacctgtaca acaacgcgct ggagcgcgtg 1550cccagtggcc tgcctcgccg cgtgcgcacc ctcatgatcc tgcacaacca 1600gatcacaggc attggccgcg aagactttgc caccacctac ttcctggagg 1650agctcaacct cagctacaac cgcatcacca gcccacaggt gcaccgcgac 1700gccttccgca agctgcgcct gctgcgctcg ctggacctgt cgggcaaccg 1750gctgcacacg ctgccacctg ggctgcctcg aaatgtccat gtgctgaagg 1800tcaagcgcaa tgagctggct gccttggcac gaggggcgct ggcgggcatg 1850gctcagctgc gtgagctgta cctcaccagc aaccgactgc gcagccgagc 1900cctgggcccc cgtgcctggg tggacctcgc ccatctgcag ctgctggaca 1950tcgccgggaa tcagctcaca gagatccccg aggggctccc cgagtcactt 2000gagtacctgt acctgcagaa caacaagatt agtgcggtgc ccgccaatgc 2050cttcgactcc acgcccaacc tcaaggggat ctttctcagg tttaacaagc 2100tggctgtggg ctccgtggtg gacagtgcct tccggaggct gaagcacctg 2150caggtcttgg acattgaagg caacttagag tttggtgaca tttccaagga 2200ccgtggccgc ttggggaagg aaaaggagga ggaggaagag gaggaggagg 2250aggaagagga aacaagatag tgacaaggtg atgcagatgt gacctaggat 2300gatggaccgc cggactcttt tctgcagcac acgcctgtgt gctgtgagcc 2350ccccactctg ccgtgctcac acagacacac ccagctgcac acatgaggca 2400tcccacatga cacgggctga cacagtctca tatccccacc ccttcccacg 2450gcgtgtccca cggccagaca catgcacaca catcacaccc tcaaacaccc 2500agctcagcca cacacaacta ccctccaaac caccacagtc tctgtcacac 2550ccccactacc gctgccacgc cctctgaatc atgcagggaa gggtctgccc 2600ctgccctggc acacacaggc acccattccc tccccctgct gacatgtgta 2650tgcgtatgca tacacaccac acacacacac atgcacaagt catgtgcgaa 2700cagccctcca aagcctatgc cacagacagc tcttgcccca gccagaatca 2750gccatagcag ctcgccgtct gccctgtcca tctgtccgtc cgttccctgg 2800agaagacaca agggtatcca tgctctgtgg ccaggtgcct gccaccctct 2850ggaactcaca aaagctggct tttattcctt tcccatccta tggggacagg 2900agccttcagg actgctggcc tggcctggcc caccctgctc ctccaggtgc 2950tgggcagtca ctctgctaag agtccctccc tgccacgccc tggcaggaca 3000caggcacttt tccaatgggc aagcccagtg gaggcaggat gggagagccc 3050cctgggtgct gctggggcct tggggcagga gtgaagcaga ggtgatgggg 3100ctgggctgag ccagggagga aggacccagc tgcacctagg agacaccttt 3150gttcttcagg cctgtggggg aagttccggg tgcctttatt ttttattctt 3200ttctaaggaa aaaaatgata aaaatctcaa agctgatttt tcttgttata 3250gaaaaactaa tataaaagca ttatccctat ccctgcaaaa aaaaaa 329616642PRTHomo sapiens 16Met Glu Gly Glu Glu Ala Glu Gln Pro Ala Trp Phe His Gln Pro1 5 10 15Trp Arg Pro Gly Ala Ser Asp Ser Ala Pro Pro Ala Gly Thr Met 20 25 30Ala Gln Ser Arg Val Leu Leu Leu Leu Leu Leu Leu Pro Pro Gln 35 40 45Leu His Leu Gly Pro Val Leu Ala Val Arg Ala Pro Gly Phe Gly 50 55 60Arg Ser Gly Gly His Ser Leu Ser Pro Glu Glu Asn Glu Phe Ala 65 70 75Glu Glu Glu Pro Val Leu Val Leu Ser Pro Glu Glu Pro Gly Pro 80 85 90Gly Pro Ala Ala Val Ser Cys Pro Arg Asp Cys Ala Cys Ser Gln 95 100 105Glu Gly Val Val Asp Cys Gly Gly Ile Asp Leu Arg Glu Phe Pro 110 115 120Gly Asp Leu Pro Glu His Thr Asn His Leu Ser Leu Gln Asn Asn 125 130 135Gln Leu Glu Lys Ile Tyr Pro Glu Glu Leu Ser Arg Leu His Arg 140 145 150Leu Glu Thr Leu Asn Leu Gln Asn Asn Arg Leu Thr Ser Arg Gly 155 160 165Leu Pro Glu Lys Ala Phe Glu His Leu Thr Asn Leu Asn Tyr Leu 170 175 180Tyr Leu Ala Asn Asn Lys Leu Thr Leu Ala Pro Arg Phe Leu Pro 185 190 195Asn Ala Leu Ile Ser Val Asp Phe Ala Ala Asn Tyr Leu Thr Lys 200 205 210Ile Tyr Gly Leu Thr Phe Gly Gln Lys Pro Asn Leu Arg Ser Val 215 220 225Tyr Leu His Asn Asn Lys Leu Ala Asp Ala Gly Leu Pro Asp Asn 230 235 240Met Phe Asn Gly Ser Ser Asn Val Glu Val Leu Ile Leu Ser Ser 245 250 255Asn Phe Leu Arg His Val Pro Lys His Leu Pro Pro Ala Leu Tyr 260 265 270Lys Leu His Leu Lys Asn Asn Lys Leu Glu Lys Ile Pro Pro Gly 275 280 285Ala Phe Ser Glu Leu Ser Ser Leu Arg Glu Leu Tyr Leu Gln Asn 290 295 300Asn Tyr Leu Thr Asp Glu Gly Leu Asp Asn Glu Thr Phe Trp Lys 305 310 315Leu Ser Ser Leu Glu Tyr Leu Asp Leu Ser Ser Asn Asn Leu Ser 320 325 330Arg Val Pro Ala Gly Leu Pro Arg Ser Leu Val Leu Leu His Leu 335 340 345Glu Lys Asn Ala Ile Arg Ser Val Asp Ala Asn Val Leu Thr Pro 350 355 360Ile Arg Ser Leu Glu Tyr Leu Leu Leu His Ser Asn Gln Leu Arg 365 370 375Glu Gln Gly Ile His Pro Leu Ala Phe Gln Gly Leu Lys Arg Leu 380 385 390His Thr Val His Leu Tyr Asn Asn Ala Leu Glu Arg Val Pro Ser 395 400 405Gly Leu Pro Arg Arg Val Arg Thr Leu Met Ile Leu His Asn Gln 410 415 420Ile Thr Gly Ile Gly Arg Glu Asp Phe Ala Thr Thr Tyr Phe Leu 425 430 435Glu Glu Leu Asn Leu Ser Tyr Asn Arg Ile Thr Ser Pro Gln Val 440 445 450His Arg Asp Ala Phe Arg Lys Leu Arg Leu Leu Arg Ser Leu Asp 455 460 465Leu Ser Gly Asn Arg Leu His Thr Leu Pro Pro Gly Leu Pro Arg 470 475 480Asn Val His Val Leu Lys Val Lys Arg Asn Glu Leu Ala Ala Leu 485 490 495Ala Arg Gly Ala Leu Ala Gly Met Ala Gln Leu Arg Glu Leu Tyr 500 505 510Leu Thr Ser Asn Arg Leu Arg Ser Arg Ala Leu Gly Pro Arg Ala 515 520 525Trp Val Asp Leu Ala His Leu Gln Leu Leu Asp Ile Ala Gly Asn 530 535 540Gln Leu Thr Glu Ile Pro Glu Gly Leu Pro Glu Ser Leu Glu Tyr 545 550 555Leu Tyr Leu Gln Asn Asn Lys Ile Ser Ala Val Pro Ala Asn Ala 560 565 570Phe Asp Ser Thr Pro Asn Leu Lys Gly Ile Phe Leu Arg Phe Asn 575 580 585Lys Leu Ala Val Gly Ser Val Val Asp Ser Ala Phe Arg Arg Leu 590 595 600Lys His Leu Gln Val Leu Asp Ile Glu Gly Asn Leu Glu Phe Gly 605 610 615Asp Ile Ser Lys Asp Arg Gly Arg Leu Gly Lys Glu Lys Glu Glu 620 625 630Glu Glu Glu Glu Glu Glu Glu Glu Glu Glu Thr Arg 635 640171649DNAHomo sapiens 17agtcctgccc agctcttgga tcagtctgct ggccgaggag cccggtggag 50ccaggggtga ccctggagcc cagcctgccc cgaggaggcc ccggctcaga 100gccatgccag gtgtctgtga tagggcccct gacttcctct ccccgtctga 150agaccaggtg ctgaggcctg ccttgggcag ctcagtggct ctgaactgca 200cggcttgggt agtctctggg ccccactgct ccctgccttc agtccagtgg 250ctgaaagacg ggcttccatt gggaattggg ggccactaca gcctccacga 300gtactcctgg gtcaaggcca acctgtcaga ggtgcttgtg tccagtgtcc 350tgggggtcaa cgtgaccagc actgaagtct atggggcctt cacctgctcc 400atccagaaca tcagcttctc ctccttcact cttcagagag ctggccctac 450aagccacgtg gctgcggtgc tggcctccct cctggtcctg ctggccctgc 500tgctggccgc cctgctctat gtcaagtgcc gtctcaacgt gctgctctgg 550taccaggacg cgtatgggga ggtggagata aacgacggga agctctacga 600cgcctacgtc tcctacagcg actgccccga ggaccgcaag ttcgtgaact 650tcatcctaaa gccgcagctg gagcggcgtc ggggctacaa gctcttcctg 700gacgaccgcg acctcctgcc gcgcgctgag ccctccgccg acctcttggt 750gaacctgagc cgctgccgac gcctcatcgt ggtgctttcg gacgccttcc 800tgagccgggc ctggtgcagc cacagcttcc gggagggcct gtgccggctg 850ctggagctca cccgcagacc catcttcatc accttcgagg gccagaggcg 900cgaccccgcg cacccggcgc tccgcctgct gcgccagcac cgccacctgg 950tgaccttgct gctctggagg cccggctccg tgactccttc ctccgatttt 1000tggaaagaag tgcagctggc gctgccgcgg aaggtgcggt acaggccggt 1050ggaaggagac ccccagacgc agctgcagga cgacaaggac cccatgctga 1100ttcttcgagg ccgagtccct gagggccggg ccctggactc agaggtggac 1150ccggaccctg agggcgacct gggtatgccc gcccagcccc actccccaac 1200tggagaagct cagcacaggg cggagtgggg gcaggcacag ggcacagggc 1250ctggaggggc tctaggtgtt gaggactctt cccggcaccg ggagcccctg 1300cacggcctct gccctggagg tgctcggccc tcggtctgcc tgggaacttc 1350ctgggcctca caggccatca cagcaggggg tgagcagggg cagcccctgg 1400cagtgggtct gggccaaggc tgtgggtggc cacctcaggc gtctcggtct 1450ccccacccca ggtgtccggg ggcctgtttt tggagagcca tcagctccac 1500cgcacaccag tggggtctcg ctgggagaga gccggagcag cgaagtggac 1550gtctcggatc tcggctcgcg aaactacagt gcccgcacag acttctactg 1600cctggtgtcc aaggatgata tgtagctccc accccagagt gcaggatca 164918504PRTHomo sapiens 18Met Pro Gly Val Cys Asp Arg Ala Pro Asp Phe Leu Ser Pro Ser1 5 10 15Glu Asp Gln Val Leu Arg Pro Ala Leu Gly Ser Ser Val Ala Leu 20 25 30Asn Cys Thr Ala Trp Val Val Ser Gly Pro His Cys Ser Leu Pro 35 40 45Ser Val Gln Trp Leu Lys Asp Gly Leu Pro Leu Gly Ile Gly Gly 50 55 60His Tyr Ser Leu His Glu Tyr Ser Trp Val Lys Ala Asn Leu Ser 65 70 75Glu Val Leu Val Ser Ser Val Leu Gly Val Asn Val Thr Ser Thr 80 85 90Glu Val Tyr Gly Ala Phe Thr Cys Ser Ile Gln Asn Ile Ser Phe 95 100 105Ser Ser Phe Thr Leu Gln Arg Ala Gly Pro Thr Ser His Val Ala 110 115 120Ala Val Leu Ala Ser Leu Leu Val Leu Leu Ala Leu Leu Leu Ala 125 130 135Ala Leu Leu Tyr Val Lys Cys Arg Leu Asn Val Leu Leu Trp Tyr 140 145 150Gln Asp Ala Tyr Gly Glu Val Glu Ile Asn Asp Gly Lys Leu Tyr 155 160 165Asp Ala Tyr Val Ser Tyr Ser Asp Cys Pro Glu Asp Arg Lys Phe 170 175 180Val Asn Phe Ile Leu Lys Pro Gln Leu Glu Arg Arg Arg Gly Tyr 185 190 195Lys Leu Phe Leu Asp Asp Arg Asp Leu Leu Pro Arg Ala Glu Pro 200 205 210Ser Ala Asp Leu Leu Val Asn Leu Ser Arg Cys Arg Arg Leu Ile 215 220 225Val Val Leu Ser Asp Ala Phe Leu Ser Arg Ala Trp Cys Ser His 230 235 240Ser Phe Arg Glu Gly Leu Cys Arg Leu Leu Glu Leu Thr Arg Arg 245 250 255Pro Ile Phe Ile Thr Phe Glu Gly Gln Arg Arg Asp Pro Ala His 260 265 270Pro Ala Leu Arg Leu Leu Arg Gln His Arg His Leu Val Thr Leu 275 280 285Leu Leu Trp Arg Pro Gly Ser Val Thr Pro Ser Ser Asp Phe Trp 290 295 300Lys Glu Val Gln Leu Ala Leu Pro Arg Lys Val Arg Tyr Arg Pro 305 310 315Val Glu Gly Asp Pro Gln Thr Gln Leu Gln Asp Asp Lys Asp Pro 320 325 330Met Leu Ile Leu Arg Gly Arg Val Pro Glu Gly Arg Ala Leu Asp 335 340 345Ser Glu Val Asp Pro Asp Pro Glu Gly Asp Leu Gly Met Pro Ala 350 355 360Gln Pro His Ser Pro Thr Gly Glu Ala Gln His Arg Ala Glu Trp 365 370 375Gly Gln Ala Gln Gly Thr Gly Pro Gly Gly Ala Leu Gly Val Glu 380 385 390Asp Ser Ser Arg His Arg Glu Pro Leu His Gly Leu Cys Pro Gly 395 400 405Gly Ala Arg Pro Ser Val Cys Leu Gly Thr Ser Trp Ala Ser Gln 410 415 420Ala Ile Thr Ala Gly Gly Glu Gln Gly Gln Pro Leu Ala Val Gly 425 430 435Leu Gly Gln Gly Cys Gly Trp Pro Pro Gln Ala Ser Arg Ser Pro 440 445 450His Pro Arg Cys Pro Gly Ala Cys Phe Trp Arg Ala Ile Ser Ser 455 460 465Thr Ala His Gln Trp Gly Leu Ala Gly Arg Glu Pro Glu Gln Arg 470 475 480Ser Gly Arg Leu Gly Ser Arg Leu Ala Lys Leu Gln Cys Pro His 485 490 495Arg Leu Leu Leu Pro Gly Val Gln Gly 500192211DNAHomo sapiens 19gaaagctata ggctacccat tcagctcccc tgtcagagac tcaagctttg 50agaaaggcta gcaaagagca aggaaagaga gaaaacaaca aagtggcgag 100gccctcagag tgaaagcgta aggttcagtc agcctgctgc agctttgcag 150acctcagctg ggcatctcca gactcccctg aaggaagagc cttcctcacc 200caaacccaca aaagatgctg aaaaagcctc tctcagctgt gacctggctc 250tgcattttca tcgtggcctt tgtcagccac ccagcgtggc tgcagaagct 300ctctaagcac aagacaccag cacagccaca gctcaaagcg gccaactgct 350gtgaggaggt gaaggagctc aaggcccaag ttgccaacct tagcagcctg 400ctgagtgaac tgaacaagaa gcaggagagg gactgggtca gcgtggtcat 450gcaggtgatg gagctggaga gcaacagcaa gcgcatggag tcgcggctca 500cagatgctga gagcaagtac tccgagatga acaaccaaat tgacatcatg 550cagctgcagg cagcacagac ggtcactcag acctccgcag atgccatcta 600cgactgctct tccctctacc agaagaacta ccgcatctct ggagtgtata 650agcttcctcc tgatgacttc ctgggcagcc ctgaactgga ggtgttctgt 700gacatggaga cttcaggcgg aggctggacc atcatccaga gacgaaaaag 750tggccttgtc tccttctacc gggactggaa gcagtacaag cagggctttg 800gcagcatccg tggggacttc tggctgggga acgaacacat ccaccggctc 850tccagacagc caacccggct gcgtgtagag atggaggact gggagggcaa 900cctgcgctac gctgagtata gccactttgt tttgggcaat gaactcaaca 950gctatcgcct cttcctgggg aactacactg gcaatgtggg gaacacgccc 1000tccagtatca taacaacaca gccttcagca ccaaggacaa ggacaatgac 1050aactgcttgg acaagtgtgc acagctccgc aaaggtggct actggtacaa 1100ctgctgcaca gactccaacc tcaatggagt gtactaccgc ctgggtgagc 1150acaataagca cctggatggc atcacctggt atggctggca tggatctacc 1200tactccctca aacgggtgga gatgaaaatc cgcccagaag acttcaagcc 1250ttaaaaggag gctgccgtgg agcacggata cagaaactga gacacgtgga 1300gactggatga gggcagatga ggacaggaag agagtgttag aaagggtagg 1350actgagaaac agcctataat ctccaaagaa agaataagtc tccaaggagc 1400acaaaaaaat catatgtacc aaggatgtta cagtaaacag gatgaactat 1450ttaaacccac tgggtcctgc cacatccttc tcaaggtggt agactgagtg 1500gggtctctct gcccaagatc cctgacatag cagtagcttg tcttttccac 1550atgatttgtc tgtgaaagaa aataattttg agatcgtttt atctattttc 1600tctacggctt aggctatgtg agggcaaaac acaaatccct ttgctaaaaa 1650gaaccatatt attttgattc tcaaaggata ggcctttgag tgttagagaa 1700aggagtgaag gaggcaggtg ggaaatggta tttctatttt taaatccagt 1750gaaattatct tgagtctaca cattattttt aaaacacaaa aattgttcgg 1800ctggaactga cccaggctgg acttgcgggg aggaaactcc agggcactgc 1850atctggcgat cagactctga gcactgcccc tgctcgcctt ggtcatgtac 1900agcactgaaa ggaatgaagc accagcagga ggtggacaga gtctctcatg 1950gatgccggca caaaactgcc ttaaaatatt catagttaat acaggtatat 2000ctatttttat ttactttgta agaaacaagc tcaaggagct tccttttaaa 2050ttttgtctgt aggaaatggt tgaaaactga aggtagatgg tgttatagtt 2100aataataaat gctgtaaata agcatctcac tttgtaaaaa taaaatattg 2150tggttttgtt ttaaacattc aacgtttctt ttccttctac aataaacact 2200ttcaaaatgt g 221120346PRTHomo sapiens 20Met Leu Lys Lys Pro Leu Ser Ala Val Thr Trp Leu Cys Ile Phe1 5 10 15Ile Val Ala Phe Val Ser His Pro Ala Trp Leu Gln Lys Leu Ser 20 25 30Lys His Lys Thr Pro Ala Gln Pro Gln Leu Lys Ala Ala Asn Cys 35 40 45Cys Glu Glu Val Lys Glu Leu Lys Ala Gln Val Ala Asn Leu Ser 50 55 60Ser Leu Leu

Ser Glu Leu Asn Lys Lys Gln Glu Arg Asp Trp Val 65 70 75Ser Val Val Met Gln Val Met Glu Leu Glu Ser Asn Ser Lys Arg 80 85 90Met Glu Ser Arg Leu Thr Asp Ala Glu Ser Lys Tyr Ser Glu Met 95 100 105Asn Asn Gln Ile Asp Ile Met Gln Leu Gln Ala Ala Gln Thr Val 110 115 120Thr Gln Thr Ser Ala Asp Ala Ile Tyr Asp Cys Ser Ser Leu Tyr 125 130 135Gln Lys Asn Tyr Arg Ile Ser Gly Val Tyr Lys Leu Pro Pro Asp 140 145 150Asp Phe Leu Gly Ser Pro Glu Leu Glu Val Phe Cys Asp Met Glu 155 160 165Thr Ser Gly Gly Gly Trp Thr Ile Ile Gln Arg Arg Lys Ser Gly 170 175 180Leu Val Ser Phe Tyr Arg Asp Trp Lys Gln Tyr Lys Gln Gly Phe 185 190 195Gly Ser Ile Arg Gly Asp Phe Trp Leu Gly Asn Glu His Ile His 200 205 210Arg Leu Ser Arg Gln Pro Thr Arg Leu Arg Val Glu Met Glu Asp 215 220 225Trp Glu Gly Asn Leu Arg Tyr Ala Glu Tyr Ser His Phe Val Leu 230 235 240Gly Asn Glu Leu Asn Ser Tyr Arg Leu Phe Leu Gly Asn Tyr Thr 245 250 255Gly Asn Val Gly Asn Asp Ala Leu Gln Tyr His Asn Asn Thr Ala 260 265 270Phe Ser Thr Lys Asp Lys Asp Asn Asp Asn Cys Leu Asp Lys Cys 275 280 285Ala Gln Leu Arg Lys Gly Gly Tyr Trp Tyr Asn Cys Cys Thr Asp 290 295 300Ser Asn Leu Asn Gly Val Tyr Tyr Arg Leu Gly Glu His Asn Lys 305 310 315His Leu Asp Gly Ile Thr Trp Tyr Gly Trp His Gly Ser Thr Tyr 320 325 330Ser Leu Lys Arg Val Glu Met Lys Ile Arg Pro Glu Asp Phe Lys 335 340 345Pro 212680DNAHomo sapiens 21tgcggcgacc gtcgtacacc atgggcctcc acctccgccc ctaccgtgtg 50gggctgctcc cggatggcct cctgttcctc ttgctgctgc taatgctgct 100cgcggaccca gcgctcccgg ccggacgtca ccccccagtg gtgctggtcc 150ctggtgattt gggtaaccaa ctggaagcca agctggacaa gccgacagtg 200gtgcactacc tctgctccaa gaagaccgaa agctacttca caatctggct 250gaacctggaa ctgctgctgc ctgtcatcat tgactgctgg attgacaata 300tcaggctggt ttacaacaaa acatccaggg ccacccagtt tcctgatggt 350gtggatgtac gtgtccctgg ctttgggaag accttctcac tggagttcct 400ggaccccagc aaaagcagcg tgggttccta tttccacacc atggtggaga 450gccttgtggg ctggggctac acacggggtg aggatgtccg aggggctccc 500tatgactggc gccgagcccc aaatgaaaac gggccctact tcctggccct 550ccgcgagatg atcgaggaga tgtaccagct gtatgggggc cccgtggtgc 600tggttgccca cagtatgggc aacatgtaca cgctctactt tctgcagcgg 650cagccgcagg cctggaagga caagtatatc cgggccttcg tgtcactggg 700tgcgccctgg gggggcgtgg ccaagaccct gcgcgtcctg gcttcaggag 750acaacaaccg gatcccagtc atcgggcccc tgaagatccg ggagcagcag 800cggtcagctg tctccaccag ctggctgctg ccctacaact acacatggtc 850acctgagaag gtgttcgtgc agacacccac aatcaactac acactgcggg 900actaccgcaa gttcttccag gacatcggct ttgaagatgg ctggctcatg 950cggcaggaca cagaagggct ggtggaagcc acgatgccac ctggcgtgca 1000gctgcactgc ctctatggta ctggcgtccc cacaccagac tccttctact 1050atgagagctt ccctgaccgt gaccctaaaa tctgctttgg tgacggcgat 1100ggtactgtga acttgaagag tgccctgcag tgccaggcct ggcagagccg 1150ccaggagcac caagtgttgc tgcaggagct gccaggcagc gagcacatcg 1200agatgctggc caacgccacc accctggcct atctgaaacg tgtgctcctt 1250gggccctgac tcctgtgcca caggactcct gtggctcggc cgtggacctg 1300ctgttggcct ctggggctgt catggcccac gcgttttgca aagtttgtga 1350ctcaccattc aaggccccga gtcttggact gtgaagcatc tgccatgggg 1400aagtgctgtt tgttatcctt tctctgtggc agtgaagaag gaagaaatga 1450gagtctagac tcaagggaca ctggatggca agaatgctgc tgatggtgga 1500actgctgtga ccttaggact ggctccacag ggtggactgg ctgggccctg 1550gtcccagtcc ctgcctgggg ccatgtgtcc ccctattcct gtgggctttt 1600catacttgcc tactgggccc tggccccgca gccttcctat gagggatgtt 1650actgggctgt ggtcctgtac ccagaggtcc cagggatcgg ctcctggccc 1700ctcgggtgac ccttcccaca caccagccac agataggcct gccactggtc 1750atgggtagct agagctgctg gcttccctgt ggcttagctg gtggccagcc 1800tgactggctt cctgggcgag cctagtagct cctgcaggca ggggcagttt 1850gttgcgttct tcgtggttcc caggccctgg gacatctcac tccactccta 1900cctcccttac caccaggagc attcaagctc tggattgggc agcagatgtg 1950cccccagtcc cgcaggctgt gttccagggg ccctgatttc ctcggatgtg 2000ctattggccc caggactgaa gctgcctccc ttcaccctgg gactgtggtt 2050ccaaggatga gagcaggggt tggagccatg gccttctggg aacctatgga 2100gaaagggaat ccaaggaagc agccaaggct gctcgcagct tccctgagct 2150gcacctcttg ctaaccccac catcacactg ccaccctgcc ctagggtctc 2200actagtacca agtgggtcag cacagggctg aggatggggc tcctatccac 2250cctggccagc acccagctta gtgctgggac tagcccagaa acttgaatgg 2300gaccctgaga gagccagggg tcccctgagg cccccctagg ggctttctgt 2350ctgccccagg gtgctccatg gatctccctg tggcagcagg catggagagt 2400cagggctgcc ttcatggcag taggctctaa gtgggtgact ggccacaggc 2450cgagaaaagg gtacagcctc taggtggggt tcccaaagac gccttcaggc 2500tggactgagc tgctctccca cagggtttct gtgcagctgg attttctctg 2550ttgcatacat gcctggcatc tgtctcccct tgttcctgag tggccccaca 2600tggggctctg agcaggctgt atctggattc tggcaataaa agtactctgg 2650atgctgtaaa aaaaaaaaaa aaaaaaaaaa 268022412PRTHomo sapiens 22Met Gly Leu His Leu Arg Pro Tyr Arg Val Gly Leu Leu Pro Asp1 5 10 15Gly Leu Leu Phe Leu Leu Leu Leu Leu Met Leu Leu Ala Asp Pro 20 25 30Ala Leu Pro Ala Gly Arg His Pro Pro Val Val Leu Val Pro Gly 35 40 45Asp Leu Gly Asn Gln Leu Glu Ala Lys Leu Asp Lys Pro Thr Val 50 55 60Val His Tyr Leu Cys Ser Lys Lys Thr Glu Ser Tyr Phe Thr Ile 65 70 75Trp Leu Asn Leu Glu Leu Leu Leu Pro Val Ile Ile Asp Cys Trp 80 85 90Ile Asp Asn Ile Arg Leu Val Tyr Asn Lys Thr Ser Arg Ala Thr 95 100 105Gln Phe Pro Asp Gly Val Asp Val Arg Val Pro Gly Phe Gly Lys 110 115 120Thr Phe Ser Leu Glu Phe Leu Asp Pro Ser Lys Ser Ser Val Gly 125 130 135Ser Tyr Phe His Thr Met Val Glu Ser Leu Val Gly Trp Gly Tyr 140 145 150Thr Arg Gly Glu Asp Val Arg Gly Ala Pro Tyr Asp Trp Arg Arg 155 160 165Ala Pro Asn Glu Asn Gly Pro Tyr Phe Leu Ala Leu Arg Glu Met 170 175 180Ile Glu Glu Met Tyr Gln Leu Tyr Gly Gly Pro Val Val Leu Val 185 190 195Ala His Ser Met Gly Asn Met Tyr Thr Leu Tyr Phe Leu Gln Arg 200 205 210Gln Pro Gln Ala Trp Lys Asp Lys Tyr Ile Arg Ala Phe Val Ser 215 220 225Leu Gly Ala Pro Trp Gly Gly Val Ala Lys Thr Leu Arg Val Leu 230 235 240Ala Ser Gly Asp Asn Asn Arg Ile Pro Val Ile Gly Pro Leu Lys 245 250 255Ile Arg Glu Gln Gln Arg Ser Ala Val Ser Thr Ser Trp Leu Leu 260 265 270Pro Tyr Asn Tyr Thr Trp Ser Pro Glu Lys Val Phe Val Gln Thr 275 280 285Pro Thr Ile Asn Tyr Thr Leu Arg Asp Tyr Arg Lys Phe Phe Gln 290 295 300Asp Ile Gly Phe Glu Asp Gly Trp Leu Met Arg Gln Asp Thr Glu 305 310 315Gly Leu Val Glu Ala Thr Met Pro Pro Gly Val Gln Leu His Cys 320 325 330Leu Tyr Gly Thr Gly Val Pro Thr Pro Asp Ser Phe Tyr Tyr Glu 335 340 345Ser Phe Pro Asp Arg Asp Pro Lys Ile Cys Phe Gly Asp Gly Asp 350 355 360Gly Thr Val Asn Leu Lys Ser Ala Leu Gln Cys Gln Ala Trp Gln 365 370 375Ser Arg Gln Glu His Gln Val Leu Leu Gln Glu Leu Pro Gly Ser 380 385 390Glu His Ile Glu Met Leu Ala Asn Ala Thr Thr Leu Ala Tyr Leu 395 400 405Lys Arg Val Leu Leu Gly Pro 410233143DNAHomo sapiens 23gagccaccta ccctgctccg aggccaggcc tgcagggcct catcggccag 50agggtgatca gtgagcagaa ggatgcccgt ggccgaggcc ccccaggtgg 100ctggcgggca gggggacgga ggtgatggcg aggaagcgga gccagagggg 150atgttcaagg cctgtgagga ctccaagaga aaagcccggg gctacctccg 200cctggtgccc ctgtttgtgc tgctggccct gctcgtgctg gcttcggcgg 250gggtgctact ctggtatttc ctagggtaca aggcggaggt gatggtcagc 300caggtgtact caggcagtct gcgtgtactc aatcgccact tctcccagga 350tcttacccgc cgggaatcta gtgccttccg cagtgaaacc gccaaagccc 400agaagatgct caaggagctc atcaccagca cccgcctggg aacttactac 450aactccagct ccgtctattc ctttggggag ggacccctca cctgcttctt 500ctggttcatt ctccaaatcc ccgagcaccg ccggctgatg ctgagccccg 550aggtggtgca ggcactgctg gtggaggagc tgctgtccac agtcaacagc 600tcggctgccg tcccctacag ggccgagtac gaagtggacc ccgagggcct 650agtgatcctg gaagccagtg tgaaagacat agctgcattg aattccacgc 700tgggttgtta ccgctacagc tacgtgggcc agggccaggt cctccggctg 750aaggggcctg accacctggc ctccagctgc ctgtggcacc tgcagggccc 800caaggacctc atgctcaaac tccggctgga gtggacgctg gcagagtgcc 850gggaccgact ggccatgtat gacgtggccg ggcccctgga gaagaggctc 900atcacctcgg tgtacggctg cagccgccag gagcccgtgg tggaggttct 950ggcgtcgggg gccatcatgg cggtcgtctg gaagaagggc ctgcacagct 1000actacgaccc cttcgtgctc tccgtgcagc cggtggtctt ccaggcctgt 1050gaagtgaacc tgacgctgga caacaggctc gactcccagg gcgtcctcag 1100caccccgtac ttccccagct actactcgcc ccaaacccac tgctcctggc 1150acctcacggt gccctctctg gactacggct tggccctctg gtttgatgcc 1200tatgcactga ggaggcagaa gtatgatttg ccgtgcaccc agggccagtg 1250gacgatccag aacaggaggc tgtgtggctt gcgcatcctg cagccctacg 1300ccgagaggat ccccgtggtg gccacggccg ggatcaccat caacttcacc 1350tcccagatct ccctcaccgg gcccggtgtg cgggtgcact atggcttgta 1400caaccagtcg gacccctgcc ctggagagtt cctctgttct gtgaatggac 1450tctgtgtccc tgcctgtgat ggggtcaagg actgccccaa cggcctggat 1500gagagaaact gcgtttgcag agccacattc cagtgcaaag aggacagcac 1550atgcatctca ctgcccaagg tctgtgatgg gcagcctgat tgtctcaacg 1600gcagcgatga agagcagtgc caggaagggg tgccatgtgg gacattcacc 1650ttccagtgtg aggaccggag ctgcgtgaag aagcccaacc cgcagtgtga 1700tgggcggccc gactgcaggg acggctcgga tgaggagcac tgtgactgtg 1750gcctccaggg cccctccagc cgcattgttg gtggagctgt gtcctccgag 1800ggtgagtggc catggcaggc cagcctccag gttcggggtc gacacatctg 1850tgggggggcc ctcatcgctg accgctgggt gataacagct gcccactgct 1900tccaggagga cagcatggcc tccacggtgc tgtggaccgt gttcctgggc 1950aaggtgtggc agaactcgcg ctggcctgga gaggtgtcct tcaaggtgag 2000ccgcctgctc ctgcacccgt accacgaaga ggacagccat gactacgacg 2050tggcgctgct gcagctcgac cacccggtgg tgcgctcggc cgccgtgcgc 2100cccgtctgcc tgcccgcgcg ctcccacttc ttcgagcccg gcctgcactg 2150ctggattacg ggctggggcg ccttgcgcga gggcggcccc atcagcaacg 2200ctctgcagaa agtggatgtg cagttgatcc cacaggacct gtgcagcgag 2250gcctatcgct accaggtgac gccacgcatg ctgtgtgccg gctaccgcaa 2300gggcaagaag gatgcctgtc agggtgactc aggtggtccg ctggtgtgca 2350aggcactcag tggccgctgg ttcctggcgg ggctggtcag ctggggcctg 2400ggctgtggcc ggcctaacta cttcggcgtc tacacccgca tcacaggtgt 2450gatcagctgg atccagcaag tggtgacctg aggaactgcc cccctgcaaa 2500gcagggccca cctcctggac tcagagagcc cagggcaact gccaagcagg 2550gggacaagta ttctggcggg gggtggggga gagagcaggc cctgtggtgg 2600caggaggtgg catcttgtct cgtccctgat gtctgctcca gtgatggcag 2650gaggatggag aagtgccagc agctgggggt caagacgtcc cctgaggacc 2700caggcccaca cccagccctt ctgcctccca attctctctc ctccgtcccc 2750ttcctccact gctgcctaat gcaaggcagt ggctcagcag caagaatgct 2800ggttctacat cccgaggagt gtctgaggtg cgccccactc tgtacagagg 2850ctgtttgggc agccttgcct ccagagagca gattccagct tcggaagccc 2900ctggtctaac ttgggatctg ggaatggaag gtgctcccat cggaggggac 2950cctcagagcc ctggagactg ccaggtgggc ctgctgccac tgtaagccaa 3000aaggtgggga agtcctgact ccagggtcct tgccccaccc ctgcctgcca 3050cctgggccct cacagcccag accctcactg ggaggtgagc tcagctgccc 3100tttggaataa agctgcctga tcaaaaaaaa aaaaaaaaaa aaa 314324802PRTHomo sapiens 24Met Pro Val Ala Glu Ala Pro Gln Val Ala Gly Gly Gln Gly Asp1 5 10 15Gly Gly Asp Gly Glu Glu Ala Glu Pro Glu Gly Met Phe Lys Ala 20 25 30Cys Glu Asp Ser Lys Arg Lys Ala Arg Gly Tyr Leu Arg Leu Val 35 40 45Pro Leu Phe Val Leu Leu Ala Leu Leu Val Leu Ala Ser Ala Gly 50 55 60Val Leu Leu Trp Tyr Phe Leu Gly Tyr Lys Ala Glu Val Met Val 65 70 75Ser Gln Val Tyr Ser Gly Ser Leu Arg Val Leu Asn Arg His Phe 80 85 90Ser Gln Asp Leu Thr Arg Arg Glu Ser Ser Ala Phe Arg Ser Glu 95 100 105Thr Ala Lys Ala Gln Lys Met Leu Lys Glu Leu Ile Thr Ser Thr 110 115 120Arg Leu Gly Thr Tyr Tyr Asn Ser Ser Ser Val Tyr Ser Phe Gly 125 130 135Glu Gly Pro Leu Thr Cys Phe Phe Trp Phe Ile Leu Gln Ile Pro 140 145 150Glu His Arg Arg Leu Met Leu Ser Pro Glu Val Val Gln Ala Leu 155 160 165Leu Val Glu Glu Leu Leu Ser Thr Val Asn Ser Ser Ala Ala Val 170 175 180Pro Tyr Arg Ala Glu Tyr Glu Val Asp Pro Glu Gly Leu Val Ile 185 190 195Leu Glu Ala Ser Val Lys Asp Ile Ala Ala Leu Asn Ser Thr Leu 200 205 210Gly Cys Tyr Arg Tyr Ser Tyr Val Gly Gln Gly Gln Val Leu Arg 215 220 225Leu Lys Gly Pro Asp His Leu Ala Ser Ser Cys Leu Trp His Leu 230 235 240Gln Gly Pro Lys Asp Leu Met Leu Lys Leu Arg Leu Glu Trp Thr 245 250 255Leu Ala Glu Cys Arg Asp Arg Leu Ala Met Tyr Asp Val Ala Gly 260 265 270Pro Leu Glu Lys Arg Leu Ile Thr Ser Val Tyr Gly Cys Ser Arg 275 280 285Gln Glu Pro Val Val Glu Val Leu Ala Ser Gly Ala Ile Met Ala 290 295 300Val Val Trp Lys Lys Gly Leu His Ser Tyr Tyr Asp Pro Phe Val 305 310 315Leu Ser Val Gln Pro Val Val Phe Gln Ala Cys Glu Val Asn Leu 320 325 330Thr Leu Asp Asn Arg Leu Asp Ser Gln Gly Val Leu Ser Thr Pro 335 340 345Tyr Phe Pro Ser Tyr Tyr Ser Pro Gln Thr His Cys Ser Trp His 350 355 360Leu Thr Val Pro Ser Leu Asp Tyr Gly Leu Ala Leu Trp Phe Asp 365 370 375Ala Tyr Ala Leu Arg Arg Gln Lys Tyr Asp Leu Pro Cys Thr Gln 380 385 390Gly Gln Trp Thr Ile Gln Asn Arg Arg Leu Cys Gly Leu Arg Ile 395 400 405Leu Gln Pro Tyr Ala Glu Arg Ile Pro Val Val Ala Thr Ala Gly 410 415 420Ile Thr Ile Asn Phe Thr Ser Gln Ile Ser Leu Thr Gly Pro Gly 425 430 435Val Arg Val His Tyr Gly Leu Tyr Asn Gln Ser Asp Pro Cys Pro 440 445 450Gly Glu Phe Leu Cys Ser Val Asn Gly Leu Cys Val Pro Ala Cys 455 460 465Asp Gly Val Lys Asp Cys Pro Asn Gly Leu Asp Glu Arg Asn Cys 470 475 480Val Cys Arg Ala Thr Phe Gln Cys Lys Glu Asp Ser Thr Cys Ile 485 490 495Ser Leu Pro Lys Val Cys Asp Gly Gln Pro Asp Cys Leu Asn Gly 500 505 510Ser Asp Glu Glu Gln Cys Gln Glu Gly Val Pro Cys Gly Thr Phe 515 520 525Thr Phe Gln Cys Glu Asp Arg Ser Cys Val Lys Lys

Pro Asn Pro 530 535 540Gln Cys Asp Gly Arg Pro Asp Cys Arg Asp Gly Ser Asp Glu Glu 545 550 555His Cys Asp Cys Gly Leu Gln Gly Pro Ser Ser Arg Ile Val Gly 560 565 570Gly Ala Val Ser Ser Glu Gly Glu Trp Pro Trp Gln Ala Ser Leu 575 580 585Gln Val Arg Gly Arg His Ile Cys Gly Gly Ala Leu Ile Ala Asp 590 595 600Arg Trp Val Ile Thr Ala Ala His Cys Phe Gln Glu Asp Ser Met 605 610 615Ala Ser Thr Val Leu Trp Thr Val Phe Leu Gly Lys Val Trp Gln 620 625 630Asn Ser Arg Trp Pro Gly Glu Val Ser Phe Lys Val Ser Arg Leu 635 640 645Leu Leu His Pro Tyr His Glu Glu Asp Ser His Asp Tyr Asp Val 650 655 660Ala Leu Leu Gln Leu Asp His Pro Val Val Arg Ser Ala Ala Val 665 670 675Arg Pro Val Cys Leu Pro Ala Arg Ser His Phe Phe Glu Pro Gly 680 685 690Leu His Cys Trp Ile Thr Gly Trp Gly Ala Leu Arg Glu Gly Gly 695 700 705Pro Ile Ser Asn Ala Leu Gln Lys Val Asp Val Gln Leu Ile Pro 710 715 720Gln Asp Leu Cys Ser Glu Ala Tyr Arg Tyr Gln Val Thr Pro Arg 725 730 735Met Leu Cys Ala Gly Tyr Arg Lys Gly Lys Lys Asp Ala Cys Gln 740 745 750Gly Asp Ser Gly Gly Pro Leu Val Cys Lys Ala Leu Ser Gly Arg 755 760 765Trp Phe Leu Ala Gly Leu Val Ser Trp Gly Leu Gly Cys Gly Arg 770 775 780Pro Asn Tyr Phe Gly Val Tyr Thr Arg Ile Thr Gly Val Ile Ser 785 790 795Trp Ile Gln Gln Val Val Thr 800252747DNAHomo sapiens 25gcaacctcag cttctagtat ccagactcca gcgccgcccc gggcgcggac 50cccaaccccg acccagagct tctccagcgg cggcgcagcg agcagggctc 100cccgccttaa cttcctccgc ggggcccagc caccttcggg agtccgggtt 150gcccacctgc aaactctccg ccttctgcac ctgccacccc tgagccagcg 200cgggcccccg agcgagtcat ggccaacgcg gggctgcagc tgttgggctt 250cattctcgcc ttcctgggat ggatcggcgc catcgtcagc actgccctgc 300cccagtggag gatttactcc tatgccggcg acaacatcgt gaccgcccag 350gccatgtacg aggggctgtg gatgtcctgc gtgtcgcaga gcaccgggca 400gatccagtgc aaagtctttg actccttgct gaatctgagc agcacattgc 450aagcaacccg tgccttgatg gtggttggca tcctcctggg agtgatagca 500atctttgtgg ccaccgttgg catgaagtgt atgaagtgct tggaagacga 550tgaggtgcag aagatgagga tggctgtcat tgggggtgcg atatttcttc 600ttgcaggtct ggctatttta gttgccacag catggtatgg caatagaatc 650gttcaagaat tctatgaccc tatgacccca gtcaatgcca ggtacgaatt 700tggtcaggct ctcttcactg gctgggctgc tgcttctctc tgccttctgg 750gaggtgccct actttgctgt tcctgtcccc gaaaaacaac ctcttaccca 800acaccaaggc cctatccaaa acctgcacct tccagcggga aagactacgt 850gtgacacaga ggcaaaagga gaaaatcatg ttgaaacaaa ccgaaaatgg 900acattgagat actatcatta acattaggac cttagaattt tgggtattgt 950aatctgaagt atggtattac aaaacaaaca aacaaacaaa aaacccatgt 1000gttaaaatac tcagtgctaa acatggctta atcttatttt atcttctttc 1050ctcaatatag gagggaagat ttttccattt gtattactgc ttcccattga 1100gtaatcatac tcaaatgggg gaaggggtgc tccttaaata tatatagata 1150tgtatatata catgtttttc tattaaaaat agacagtaaa atactattct 1200cattatgttg atactagcat acttaaaata tctctaaaat aggtaaatgt 1250atttaattcc atattgatga agatgtttat tggtatattt tctttttcgt 1300ccttatatac atatgtaaca gtcaaatatc atttactctt cttcattagc 1350tttgggtgcc tttgccacaa gacctagcct aatttaccaa ggatgaattc 1400tttcaattct tcatgcgtgc ccttttcata tacttatttt attttttacc 1450ataatcttat agcacttgca tcgttattaa gcccttattt gttttgtgtt 1500tcattggtct ctatctcctg aatctaacac atttcatagc ctacatttta 1550gtttctaaag ccaagaagaa tttattacaa atcagaactt tggaggcaaa 1600tctttctgca tgaccaaagt gataaattcc tgttgacctt cccacacaat 1650ccctgtactc tgacccatag cactcttgtt tgctttgaaa atatttgtcc 1700aattgagtag ctgcatgctg ttcccccagg tgttgtaaca caactttatt 1750gattgaattt ttaagctact tattcatagt tttatatccc cctaaactac 1800ctttttgttc cccattcctt aattgtattg ttttcccaag tgtaattatc 1850atgcgtttta tatcttccta ataaggtgtg gtctgtttgt ctgaacaaag 1900tgctagactt tctggagtga taatctggtg acaaatattc tctctgtagc 1950tgtaagcaag tcacttaatc tttctacctc ttttttctat ctgccaaatt 2000gagataatga tacttaacca gttagaagag gtagtgtgaa tattaattag 2050tttatattac tcttattctt tgaacatgaa ctatgcctat gtagtgtctt 2100tatttgctca gctggctgag acactgaaga agtcactgaa caaaacctac 2150acacgtacct tcatgtgatt cactgccttc ctctctctac cagtctattt 2200ccactgaaca aaacctacac acataccttc atgtggttca gtgccttcct 2250ctctctacca gtctatttcc actgaacaaa acctacgcac ataccttcat 2300gtggctcagt gccttcctct ctctaccagt ctatttccat tctttcagct 2350gtgtctgaca tgtttgtgct ctgttccatt ttaacaactg ctcttacttt 2400tccagtctgt acagaatgct atttcacttg agcaagatga tgtaatggaa 2450agggtgttgg cactggtgtc tggagacctg gatttgagtc ttggtgctat 2500caatcaccgt ctgtgtttga gcaaggcatt tggctgctgt aagcttattg 2550cttcatctgt aagcggtggt ttgtaattcc tgatcttccc acctcacagt 2600gatgttgtgg ggatccagtg agatagaata catgtaagtg tggttttgta 2650atttaaaaag tgctatacta agggaaagaa ttgaggaatt aactgcatac 2700gttttggtgt tgcttttcaa atgtttgaaa ataaaaaaaa tgttaag 274726211PRTHomo sapiens 26Met Ala Asn Ala Gly Leu Gln Leu Leu Gly Phe Ile Leu Ala Phe1 5 10 15Leu Gly Trp Ile Gly Ala Ile Val Ser Thr Ala Leu Pro Gln Trp 20 25 30Arg Ile Tyr Ser Tyr Ala Gly Asp Asn Ile Val Thr Ala Gln Ala 35 40 45Met Tyr Glu Gly Leu Trp Met Ser Cys Val Ser Gln Ser Thr Gly 50 55 60Gln Ile Gln Cys Lys Val Phe Asp Ser Leu Leu Asn Leu Ser Ser 65 70 75Thr Leu Gln Ala Thr Arg Ala Leu Met Val Val Gly Ile Leu Leu 80 85 90Gly Val Ile Ala Ile Phe Val Ala Thr Val Gly Met Lys Cys Met 95 100 105Lys Cys Leu Glu Asp Asp Glu Val Gln Lys Met Arg Met Ala Val 110 115 120Ile Gly Gly Ala Ile Phe Leu Leu Ala Gly Leu Ala Ile Leu Val 125 130 135Ala Thr Ala Trp Tyr Gly Asn Arg Ile Val Gln Glu Phe Tyr Asp 140 145 150Pro Met Thr Pro Val Asn Ala Arg Tyr Glu Phe Gly Gln Ala Leu 155 160 165Phe Thr Gly Trp Ala Ala Ala Ser Leu Cys Leu Leu Gly Gly Ala 170 175 180Leu Leu Cys Cys Ser Cys Pro Arg Lys Thr Thr Ser Tyr Pro Thr 185 190 195Pro Arg Pro Tyr Pro Lys Pro Ala Pro Ser Ser Gly Lys Asp Tyr 200 205 210Val 27766DNAHomo sapiens 27ggctcgagcg tttctgagcc aggggtgacc atgacctgct gcgaaggatg 50gacatcctgc aatggattca gcctgctggt tctactgctg ttaggagtag 100ttctcaatgc gatacctcta attgtcagct tagttgagga agaccaattt 150tctcaaaacc ccatctcttg ctttgagtgg tggttcccag gaattatagg 200agcaggtctg atggccattc cagcaacaac aatgtccttg acagcaagaa 250aaagagcgtg ctgcaacaac agaactggaa tgtttctttc atcatttttc 300agtgtgatca cagtcattgg tgctctgtat tgcatgctga tatccatcca 350ggctctctta aaaggtcctc tcatgtgtaa ttctccaagc aacagtaatg 400ccaattgtga attttcattg aaaaacatca gtgacattca tccagaatcc 450ttcaacttgc agtggttttt caatgactct tgtgcacctc ctactggttt 500caataaaccc accagtaacg acaccatggc gagtggctgg agagcatcta 550gtttccactt cgattctgaa gaaaacaaac ataggcttat ccacttctca 600gtatttttag gtctattgct tgttggaatt ctggaggtcc tgtttgggct 650cagtcagata gtcatcggtt tccttggctg tctgtgtgga gtctctaagc 700gaagaagtca aattgtgtag tttaatggga ataaaatgta agtatcagta 750gtttgaaaaa aaaaaa 76628229PRTHomo sapiens 28Met Thr Cys Cys Glu Gly Trp Thr Ser Cys Asn Gly Phe Ser Leu1 5 10 15Leu Val Leu Leu Leu Leu Gly Val Val Leu Asn Ala Ile Pro Leu 20 25 30Ile Val Ser Leu Val Glu Glu Asp Gln Phe Ser Gln Asn Pro Ile 35 40 45Ser Cys Phe Glu Trp Trp Phe Pro Gly Ile Ile Gly Ala Gly Leu 50 55 60Met Ala Ile Pro Ala Thr Thr Met Ser Leu Thr Ala Arg Lys Arg 65 70 75Ala Cys Cys Asn Asn Arg Thr Gly Met Phe Leu Ser Ser Phe Phe 80 85 90Ser Val Ile Thr Val Ile Gly Ala Leu Tyr Cys Met Leu Ile Ser 95 100 105Ile Gln Ala Leu Leu Lys Gly Pro Leu Met Cys Asn Ser Pro Ser 110 115 120Asn Ser Asn Ala Asn Cys Glu Phe Ser Leu Lys Asn Ile Ser Asp 125 130 135Ile His Pro Glu Ser Phe Asn Leu Gln Trp Phe Phe Asn Asp Ser 140 145 150Cys Ala Pro Pro Thr Gly Phe Asn Lys Pro Thr Ser Asn Asp Thr 155 160 165Met Ala Ser Gly Trp Arg Ala Ser Ser Phe His Phe Asp Ser Glu 170 175 180Glu Asn Lys His Arg Leu Ile His Phe Ser Val Phe Leu Gly Leu 185 190 195Leu Leu Val Gly Ile Leu Glu Val Leu Phe Gly Leu Ser Gln Ile 200 205 210Val Ile Gly Phe Leu Gly Cys Leu Cys Gly Val Ser Lys Arg Arg 215 220 225Ser Gln Ile Val291532DNAHomo sapiens 29ggcacgaggc ggcggggcag tcgcgggatg cgcccgggag ccacagcctg 50aggccctcag gtctctgcag gtgtcgtgga ggaacctagc acctgccatc 100ctcttcccca atttgccact tccagcagct ttagcccatg aggaggatgt 150gaccgggact gagtcaggag ccctctggaa gcatggagac tgtggtgatt 200gttgccatag gtgtgctggc caccatcttt ctggcttcgt ttgcagcctt 250ggtgctggtt tgcaggcagc gctactgccg gccgcgagac ctgctgcagc 300gctatgattc taagcccatt gtggacctca ttggtgccat ggagacccag 350tctgagccct ctgagttaga actggacgat gtcgttatca ccaaccccca 400cattgaggcc attctggaga atgaagactg gatcgaagat gcctcgggtc 450tcatgtccca ctgcattgcc atcttgaaga tttgtcacac tctgacagag 500aagcttgttg ccatgacaat gggctctggg gccaagatga agacttcagc 550cagtgtcagc gacatcattg tggtggccaa gcggatcagc cccagggtgg 600atgatgttgt gaagtcgatg taccctccgt tggaccccaa actcctggac 650gcacggacga ctgccctgct cctgtctgtc agtcacctgg tgctggtgac 700aaggaatgcc tgccatctga cgggaggcct ggactggatt gaccagtctc 750tgtcggctgc tgaggagcat ttggaagtcc ttcgagaagc agccctagct 800tctgagccag ataaaggcct cccaggccct gaaggcttcc tgcaggagca 850gtctgcaatt tagtgcctac aggccagcag ctagccatga aggcccctgc 900cgccatccct ggatggctca gcttagcctt ctactttttc ctatagagtt 950agttgttctc cacggctgga gagttcagct gtgtgtgcat agtaaagcag 1000gagatccccg tcagtttatg cctcttttgc agttgcaaac tgtggctggt 1050gagtggcagt ctaatactac agttagggga gatgccattc actctctgca 1100agaggagtat tgaaaactgg tggactgtca gctttattta gctcacctag 1150tgttttcaag aaaattgagc caccgtctaa gaaatcaaga ggtttcacat 1200taaaattaga atttctggcc tctctcgatc ggtcagaatg tgtggcaatt 1250ctgatctgca ttttcagaag aggacaatca attgaaacta agtaggggtt 1300tcttcttttg gcaagacttg tactctctca cctggcctgt ttcatttatt 1350tgtattatct gcctggtccc tgaggcgtct gggtctctcc tctcccttgc 1400aggtttgggt ttgaagctga ggaactacaa agttgatgat ttctttttta 1450tctttatgcc tgcaatttta cctagctacc actaggtgga tagtaaattt 1500atacttatgt ttccctcaaa aaaaaaaaaa aa 153230226PRTHomo sapiens 30Met Glu Thr Val Val Ile Val Ala Ile Gly Val Leu Ala Thr Ile1 5 10 15Phe Leu Ala Ser Phe Ala Ala Leu Val Leu Val Cys Arg Gln Arg 20 25 30Tyr Cys Arg Pro Arg Asp Leu Leu Gln Arg Tyr Asp Ser Lys Pro 35 40 45Ile Val Asp Leu Ile Gly Ala Met Glu Thr Gln Ser Glu Pro Ser 50 55 60Glu Leu Glu Leu Asp Asp Val Val Ile Thr Asn Pro His Ile Glu 65 70 75Ala Ile Leu Glu Asn Glu Asp Trp Ile Glu Asp Ala Ser Gly Leu 80 85 90Met Ser His Cys Ile Ala Ile Leu Lys Ile Cys His Thr Leu Thr 95 100 105Glu Lys Leu Val Ala Met Thr Met Gly Ser Gly Ala Lys Met Lys 110 115 120Thr Ser Ala Ser Val Ser Asp Ile Ile Val Val Ala Lys Arg Ile 125 130 135Ser Pro Arg Val Asp Asp Val Val Lys Ser Met Tyr Pro Pro Leu 140 145 150Asp Pro Lys Leu Leu Asp Ala Arg Thr Thr Ala Leu Leu Leu Ser 155 160 165Val Ser His Leu Val Leu Val Thr Arg Asn Ala Cys His Leu Thr 170 175 180Gly Gly Leu Asp Trp Ile Asp Gln Ser Leu Ser Ala Ala Glu Glu 185 190 195His Leu Glu Val Leu Arg Glu Ala Ala Leu Ala Ser Glu Pro Asp 200 205 210Lys Gly Leu Pro Gly Pro Glu Gly Phe Leu Gln Glu Gln Ser Ala 215 220 225Ile312128DNAHomo sapiens 31ctgtcgtctt tgcttcagcc gcagtcgcca ctggctgcct gaggtgctct 50tacagcctgt tccaagtgtg gcttaatccg tctccaccac cagatctttc 100tccgtggatt cctctgctaa gaccgctgcc atgccagtga cggtaacccg 150caccaccatc acaaccacca cgacgtcatc ttcgggcctg gggtccccca 200tgatcgtggg gtcccctcgg gccctgacac agcccctggg tctccttcgc 250ctgctgcagc tggtgtctac ctgcgtggcc ttctcgctgg tggctagcgt 300gggcgcctgg acggggtcca tgggcaactg gtccatgttc acctggtgct 350tctgcttctc cgtgaccctg atcatcctca tcgtggagct gtgcgggctc 400caggcccgct tccccctgtc ttggcgcaac ttccccatca ccttcgcctg 450ctatgcggcc ctcttctgcc tctcggcctc catcatctac cccaccacct 500atgtccagtt cctgtcccac ggccgttcgc gggaccacgc catcgccgcc 550accttcttct cctgcatcgc gtgtgtggct tacgccaccg aagtggcctg 600gacccgggcc cggcccggcg agatcactgg ctatatggcc accgtacccg 650ggctgctgaa ggtgctggag accttcgttg cctgcatcat cttcgcgttc 700atcagcgacc ccaacctgta ccagcaccag ccggccctgg agtggtgcgt 750ggcggtgtac gccatctgct tcatcctagc ggccatcgcc atcctgctga 800acctggggga gtgcaccaac gtgctaccca tccccttccc cagcttcctg 850tcggggctgg ccttgctgtc tgtcctcctc tatgccaccg cccttgttct 900ctggcccctc taccagttcg atgagaagta tggcggccag cctcggcgct 950cgagagatgt aagctgcagc cgcagccatg cctactacgt gtgtgcctgg 1000gaccgccgac tggctgtggc catcctgacg gccatcaacc tactggcgta 1050tgtggctgac ctggtgcact ctgcccacct ggtttttgtc aaggtctaag 1100actctcccaa gaggctcccg ttccctctcc aacctctttg ttcttcttgc 1150ccgagttttc tttatggagt acttctttcc tccgcctttc ctctgttttc 1200ctcttcctgt ctcccctccc tcccaccttt ttctttcctt cccaattcct 1250tgcactctaa ccagttcttg gatgcatctt cttccttccc tttcctcttg 1300ctgtttcctt cctgtgttgt tttgttgccc acatcctgtt ttcacccctg 1350agctgtttct ctttttcttt tctttctttt tttttttttt ttttaagacg 1400gattctcact ctgtggccca ggctggagtg cagtggtgcg atctcagctc 1450actgcaaccc ccgcctcctg ggttcaagcg attctcctcc cccagcctcc 1500caagtagctg ggaggacagg tgtgagctgc cgcacccagc ctgtttctct 1550ttttccactc ttcttttttc tcatctcttt tctgggttgc ctgtcggctt 1600tcttatctgc ctgttttgca agcaccttct cctgtgtcct tgggagccct 1650gagacttctt tctctccttg cctccaccca cctccaaagg tgctgagctc 1700acatccacac cccttgcagc cgtccatgcc acagcccccc aaggggcccc 1750attgccaaag catgcctgcc caccctcgct gtgccttagt cagtgtgtac 1800gtgtgtgtgt gtgtgtgttt ggggggtggg gggtgggtag ctggggattg 1850ggccctcttt ctcccagtgg aggaaggtgt gcagtgtact tcccctttaa 1900attaaaaaac atatatatat atatatttgg aggtcagtaa tttccaatgg 1950gcgggaggca ttaagcaccg accctgggtc cctaggcccc gcctggcact 2000cagccttgcc agagattggc tccagaattt ttgccaggct tacagaacac 2050ccactgccta gaggccatct taaaggaagc aggggctgga tgcctttcat 2100cccaactatt ctctgtggta tgaaaaag 212832322PRTHomo sapiens 32Met Pro Val Thr Val Thr Arg Thr Thr Ile Thr Thr Thr Thr Thr1 5 10 15Ser Ser Ser Gly Leu Gly Ser Pro Met Ile Val Gly Ser Pro Arg 20 25

30Ala Leu Thr Gln Pro Leu Gly Leu Leu Arg Leu Leu Gln Leu Val 35 40 45Ser Thr Cys Val Ala Phe Ser Leu Val Ala Ser Val Gly Ala Trp 50 55 60Thr Gly Ser Met Gly Asn Trp Ser Met Phe Thr Trp Cys Phe Cys 65 70 75Phe Ser Val Thr Leu Ile Ile Leu Ile Val Glu Leu Cys Gly Leu 80 85 90Gln Ala Arg Phe Pro Leu Ser Trp Arg Asn Phe Pro Ile Thr Phe 95 100 105Ala Cys Tyr Ala Ala Leu Phe Cys Leu Ser Ala Ser Ile Ile Tyr 110 115 120Pro Thr Thr Tyr Val Gln Phe Leu Ser His Gly Arg Ser Arg Asp 125 130 135His Ala Ile Ala Ala Thr Phe Phe Ser Cys Ile Ala Cys Val Ala 140 145 150Tyr Ala Thr Glu Val Ala Trp Thr Arg Ala Arg Pro Gly Glu Ile 155 160 165Thr Gly Tyr Met Ala Thr Val Pro Gly Leu Leu Lys Val Leu Glu 170 175 180Thr Phe Val Ala Cys Ile Ile Phe Ala Phe Ile Ser Asp Pro Asn 185 190 195Leu Tyr Gln His Gln Pro Ala Leu Glu Trp Cys Val Ala Val Tyr 200 205 210Ala Ile Cys Phe Ile Leu Ala Ala Ile Ala Ile Leu Leu Asn Leu 215 220 225Gly Glu Cys Thr Asn Val Leu Pro Ile Pro Phe Pro Ser Phe Leu 230 235 240Ser Gly Leu Ala Leu Leu Ser Val Leu Leu Tyr Ala Thr Ala Leu 245 250 255Val Leu Trp Pro Leu Tyr Gln Phe Asp Glu Lys Tyr Gly Gly Gln 260 265 270Pro Arg Arg Ser Arg Asp Val Ser Cys Ser Arg Ser His Ala Tyr 275 280 285Tyr Val Cys Ala Trp Asp Arg Arg Leu Ala Val Ala Ile Leu Thr 290 295 300Ala Ile Asn Leu Leu Ala Tyr Val Ala Asp Leu Val His Ser Ala 305 310 315His Leu Val Phe Val Lys Val 320331047DNAHomo sapiens 33gccaggtgtg caggccgctc caagcccagc ctgccccgct gccgccacca 50tgacgctcct ccccggcctc ctgtttctga cctggctgca cacatgcctg 100gcccaccatg acccctccct cagggggcac ccccacagtc acggtacccc 150acactgctac tcggctgagg aactgcccct cggccaggcc cccccacacc 200tgctggctcg aggtgccaag tgggggcagg ctttgcctgt agccctggtg 250tccagcctgg aggcagcaag ccacaggggg aggcacgaga ggccctcagc 300tacgacccag tgcccggtgc tgcggccgga ggaggtgttg gaggcagaca 350cccaccagcg ctccatctca ccctggagat accgtgtgga cacggatgag 400gaccgctatc cacagaagct ggccttcgcc gagtgcctgt gcagaggctg 450tatcgatgca cggacgggcc gcgagacagc tgcgctcaac tccgtgcggc 500tgctccagag cctgctggtg ctgcgccgcc ggccctgctc ccgcgacggc 550tcggggctcc ccacacctgg ggcctttgcc ttccacaccg agttcatcca 600cgtccccgtc ggctgcacct gcgtgctgcc ccgttcagtg tgaccgccga 650ggccgtgggg cccctagact ggacacgtgt gctccccaga gggcaccccc 700tatttatgtg tatttattgt tatttatatg cctcccccaa cactaccctt 750ggggtctggg cattccccgt gtctggagga cagcccccca ctgttctcct 800catctccagc ctcagtagtt gggggtagaa ggagctcagc acctcttcca 850gcccttaaag ctgcagaaaa ggtgtcacac ggctgcctgt accttggctc 900cctgtcctgc tcccggcttc ccttacccta tcactggcct caggccccgc 950aggctgcctc ttcccaacct ccttggaagt acccctgttt cttaaacaat 1000tatttaagtg tacgtgtatt attaaactga tgaacacatc cccaaaa 104734197PRTHomo sapiens 34Met Thr Leu Leu Pro Gly Leu Leu Phe Leu Thr Trp Leu His Thr1 5 10 15Cys Leu Ala His His Asp Pro Ser Leu Arg Gly His Pro His Ser 20 25 30His Gly Thr Pro His Cys Tyr Ser Ala Glu Glu Leu Pro Leu Gly 35 40 45Gln Ala Pro Pro His Leu Leu Ala Arg Gly Ala Lys Trp Gly Gln 50 55 60Ala Leu Pro Val Ala Leu Val Ser Ser Leu Glu Ala Ala Ser His 65 70 75Arg Gly Arg His Glu Arg Pro Ser Ala Thr Thr Gln Cys Pro Val 80 85 90Leu Arg Pro Glu Glu Val Leu Glu Ala Asp Thr His Gln Arg Ser 95 100 105Ile Ser Pro Trp Arg Tyr Arg Val Asp Thr Asp Glu Asp Arg Tyr 110 115 120Pro Gln Lys Leu Ala Phe Ala Glu Cys Leu Cys Arg Gly Cys Ile 125 130 135Asp Ala Arg Thr Gly Arg Glu Thr Ala Ala Leu Asn Ser Val Arg 140 145 150Leu Leu Gln Ser Leu Leu Val Leu Arg Arg Arg Pro Cys Ser Arg 155 160 165Asp Gly Ser Gly Leu Pro Thr Pro Gly Ala Phe Ala Phe His Thr 170 175 180Glu Phe Ile His Val Pro Val Gly Cys Thr Cys Val Leu Pro Arg 185 190 195Ser Val 351076DNAHomo sapiens 35gtggcttcat ttcagtggct gacttccaga gagcaatatg gctggttccc 50caacatgcct caccctcatc tatatccttt ggcagctcac agggtcagca 100gcctctggac ccgtgaaaga gctggtcggt tccgttggtg gggccgtgac 150tttccccctg aagtccaaag taaagcaagt tgactctatt gtctggacct 200tcaacacaac ccctcttgtc accatacagc cagaaggggg cactatcata 250gtgacccaaa atcgtaatag ggagagagta gacttcccag atggaggcta 300ctccctgaag ctcagcaaac tgaagaagaa tgactcaggg atctactatg 350tggggatata cagctcatca ctccagcagc cctccaccca ggagtacgtg 400ctgcatgtct acgagcacct gtcaaagcct aaagtcacca tgggtctgca 450gagcaataag aatggcacct gtgtgaccaa tctgacatgc tgcatggaac 500atggggaaga ggatgtgatt tatacctgga aggccctggg gcaagcagcc 550aatgagtccc ataatgggtc catcctcccc atctcctgga gatggggaga 600aagtgatatg accttcatct gcgttgccag gaaccctgtc agcagaaact 650tctcaagccc catccttgcc aggaagctct gtgaaggtgc tgctgatgac 700ccagattcct ccatggtcct cctgtgtctc ctgttggtgc ccctcctgct 750cagtctcttt gtactggggc tatttctttg gtttctgaag agagagagac 800aagaagagta cattgaagag aagaagagag tggacatttg tcgggaaact 850cctaacatat gcccccattc tggagagaac acagagtacg acacaatccc 900tcacactaat agaacaatcc taaaggaaga tccagcaaat acggtttact 950ccactgtgga aataccgaaa aagatggaaa atccccactc actgctcacg 1000atgccagaca caccaaggct atttgcctat gagaatgtta tctagacagc 1050agtgcactcc cctaagtctc tgctca 107636335PRTHomo sapiens 36Met Ala Gly Ser Pro Thr Cys Leu Thr Leu Ile Tyr Ile Leu Trp1 5 10 15Gln Leu Thr Gly Ser Ala Ala Ser Gly Pro Val Lys Glu Leu Val 20 25 30Gly Ser Val Gly Gly Ala Val Thr Phe Pro Leu Lys Ser Lys Val 35 40 45Lys Gln Val Asp Ser Ile Val Trp Thr Phe Asn Thr Thr Pro Leu 50 55 60Val Thr Ile Gln Pro Glu Gly Gly Thr Ile Ile Val Thr Gln Asn 65 70 75Arg Asn Arg Glu Arg Val Asp Phe Pro Asp Gly Gly Tyr Ser Leu 80 85 90Lys Leu Ser Lys Leu Lys Lys Asn Asp Ser Gly Ile Tyr Tyr Val 95 100 105Gly Ile Tyr Ser Ser Ser Leu Gln Gln Pro Ser Thr Gln Glu Tyr 110 115 120Val Leu His Val Tyr Glu His Leu Ser Lys Pro Lys Val Thr Met 125 130 135Gly Leu Gln Ser Asn Lys Asn Gly Thr Cys Val Thr Asn Leu Thr 140 145 150Cys Cys Met Glu His Gly Glu Glu Asp Val Ile Tyr Thr Trp Lys 155 160 165Ala Leu Gly Gln Ala Ala Asn Glu Ser His Asn Gly Ser Ile Leu 170 175 180Pro Ile Ser Trp Arg Trp Gly Glu Ser Asp Met Thr Phe Ile Cys 185 190 195Val Ala Arg Asn Pro Val Ser Arg Asn Phe Ser Ser Pro Ile Leu 200 205 210Ala Arg Lys Leu Cys Glu Gly Ala Ala Asp Asp Pro Asp Ser Ser 215 220 225Met Val Leu Leu Cys Leu Leu Leu Val Pro Leu Leu Leu Ser Leu 230 235 240Phe Val Leu Gly Leu Phe Leu Trp Phe Leu Lys Arg Glu Arg Gln 245 250 255Glu Glu Tyr Ile Glu Glu Lys Lys Arg Val Asp Ile Cys Arg Glu 260 265 270Thr Pro Asn Ile Cys Pro His Ser Gly Glu Asn Thr Glu Tyr Asp 275 280 285Thr Ile Pro His Thr Asn Arg Thr Ile Leu Lys Glu Asp Pro Ala 290 295 300Asn Thr Val Tyr Ser Thr Val Glu Ile Pro Lys Lys Met Glu Asn 305 310 315Pro His Ser Leu Leu Thr Met Pro Asp Thr Pro Arg Leu Phe Ala 320 325 330Tyr Glu Asn Val Ile 335374277DNAHomo sapiens 37gtttctcata gttggcgtct tctaaaggaa aaacactaaa atgaggaact 50cagcggaccg ggagcgacgc agcttgaggg aagcatccct agctgttggc 100gcagaggggc gaggctgaag ccgagtggcc cgaggtgtct gaggggctgg 150ggcaaaggtg aaagagtttc agaacaagct tcctggaacc catgacccat 200gaagtcttgt cgacatttat accgtctgag ggtagcagct cgaaactaga 250agaagtggag tgttgccagg gacggcagta tctctttgtg tgaccctggc 300ggcctatggg acgttggctt cagacctttg tgatacacca tgctgcgtgg 350gacgatgacg gcgtggagag gaatgaggcc tgaggtcaca ctggcttgcc 400tcctcctagc cacagcaggc tgctttgctg acttgaacga ggtccctcag 450gtcaccgtcc agcctgcgtc caccgtccag aagcccggag gcactgtgat 500cttgggctgc gtggtggaac ctccaaggat gaatgtaacc tggcgcctga 550atggaaagga gctgaatggc tcggatgatg ctctgggtgt cctcatcacc 600cacgggaccc tcgtcatcac tgcccttaac aaccacactg tgggacggta 650ccagtgtgtg gcccggatgc ctgcgggggc tgtggccagc gtgccagcca 700ctgtgacact agccaatctc caggacttca agttagatgt gcagcacgtg 750attgaagtgg atgagggaaa cacagcagtc attgcctgcc acctgcctga 800gagccacccc aaagcccagg tccggtacag cgtcaaacaa gagtggctgg 850aggcctccag aggtaactac ctgatcatgc cctcagggaa cctccagatt 900gtgaatgcca gccaggagga cgagggcatg tacaagtgtg cagcctacaa 950cccagtgacc caggaagtga aaacctccgg ctccagcgac aggctacgtg 1000tgcgccgctc caccgctgag gctgcccgca tcatctaccc cccagaggcc 1050caaaccatca tcgtcaccaa aggccagagt ctcattctgg agtgtgtggc 1100cagtggaatc ccacccccac gggtcacctg ggccaaggat gggtccagtg 1150tcaccggcta caacaagacg cgcttcctgc tgagcaacct cctcatcgac 1200accaccagcg aggaggactc aggcacctac cgctgcatgg ccgacaatgg 1250ggttgggcag cccggggcag cggtcatcct ctacaatgtc caggtgtttg 1300aaccccctga ggtcaccatg gagctatccc agctggtcat cccctggggc 1350cagagtgcca agcttacctg tgaggtgcgt gggaaccccc cgccctccgt 1400gctgtggctg aggaatgctg tgcccctcat ctccagccag cgcctccggc 1450tctcccgcag ggccctgcgc gtgctcagca tggggcctga ggacgaaggc 1500gtctaccagt gcatggccga gaacgaggtt gggagcgccc atgccgtagt 1550ccagctgcgg acctccaggc caagcataac cccaaggcta tggcaggatg 1600ctgagctggc tactggcaca cctcctgtat caccctccaa actcggcaac 1650cctgagcaga tgctgagggg gcaaccggcg ctccccagac ccccaacgtc 1700agtggggcct gcttccccga agtgtccagg agagaagggg cagggggctc 1750ccgccgaggc tcccatcatc ctcagctcgc cccgcacctc caagacagac 1800tcatatgaac tggtgtggcg gcctcggcat gagggcagtg gccgggcgcc 1850aatcctctac tatgtggtga aacaccgcaa gcaggtcaca aattcctctg 1900acgattggac catctctggc attccagcca accagcaccg cctgaccctc 1950accagacttg accccgggag cttgtatgaa gtggagatgg cagcttacaa 2000ctgtgcggga gagggccaga cagccatggt caccttccga actggacggc 2050ggcccaaacc cgagatcatg gccagcaaag agcagcagat ccagagagac 2100gaccctggag ccagtcccca gagcagcagc cagccagacc acggccgcct 2150ctccccccca gaagctcccg acaggcccac catctccacg gcctccgaga 2200cctcagtgta cgtgacctgg attccccgtg ggaatggtgg gttcccaatc 2250cagtccttcc gtgtggagta caagaagcta aagaaagtgg gagactggat 2300tctggccacc agcgccatcc ccccatcgcg gctgtccgtg gagatcacgg 2350gcctagagaa aggcacctcc tacaagtttc gagtccgggc tctgaacatg 2400ctgggggaga gcgagcccag cgccccctct cggccctacg tggtgtcggg 2450ctacagcggt cgcgtgtacg agaggcccgt ggcaggtcct tatatcacct 2500tcacggatgc ggtcaatgag accaccatca tgctcaagtg gatgtacatc 2550ccagcaagta acaacaacac cccaatccat ggcttttata tctattatcg 2600acccacagac agtgacaatg atagtgacta caagaaggat atggtggaag 2650gggacaagta ctggcactcc atcagccacc tgcagccaga gacctcctac 2700gacattaaga tgcagtgctt caatgaagga ggggagagcg agttcagcaa 2750cgtgatgatc tgtgagacca aagctcggaa gtcttctggc cagcctggtc 2800gactgccacc cccaactctg gccccaccac agccgcccct tcctgaaacc 2850atagagcggc cggtgggcac tggggccatg gtggctcgct ccagcgacct 2900gccctatctg attgtcgggg tcgtcctggg ctccatcgtt ctcatcatcg 2950tcaccttcat ccccttctgc ttgtggaggg cctggtctaa gcaaaaacat 3000acaacagacc tgggttttcc tcgaagtgcc cttccaccct cctgcccgta 3050tactatggtg ccattgggag gactcccagg ccaccaggcc agtggacagc 3100cctacctcag tggcatcagt ggacgggcct gtgctaatgg gatccacatg 3150aataggggct gcccctcggc tgcagtgggc tacccgggca tgaagcccca 3200gcagcactgc ccaggcgagc ttcagcagca gagtgacacc agcagcctgc 3250tgaggcagac ccatcttggc aatggatatg acccccaaag tcaccagatc 3300acgaggggtc ccaagtctag cccggacgag ggctctttct tatacacact 3350gcccgacgac tccactcacc agctgctgca gccccatcac gactgctgcc 3400aacgccagga gcagcctgct gctgtgggcc agtcaggggt gaggagagcc 3450cccgacagtc ctgtcctgga agcagtgtgg gaccctccat ttcactcagg 3500gcccccatgc tgcttgggcc ttgtgccagt tgaagaggtg gacagtcctg 3550actcctgcca agtgagtgga ggagactggt gtccccagca ccccgtaggg 3600gcctacgtag gacaggaacc tggaatgcag ctctccccgg ggccactggt 3650gcgtgtgtct tttgaaacac cacctctcac aatttaggca gaagctgata 3700tcccagaaag actatatatt gttttttttt taaaaaaaaa agaagaaaaa 3750agagacagag aaaattggta tttatttttc tattatagcc atatttatat 3800atttatgcac ttgtaaataa atgtatatgt tttataattc tggagagaca 3850taaggagtcc tacccgttga ggttggagag ggaaaataaa gaagctgcca 3900cctaacagga gtcacccagg aaagcaccgc acaggctggc gcgggacaga 3950ctcctaacct ggggcctctg cagtggcagg cgaggctgca ggaggcccac 4000agataagctg gcaagaggaa ggatcccagg cacatggttc atcacgagca 4050tgagggaaca gcaaggggca cggtatcaca gcctggagac acccacacag 4100atggctggat ccggtgctac gggaaacatt ttcctaagat gcccatgaga 4150acagaccaag atgtgtacag cactatgagc attaaaaaac cttccagaat 4200caataatccg tggcaacata tctctgtaaa aacaaacact gtaacttcta 4250aataaatgtt tagtcttccc tgtaaaa 4277381115PRTHomo sapiens 38Met Leu Arg Gly Thr Met Thr Ala Trp Arg Gly Met Arg Pro Glu1 5 10 15Val Thr Leu Ala Cys Leu Leu Leu Ala Thr Ala Gly Cys Phe Ala 20 25 30Asp Leu Asn Glu Val Pro Gln Val Thr Val Gln Pro Ala Ser Thr 35 40 45Val Gln Lys Pro Gly Gly Thr Val Ile Leu Gly Cys Val Val Glu 50 55 60Pro Pro Arg Met Asn Val Thr Trp Arg Leu Asn Gly Lys Glu Leu 65 70 75Asn Gly Ser Asp Asp Ala Leu Gly Val Leu Ile Thr His Gly Thr 80 85 90Leu Val Ile Thr Ala Leu Asn Asn His Thr Val Gly Arg Tyr Gln 95 100 105Cys Val Ala Arg Met Pro Ala Gly Ala Val Ala Ser Val Pro Ala 110 115 120Thr Val Thr Leu Ala Asn Leu Gln Asp Phe Lys Leu Asp Val Gln 125 130 135His Val Ile Glu Val Asp Glu Gly Asn Thr Ala Val Ile Ala Cys 140 145 150His Leu Pro Glu Ser His Pro Lys Ala Gln Val Arg Tyr Ser Val 155 160 165Lys Gln Glu Trp Leu Glu Ala Ser Arg Gly Asn Tyr Leu Ile Met 170 175 180Pro Ser Gly Asn Leu Gln Ile Val Asn Ala Ser Gln Glu Asp Glu 185 190 195Gly Met Tyr Lys Cys Ala Ala Tyr Asn Pro Val Thr Gln Glu Val 200 205 210Lys Thr Ser Gly Ser Ser Asp Arg Leu Arg Val Arg Arg Ser Thr 215 220 225Ala Glu Ala Ala Arg Ile Ile Tyr Pro Pro Glu Ala Gln Thr Ile 230 235 240Ile Val Thr Lys Gly Gln Ser Leu Ile Leu Glu Cys Val Ala Ser 245 250 255Gly Ile Pro Pro Pro Arg Val Thr Trp Ala Lys Asp Gly Ser Ser 260 265 270Val Thr Gly Tyr Asn Lys Thr Arg Phe Leu Leu Ser Asn Leu Leu 275 280

285Ile Asp Thr Thr Ser Glu Glu Asp Ser Gly Thr Tyr Arg Cys Met 290 295 300Ala Asp Asn Gly Val Gly Gln Pro Gly Ala Ala Val Ile Leu Tyr 305 310 315Asn Val Gln Val Phe Glu Pro Pro Glu Val Thr Met Glu Leu Ser 320 325 330Gln Leu Val Ile Pro Trp Gly Gln Ser Ala Lys Leu Thr Cys Glu 335 340 345Val Arg Gly Asn Pro Pro Pro Ser Val Leu Trp Leu Arg Asn Ala 350 355 360Val Pro Leu Ile Ser Ser Gln Arg Leu Arg Leu Ser Arg Arg Ala 365 370 375Leu Arg Val Leu Ser Met Gly Pro Glu Asp Glu Gly Val Tyr Gln 380 385 390Cys Met Ala Glu Asn Glu Val Gly Ser Ala His Ala Val Val Gln 395 400 405Leu Arg Thr Ser Arg Pro Ser Ile Thr Pro Arg Leu Trp Gln Asp 410 415 420Ala Glu Leu Ala Thr Gly Thr Pro Pro Val Ser Pro Ser Lys Leu 425 430 435Gly Asn Pro Glu Gln Met Leu Arg Gly Gln Pro Ala Leu Pro Arg 440 445 450Pro Pro Thr Ser Val Gly Pro Ala Ser Pro Lys Cys Pro Gly Glu 455 460 465Lys Gly Gln Gly Ala Pro Ala Glu Ala Pro Ile Ile Leu Ser Ser 470 475 480Pro Arg Thr Ser Lys Thr Asp Ser Tyr Glu Leu Val Trp Arg Pro 485 490 495Arg His Glu Gly Ser Gly Arg Ala Pro Ile Leu Tyr Tyr Val Val 500 505 510Lys His Arg Lys Gln Val Thr Asn Ser Ser Asp Asp Trp Thr Ile 515 520 525Ser Gly Ile Pro Ala Asn Gln His Arg Leu Thr Leu Thr Arg Leu 530 535 540Asp Pro Gly Ser Leu Tyr Glu Val Glu Met Ala Ala Tyr Asn Cys 545 550 555Ala Gly Glu Gly Gln Thr Ala Met Val Thr Phe Arg Thr Gly Arg 560 565 570Arg Pro Lys Pro Glu Ile Met Ala Ser Lys Glu Gln Gln Ile Gln 575 580 585Arg Asp Asp Pro Gly Ala Ser Pro Gln Ser Ser Ser Gln Pro Asp 590 595 600His Gly Arg Leu Ser Pro Pro Glu Ala Pro Asp Arg Pro Thr Ile 605 610 615Ser Thr Ala Ser Glu Thr Ser Val Tyr Val Thr Trp Ile Pro Arg 620 625 630Gly Asn Gly Gly Phe Pro Ile Gln Ser Phe Arg Val Glu Tyr Lys 635 640 645Lys Leu Lys Lys Val Gly Asp Trp Ile Leu Ala Thr Ser Ala Ile 650 655 660Pro Pro Ser Arg Leu Ser Val Glu Ile Thr Gly Leu Glu Lys Gly 665 670 675Thr Ser Tyr Lys Phe Arg Val Arg Ala Leu Asn Met Leu Gly Glu 680 685 690Ser Glu Pro Ser Ala Pro Ser Arg Pro Tyr Val Val Ser Gly Tyr 695 700 705Ser Gly Arg Val Tyr Glu Arg Pro Val Ala Gly Pro Tyr Ile Thr 710 715 720Phe Thr Asp Ala Val Asn Glu Thr Thr Ile Met Leu Lys Trp Met 725 730 735Tyr Ile Pro Ala Ser Asn Asn Asn Thr Pro Ile His Gly Phe Tyr 740 745 750Ile Tyr Tyr Arg Pro Thr Asp Ser Asp Asn Asp Ser Asp Tyr Lys 755 760 765Lys Asp Met Val Glu Gly Asp Lys Tyr Trp His Ser Ile Ser His 770 775 780Leu Gln Pro Glu Thr Ser Tyr Asp Ile Lys Met Gln Cys Phe Asn 785 790 795Glu Gly Gly Glu Ser Glu Phe Ser Asn Val Met Ile Cys Glu Thr 800 805 810Lys Ala Arg Lys Ser Ser Gly Gln Pro Gly Arg Leu Pro Pro Pro 815 820 825Thr Leu Ala Pro Pro Gln Pro Pro Leu Pro Glu Thr Ile Glu Arg 830 835 840Pro Val Gly Thr Gly Ala Met Val Ala Arg Ser Ser Asp Leu Pro 845 850 855Tyr Leu Ile Val Gly Val Val Leu Gly Ser Ile Val Leu Ile Ile 860 865 870Val Thr Phe Ile Pro Phe Cys Leu Trp Arg Ala Trp Ser Lys Gln 875 880 885Lys His Thr Thr Asp Leu Gly Phe Pro Arg Ser Ala Leu Pro Pro 890 895 900Ser Cys Pro Tyr Thr Met Val Pro Leu Gly Gly Leu Pro Gly His 905 910 915Gln Ala Ser Gly Gln Pro Tyr Leu Ser Gly Ile Ser Gly Arg Ala 920 925 930Cys Ala Asn Gly Ile His Met Asn Arg Gly Cys Pro Ser Ala Ala 935 940 945Val Gly Tyr Pro Gly Met Lys Pro Gln Gln His Cys Pro Gly Glu 950 955 960Leu Gln Gln Gln Ser Asp Thr Ser Ser Leu Leu Arg Gln Thr His 965 970 975Leu Gly Asn Gly Tyr Asp Pro Gln Ser His Gln Ile Thr Arg Gly 980 985 990Pro Lys Ser Ser Pro Asp Glu Gly Ser Phe Leu Tyr Thr Leu Pro 995 1000 1005Asp Asp Ser Thr His Gln Leu Leu Gln Pro His His Asp Cys Cys 1010 1015 1020Gln Arg Gln Glu Gln Pro Ala Ala Val Gly Gln Ser Gly Val Arg 1025 1030 1035Arg Ala Pro Asp Ser Pro Val Leu Glu Ala Val Trp Asp Pro Pro 1040 1045 1050Phe His Ser Gly Pro Pro Cys Cys Leu Gly Leu Val Pro Val Glu 1055 1060 1065Glu Val Asp Ser Pro Asp Ser Cys Gln Val Ser Gly Gly Asp Trp 1070 1075 1080Cys Pro Gln His Pro Val Gly Ala Tyr Val Gly Gln Glu Pro Gly 1085 1090 1095Met Gln Leu Ser Pro Gly Pro Leu Val Arg Val Ser Phe Glu Thr 1100 1105 1110Pro Pro Leu Thr Ile 1115 39728DNAHomo sapiens 39catttccaac aagagcactg gccaagtcag cttcttctga gagagtctct 50agaagacatg atgctacact cagctttggg tctctgcctc ttactcgtca 100cagtttcttc caaccttgcc attgcaataa aaaaggaaaa gaggcctcct 150cagacactct caagaggatg gggagatgac atcacttggg tacaaactta 200tgaagaaggt ctcttttatg ctcaaaaaag taagaagcca ttaatggtta 250ttcatcacct ggaggattgt caatactctc aagcactaaa gaaagtattt 300gcccaaaatg aagaaataca agaaatggct cagaataagt tcatcatgct 350aaaccttatg catgaaacca ctgataagaa tttatcacct gatgggcaat 400atgtgcctag aatcatgttt gtagaccctt ctttaacagt tagagctgac 450atagctggaa gatactctaa cagattgtac acatatgagc ctcgggattt 500acccctattg atagaaaaca tgaagaaagc attaagactt attcagtcag 550agctataaga gatgatggaa aaaagccttc acttcaaaga agtcaaattt 600catgaagaaa acctctggca cattgacaaa tactaaatgt gcaagtatat 650agattttgta atattactat ttagtttttt taatgtgttt gcaatagtct 700tattaaaata aatgtttttt aaatctga 72840166PRTHomo sapiens 40Met Met Leu His Ser Ala Leu Gly Leu Cys Leu Leu Leu Val Thr1 5 10 15Val Ser Ser Asn Leu Ala Ile Ala Ile Lys Lys Glu Lys Arg Pro 20 25 30Pro Gln Thr Leu Ser Arg Gly Trp Gly Asp Asp Ile Thr Trp Val 35 40 45Gln Thr Tyr Glu Glu Gly Leu Phe Tyr Ala Gln Lys Ser Lys Lys 50 55 60Pro Leu Met Val Ile His His Leu Glu Asp Cys Gln Tyr Ser Gln 65 70 75Ala Leu Lys Lys Val Phe Ala Gln Asn Glu Glu Ile Gln Glu Met 80 85 90Ala Gln Asn Lys Phe Ile Met Leu Asn Leu Met His Glu Thr Thr 95 100 105Asp Lys Asn Leu Ser Pro Asp Gly Gln Tyr Val Pro Arg Ile Met 110 115 120Phe Val Asp Pro Ser Leu Thr Val Arg Ala Asp Ile Ala Gly Arg 125 130 135Tyr Ser Asn Arg Leu Tyr Thr Tyr Glu Pro Arg Asp Leu Pro Leu 140 145 150Leu Ile Glu Asn Met Lys Lys Ala Leu Arg Leu Ile Gln Ser Glu 155 160 165Leu41693DNAHomo sapiens 41ctagcctgcg ccaaggggta gtgagaccgc gcggcaacag cttgcggctg 50cggggagctc ccgtgggcgc tccgctggct gtgcaggcgg ccatggattc 100cttgcggaaa atgctgatct cagtcgcaat gctgggcgca ggggctggcg 150tgggctacgc gctcctcgtt atcgtgaccc cgggagagcg gcggaagcag 200gaaatgctaa aggagatgcc actgcaggac ccaaggagca gggaggaggc 250ggccaggacc cagcagctat tgctggccac tctgcaggag gcagcgacca 300cgcaggagaa cgtggcctgg aggaagaact ggatggttgg cggcgaaggc 350ggcgccagcg ggaggtcacc gtgagaccgg acttgcctcc gtgggcgccg 400gaccttggct tgggcgcagg aatccgaggc agcctttctc cttcgtgggc 450ccagcggaga gtccggaccg agataccatg ccaggactct ccggggtcct 500gtgagctgcc gtcgggtgag cacgtttccc ccaaaccctg gactgactgc 550tttaaggtcc gcaaggcggg ccagggccga gacgcgagtc ggatgtggtg 600aactgaaaga accaataaaa tcatgttcct ccaaaaaaaa aaaaaaaaaa 650aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaa 6934293PRTHomo sapiens 42Met Asp Ser Leu Arg Lys Met Leu Ile Ser Val Ala Met Leu Gly1 5 10 15Ala Gly Ala Gly Val Gly Tyr Ala Leu Leu Val Ile Val Thr Pro 20 25 30Gly Glu Arg Arg Lys Gln Glu Met Leu Lys Glu Met Pro Leu Gln 35 40 45Asp Pro Arg Ser Arg Glu Glu Ala Ala Arg Thr Gln Gln Leu Leu 50 55 60Leu Ala Thr Leu Gln Glu Ala Ala Thr Thr Gln Glu Asn Val Ala 65 70 75Trp Arg Lys Asn Trp Met Val Gly Gly Glu Gly Gly Ala Ser Gly 80 85 90Arg Ser Pro433580DNAHomo sapiens 43gaccggtccc tccggtcctg gatgtgcgga ctctgctgca gcgagggctg 50caggcccgcc gggcggtgct caccgtgccc tggctggtgg agtttctctc 100ctttgctgac catgttgttc ccttgctgga atattaccgg gacatcttca 150ctctcctgct gcgcctgcac cggagcttgg tgttgtcgca ggagagtgag 200gggaagatgt gtttcctgaa caagctgctg ctacttgctg tcctgggctg 250gcttttccag attcccacag tccctgagga cttgttcttt ctggaagagg 300gtccctcata tgcctttgag gtggacacag tagccccaga gcatggcttg 350gacaatgcgc ctgtggtgga ccagcagctg ctctacacct gctgccccta 400catcggagag ctccggaaac tgctcgcttc gtgggtgtca ggcagtagtg 450gacggagtgg gggcttcatg aggaaaatca cccccaccac taccaccagc 500ctgggagccc agccttccca gaccagccag gggctgcagg cacagctcgc 550ccaggccttt ttccacaacc agccgccctc cttgcgccgg accgtagagt 600tcgtggcaga aagaattgga tcaaactgtg tcaaacatat caaggctaca 650ctggtggcag atctggtgcg ccaggcagag tcacttctcc aagagcagct 700ggtgacacag ggagaggaag ggggagaccc agcccagctg ttggagatct 750tgtgttccca gctgtgccct cacggggccc aggcattggc cctggggcgg 800gagttctgtc aaaggaagag ccctggggct gtgcgggcgc tgcttccaga 850ggagaccccg gcagccgttc tgagcagtgc agagaacatt gctgtggggc 900ttgcaacaga gaaagcctgt gcttggctgt cagccaacat cacagcactg 950atcaggaggg aggtgaaagc agcagtgagt cgcacacttc gagcccaggg 1000tcctgaacct gctgcccggg gggagcggag gggctgctcc cgcgcctgac 1050gtgctctcct tggccgtggg gccacgggac cctgacgagg gagtctcccc 1100agagcatctg gaacagctcc taggccagct gggccagacg ctgcggtgcc 1150gccagttcct gtgcccacct gctgagcagc atctggcaaa gtgctctgtg 1200gagttagctt ccctcctcgt tgcagatcaa attcctatcc tagggccccc 1250ggcacagtac aggctggaga gagggcaggc tcgaaggctt ctgcacatgc 1300tgctttcctt gtggaaggaa gactttcagg ggccggttcc gctgcagctg 1350ctgctgagcc caagaaatgt ggggcttctg gcagacacaa ggccaaggga 1400gtgggacttg ctgctattct tgctacggga gctggtggag aagggtctga 1450tgggacggat ggagatagag gcctgcctgg gcagcctcca ccaggcccag 1500tggccagggg actttgctga agaattagca acactgtcta atctgtttct 1550agccgagccc cacctgccag aaccccagct aagagcctgt gagttggtgc 1600agccaaaccg gggcactgtg ctggcccaga gctagggctg agaagtggcc 1650ctgccttggg cattgcacca gaaccctgga cccccgcctc acgaggaggc 1700ccaagtgccc aatgcagacc ctcactggtt ggggtgtagc tgggtctaca 1750gtcagacttc ctgctctaag ggtgtcactg cctggcatcc caccacgcga 1800atcctagagg aaggagagtt ggcctgattt gggattatgg cagaaaagtc 1850cagagatgcc agtcctggag tagaagaggt ggtgtttgtt tatctcttgg 1900atactaaatg aaatgaggtg tgtgggcttg tcaacacaga attcaagcct 1950catttgctat cccagcatct cttaaaactt tgtagtcttg gaattcatga 2000cagaggcaaa tgactcctgc ttaacttatg aagaaagtta aaacatgaat 2050cttgggagtc tacattttct tatcaccagg agctggactg ccatctcctt 2100ataaatgcct aacacaggcc gggtctggtg gctcatgcct gtaatcccag 2150cactttgaga ggcctgaggt cggcggactg cctgaggtca ggaattcaag 2200accagcctgg ccaacatggc aaaaccccat ctctactaaa aataaaaaaa 2250ttattagctg ggcatggtgg tgtgtgcctg taatcccagc tactcaggag 2300gatgaggcag gagacctgct tgaacctgga ggtggaggtt gcagtgagcc 2350gaggtcgcac cactgcactc cagtctgggt aacagagcga gactttctag 2400aaaaagccta acaaacagat aaggtaggac tcaaccaact gaaacctgac 2450tttccccctg taccttcagc ccctgtgcag gtagtaacct cttgagacct 2500ctccctgacc agggaccaag cacagggcat ttagagcttt ttagaataaa 2550ctggttttct ttaaaaaaaa aaaaaaaaaa agggcggccg cccttttttt 2600tttttttttt tttttttttt tttttttttt tttttttttt taaaaagggc 2650ttttattaaa attctcccca cacgatggct cctgcaatct gccacagctc 2700tggggcgtgt cctgtaggga aaggccctgt tttccctgag gcggggctgg 2750gcttgtccat gggtccgcgg agctggccgt gcttggcgcc ctggcgtgtg 2800tctagctgct tcttgccggg cacagagctg cggggtctgg gggcaccggg 2850agctaagagc aggctctggt gcaggggtgg aggcctgtct cttaaccgac 2900accctgaggt gctcctgaga tgctgggtcc accctgagtg gcacggggag 2950cagctgtggc cggtgctcct tcytaggcca gtcctgggga aactaagctc 3000gggcccttct ttgcaaagac cgaggatggg gtgggtgtgg gggactcatg 3050gggaatggcc tgaggagcta cgtgtgaaga gggcgccggt ttgttggctg 3100cagcggcctg gagcgcctct ctcctgagcc tcagtttccc tttccgtcta 3150atgaagaaca tgccgtctcg gtgtctcagg gctattagga cttgccctca 3200ggaagtggcc ttggacgagc gtcatgttat tttcacaact gtcctgcgac 3250gttggcctgg gcacgtcatg gaatggccca tgtccctctg ctgcgtggac 3300gtcgcggtcg ggagtgcgca gccagaggcg gggccagacg tgcgcctggg 3350ggtgagggga ggcgccccgg gagggcctca caggaagttg ggctcccgca 3400ccaccaggca gggcgggctc ccgccgccgc cgccgccacc accgtccagg 3450ggccggtaga caaagtggaa gtcgcgcttg ggctcgctgc gcagcaggta 3500gcccttgatg cagtgcggca gcgcgtcgtc cgccagctgg aagcagcgcc 3550cgtccaccag cacgaacagc cggtgcgcct 358044280PRTHomo sapiens 44Met Cys Phe Leu Asn Lys Leu Leu Leu Leu Ala Val Leu Gly Trp1 5 10 15Leu Phe Gln Ile Pro Thr Val Pro Glu Asp Leu Phe Phe Leu Glu 20 25 30Glu Gly Pro Ser Tyr Ala Phe Glu Val Asp Thr Val Ala Pro Glu 35 40 45His Gly Leu Asp Asn Ala Pro Val Val Asp Gln Gln Leu Leu Tyr 50 55 60Thr Cys Cys Pro Tyr Ile Gly Glu Leu Arg Lys Leu Leu Ala Ser 65 70 75Trp Val Ser Gly Ser Ser Gly Arg Ser Gly Gly Phe Met Arg Lys 80 85 90Ile Thr Pro Thr Thr Thr Thr Ser Leu Gly Ala Gln Pro Ser Gln 95 100 105Thr Ser Gln Gly Leu Gln Ala Gln Leu Ala Gln Ala Phe Phe His 110 115 120Asn Gln Pro Pro Ser Leu Arg Arg Thr Val Glu Phe Val Ala Glu 125 130 135Arg Ile Gly Ser Asn Cys Val Lys His Ile Lys Ala Thr Leu Val 140 145 150Ala Asp Leu Val Arg Gln Ala Glu Ser Leu Leu Gln Glu Gln Leu 155 160 165Val Thr Gln Gly Glu Glu Gly Gly Asp Pro Ala Gln Leu Leu Glu 170 175 180Ile Leu Cys Ser Gln Leu Cys Pro His Gly Ala Gln Ala Leu Ala 185 190 195Leu Gly Arg Glu Phe Cys Gln Arg Lys Ser Pro Gly Ala Val Arg 200 205 210Ala Leu Leu Pro Glu Glu Thr Pro Ala Ala Val Leu Ser Ser Ala 215 220 225Glu Asn Ile Ala Val Gly Leu Ala Thr Glu Lys Ala Cys Ala Trp 230 235 240Leu Ser Ala Asn Ile Thr Ala Leu Ile Arg Arg Glu Val Lys Ala 245 250 255Ala Val Ser Arg Thr Leu Arg Ala Gln Gly Pro Glu Pro Ala Ala 260 265 270Arg Gly Glu Arg Arg Gly Cys Ser Arg Ala 275

280454104DNAHomo sapiens 45cccacgcgtc cgcccacgcg tccgcccacg cgtccgccca cgcgtccgcc 50cacgcgtccg cccacgcgtc cgcccacgcg tccggtgcaa gctcgcgccg 100cacactgcct ggtggaggga aggagcccgg gcgcctctcg ccgctccccg 150cgccgccgtc cgcacctccc caccgcccgc cgcccgccgc ccgccgcccg 200caaagcatga gtgagcccgc tctctgcagc tgcccggggc gcgaatggca 250ggctgtttcc gcggagtaaa aggtggcgcc ggtcagtggt cgtttccaat 300gacggacatt aaccagactg tcagatcctg gggagtcgcg agccccgagt 350ttggagtttt ttccccccac aacgtcacag tccgaactgc agagggaaag 400gaaggcggca ggaaggcgaa gctcgggctc cggcacgtag ttgggaaact 450tgcgggtcct agaagtcgcc tccccgcctt gccggccgcc cttgcagccc 500cgagccgagc agcaaagtga gacattgtgc gcctgccaga tccgccggcc 550gcggaccggg gctgcctcgg aaacacagag gggtcttctc tcgccctgca 600tataattagc ctgcacacaa agggagcagc tgaatggagg ttgtcactct 650ctggaaaagg atttctgacc gagcgcttcc aatggacatt ctccagtctc 700tctggaaaga ttctcgctaa tggatttcct gctgctcggt ctctgtctat 750actggctgct gaggaggccc tcgggggtgg tcttgtgtct gctgggggcc 800tgctttcaga tgctgcccgc cgcccccagc gggtgcccgc agctgtgccg 850gtgcgagggg cggctgctgt actgcgaggc gctcaacctc accgaggcgc 900cccacaacct gtccggcctg ctgggcttgt ccctgcgcta caacagcctc 950tcggagctgc gcgccggcca gttcacgggg ttaatgcagc tcacgtggct 1000ctatctggat cacaatcaca tctgctccgt gcagggggac gcctttcaga 1050aactgcgccg agttaaggaa ctcacgctga gttccaacca gatcacccaa 1100ctgcccaaca ccaccttccg gcccatgccc aacctgcgca gcgtggacct 1150ctcgtacaac aagctgcagg cgctcgcgcc cgacctcttc cacgggctgc 1200ggaagctcac cacgctgcat atgcgggcca acgccatcca gtttgtgccc 1250gtgcgcatct tccaggactg ccgcagcctc aagtttctcg acatcggata 1300caatcagctc aagagtctgg cgcgcaactc tttcgccggc ttgtttaagc 1350tcaccgagct gcacctcgag cacaacgact tggtcaaggt gaacttcgcc 1400cacttcccgc gcctcatctc cctgcactcg ctctgcctgc ggaggaacaa 1450ggtggccatt gtggtcagct cgctggactg ggtttggaac ctggagaaaa 1500tggacttgtc gggcaacgag atcgagtaca tggagcccca tgtgttcgag 1550accgtgccgc acctgcagtc cctgcagctg gactccaacc gcctcaccta 1600catcgagccc cggatcctca actcttggaa gtccctgaca agcatcaccc 1650tggccgggaa cctgtgggat tgcgggcgca acgtgtgtgc cctagcctcg 1700tggctcagca acttccaggg gcgctacgat ggcaacttgc agtgcgccag 1750cccggagtac gcacagggcg aggacgtcct ggacgccgtg tacgccttcc 1800acctgtgcga ggatggggcc gagcccacca gcggccacct gctctcggcc 1850gtcaccaacc gcagtgatct ggggccccct gccagctcgg ccaccacgct 1900cgcggacggc ggggaggggc agcacgacgg cacattcgag cctgccaccg 1950tggctcttcc aggcggcgag cacgccgaga acgccgtgca gatccacaag 2000gtggtcacgg gcaccatggc cctcatcttc tccttcctca tcgtggtcct 2050ggtgctctac gtgtcctgga agtgtttccc agccagcctc aggcagctca 2100gacagtgctt tgtcacgcag cgcaggaagc aaaagcagaa acagaccatg 2150catcagatgg ctgccatgtc tgcccaggaa tactacgttg attacaaacc 2200gaaccacatt gagggagccc tggtgatcat caacgagtat ggctcgtgta 2250cctgccacca gcagcccgcg agggaatgcg aggtgtgatt gtcccagtgg 2300ctctcaaccc atgcgctacc aaatacgcct gggcagccgg gacgggccgg 2350cgggcaccag gctggggtct ccttgtctgt gctctgatat gctccttgac 2400tgaaacttta aggggatctc tcccagagac ttgacatttt agctttattg 2450tgtcttaaaa acaaaagcga attaaaacac aacaaaaaac cccaccccac 2500aaccttcagg acagtctatc ttaaatttca tatgagaact ccttcctccc 2550tttgaagatc tgtccatatt caggaatctg agagtgtaaa aaaggtggcc 2600ataagacaga gagagaataa tcgtgctttg ttttatgcta ctcctcccac 2650cctgcccatg attaaacatc atgtatgtag aagatcttaa gtccatacgc 2700atttcatgaa gaaccattgg aaagaggaat ctgcaatctg ggagcttaag 2750agcaaatgat gaccatagaa agctatgttc ttactttgtg tgtgtgtctg 2800tatgtttctg cgttgtgtgt ctttgtaggc aagcaaacgt tgtctacaca 2850aacgggaatt tagctcacat catttcatgc ccctgtgcct ctagctctgg 2900agattggtgg ggggaggtgg ggggaaacgg caggaataag ggaaagtggt 2950agttttaact aaggttttgt aacacttgaa atcttttctt tctcaaatta 3000attatcttta agcttcaaga aacttgctct gacccctcta agcaaactac 3050taagcattta aaagagaatc taatttttaa aggtgtagca cctttttttt 3100tattcttccc acagagggtg ctaatctcat tatgctgtgc tatctgaaaa 3150gaacttaagg ccacaattca cgtctcgtcc tgggcattgt gatggattga 3200ccctccattt gcagtacctt cccagctgat taaagttcag cagtggtatt 3250gaggtttttc gaatatttat atagaaaaaa agtcttttca catgacaaat 3300gacactctca caccagtctt agccctagta gttttttagg ttggaccaga 3350ggaagcaggt taaatgagac ctgtcctctg ctgcactcag aaaaaatagg 3400cagtccctga tgctcagatc ttagccttga tattaatagt tgagaccacc 3450tacccacaat gcagcctata ctcccaagac tacaaagtta ccatcgcaaa 3500ggaaaggtta ttccagtaaa aggaaatagt tttctcaacc atttaaaaat 3550attcttctga actcatcaaa gtagaagagc ccccaacctt ttctctctgc 3600cttcaagaag gcagacattt ggtatgattt agcatcaaca acacatttat 3650gagtatatgt aagtaatcag aggggcaaat gccacttgtt attcctccca 3700agttttccaa gcaagtacac acagatctct ggtaggatta ggggccactt 3750gtgtttccgg cttattttag tcgacttgtc agcaagtttg atgcctagtc 3800tatctgacat ggcccagtag aacagggcat tgatggatca catgagatgg 3850tagaaggaac atcatcacat acccctctca cagagaaaat tatcaaagaa 3900ccagaaatta tatctgtttt ggagcaagag tgtcataatg tttcagggta 3950gtcaaaataa acataaatta tctcctctag atgagtggcg atgttggctg 4000atttgggtct gccattgaca gaatgtcaaa taaaaaggaa ttagctagaa 4050tatgaccatt aaatgtgctt ctgaaatata ttttgagata ggtttagaat 4100gtca 410446522PRTHomo sapiens 46Met Asp Phe Leu Leu Leu Gly Leu Cys Leu Tyr Trp Leu Leu Arg1 5 10 15Arg Pro Ser Gly Val Val Leu Cys Leu Leu Gly Ala Cys Phe Gln 20 25 30Met Leu Pro Ala Ala Pro Ser Gly Cys Pro Gln Leu Cys Arg Cys 35 40 45Glu Gly Arg Leu Leu Tyr Cys Glu Ala Leu Asn Leu Thr Glu Ala 50 55 60Pro His Asn Leu Ser Gly Leu Leu Gly Leu Ser Leu Arg Tyr Asn 65 70 75Ser Leu Ser Glu Leu Arg Ala Gly Gln Phe Thr Gly Leu Met Gln 80 85 90Leu Thr Trp Leu Tyr Leu Asp His Asn His Ile Cys Ser Val Gln 95 100 105Gly Asp Ala Phe Gln Lys Leu Arg Arg Val Lys Glu Leu Thr Leu 110 115 120Ser Ser Asn Gln Ile Thr Gln Leu Pro Asn Thr Thr Phe Arg Pro 125 130 135Met Pro Asn Leu Arg Ser Val Asp Leu Ser Tyr Asn Lys Leu Gln 140 145 150Ala Leu Ala Pro Asp Leu Phe His Gly Leu Arg Lys Leu Thr Thr 155 160 165Leu His Met Arg Ala Asn Ala Ile Gln Phe Val Pro Val Arg Ile 170 175 180Phe Gln Asp Cys Arg Ser Leu Lys Phe Leu Asp Ile Gly Tyr Asn 185 190 195Gln Leu Lys Ser Leu Ala Arg Asn Ser Phe Ala Gly Leu Phe Lys 200 205 210Leu Thr Glu Leu His Leu Glu His Asn Asp Leu Val Lys Val Asn 215 220 225Phe Ala His Phe Pro Arg Leu Ile Ser Leu His Ser Leu Cys Leu 230 235 240Arg Arg Asn Lys Val Ala Ile Val Val Ser Ser Leu Asp Trp Val 245 250 255Trp Asn Leu Glu Lys Met Asp Leu Ser Gly Asn Glu Ile Glu Tyr 260 265 270Met Glu Pro His Val Phe Glu Thr Val Pro His Leu Gln Ser Leu 275 280 285Gln Leu Asp Ser Asn Arg Leu Thr Tyr Ile Glu Pro Arg Ile Leu 290 295 300Asn Ser Trp Lys Ser Leu Thr Ser Ile Thr Leu Ala Gly Asn Leu 305 310 315Trp Asp Cys Gly Arg Asn Val Cys Ala Leu Ala Ser Trp Leu Ser 320 325 330Asn Phe Gln Gly Arg Tyr Asp Gly Asn Leu Gln Cys Ala Ser Pro 335 340 345Glu Tyr Ala Gln Gly Glu Asp Val Leu Asp Ala Val Tyr Ala Phe 350 355 360His Leu Cys Glu Asp Gly Ala Glu Pro Thr Ser Gly His Leu Leu 365 370 375Ser Ala Val Thr Asn Arg Ser Asp Leu Gly Pro Pro Ala Ser Ser 380 385 390Ala Thr Thr Leu Ala Asp Gly Gly Glu Gly Gln His Asp Gly Thr 395 400 405Phe Glu Pro Ala Thr Val Ala Leu Pro Gly Gly Glu His Ala Glu 410 415 420Asn Ala Val Gln Ile His Lys Val Val Thr Gly Thr Met Ala Leu 425 430 435Ile Phe Ser Phe Leu Ile Val Val Leu Val Leu Tyr Val Ser Trp 440 445 450Lys Cys Phe Pro Ala Ser Leu Arg Gln Leu Arg Gln Cys Phe Val 455 460 465Thr Gln Arg Arg Lys Gln Lys Gln Lys Gln Thr Met His Gln Met 470 475 480Ala Ala Met Ser Ala Gln Glu Tyr Tyr Val Asp Tyr Lys Pro Asn 485 490 495His Ile Glu Gly Ala Leu Val Ile Ile Asn Glu Tyr Gly Ser Cys 500 505 510Thr Cys His Gln Gln Pro Ala Arg Glu Cys Glu Val 515 520473170DNAHomo sapiens 47agcgggtctc gcttgggttc cgctaatttc tgtcctgagg cgtgagactg 50agttcatagg gtcctgggtc cccgaaccag gaagggttga gggaacacaa 100tctgcaagcc cccgcgaccc aagtgagggg ccccgtgttg gggtcctccc 150tccctttgca ttcccacccc tccgggcttt gcgtcttcct ggggaccccc 200tcgccgggag atggccgcgt tgatgcggag caaggattcg tcctgctgcc 250tgctcctact ggccgcggtg ctgatggtgg agagctcaca gatcggcagt 300tcgcgggcca aactcaactc catcaagtcc tctctgggcg gggagacgcc 350tggtcaggcc gccaatcgat ctgcgggcat gtaccaagga ctggcattcg 400gcggcagtaa gaagggcaaa aacctggggc aggcctaccc ttgtagcagt 450gataaggagt gtgaagttgg gaggtattgc cacagtcccc accaaggatc 500atcggcctgc atggtgtgtc ggagaaaaaa gaagcgctgc caccgagatg 550gcatgtgctg ccccagtacc cgctgcaata atggcatctg tatcccagtt 600actgaaagca tcttaacccc tcacatcccg gctctggatg gtactcggca 650cagagatcga aaccacggtc attactcaaa ccatgacttg ggatggcaga 700atctaggaag accacacact aagatgtcac atataaaagg gcatgaagga 750gacccctgcc tacgatcatc agactgcatt gaagggtttt gctgtgctcg 800tcatttctgg accaaaatct gcaaaccagt gctccatcag ggggaagtct 850gtaccaaaca acgcaagaag ggttctcatg ggctggaaat tttccagcgt 900tgcgactgtg cgaagggcct gtcttgcaaa gtatggaaag atgccaccta 950ctcctccaaa gccagactcc atgtgtgtca gaaaatttga tcaccattga 1000ggaacatcat caattgcaga ctgtgaagtt gtgtatttaa tgcattatag 1050catggtggaa aataaggttc agatgcagaa gaatggctaa aataagaaac 1100gtgataagaa tatagatgat cacaaaaagg gagaaagaaa acatgaactg 1150aatagattag aatgggtgac aaatgcagtg cagccagtgt ttccattatg 1200caacttgtct atgtaaataa tgtacacatt tgtggaaaat gctattatta 1250agagaacaag cacacagtgg aaattactga tgagtagcat gtgactttcc 1300aagagtttag gttgtgctgg aggagaggtt tccttcagat tgctgattgc 1350ttatacaaat aacctacatg ccagatttct attcaacgtt agagtttaac 1400aaaatactcc tagaataact tgttatacaa taggttctaa aaataaaatt 1450gctaaacaag aaatgaaaac atggagcatt gttaatttac aacagaaaat 1500taccttttga tttgtaacac tacttctgct gttcaatcaa gagtcttggt 1550agataagaaa aaaatcagtc aatatttcca aataattgca aaataatggc 1600cagttgttta ggaaggcctt taggaagaca aataaataac aaacaaacag 1650ccacaaatac ttttttttca aaattttagt tttacctgta attaataaga 1700actgatacaa gacaaaaaca gttccttcag attctacgga atgacagtat 1750atctctcttt atcctatgtg attcctgctc tgaatgcatt atattttcca 1800aactataccc ataaattgtg actagtaaaa tacttacaca gagcagaatt 1850ttcacagatg gcaaaaaaat ttaaagatgt ccaatatatg tgggaaaaga 1900gctaacagag agatcattat ttcttaaaga ttggccataa cctatatttt 1950gatagaatta gattggtaaa tacatgtatt catacatact ctgtggtaat 2000agagacttaa gctggatctg tactgcactg gagtaagcaa gaaaattggg 2050aaaacttttt cgtttgttca ggttttggca acacatagat catatgtctg 2100aggcacaagt tggctgttca tctttgaaac caggggatgc acagtctaaa 2150tgaatatctg catgggattt gctatcataa tatttactat gcagatgaat 2200tcagtgtgag gtcctgtgtc cgtactatcc tcaaattatt tattttatag 2250tgctgagatc ctcaaataat ctcaatttca ggaggtttca caaaatgtac 2300tcctgaagta gacagagtag tgaggtttca ttgccctcta taagcttctg 2350actagccaat ggcatcatcc aattttcttc ccaaacctct gcagcatctg 2400ctttattgcc aaagggctag tttcggtttt ctgcagccat tgcggttaaa 2450aaatataagt aggataactt gtaaaacctg catattgcta atctatagac 2500accacagttt ctaaattctt tgaaaccact ttactacttt ttttaaactt 2550aactcagttc taaatacttt gtctggagca caaaacaata aaaggttatc 2600ttatagtcgt gactttaaac ttttgtagac cacaattcac tttttagttt 2650tcttttactt aaatcccatc tgcagtctca aatttaagtt ctcccagtag 2700agattgagtt tgagcctgta tatctattaa aaatttcaac ttcccacata 2750tatttactaa gatgattaag acttacattt tctgcacagg tctgcaaaaa 2800caaaaattat aaactagtcc atccaagaac caaagtttgt ataaacaggt 2850tgctataagc ttgtgaaatg aaaatggaac atttcaatca aacatttcct 2900atataacaat tattatattt acaatttggt ttctgcaata tttttcttat 2950gtccaccctt ttaaaaatta ttatttgaag taatttattt acaggaaatg 3000ttaatgagat gtattttctt atagagatat ttcttacaga aagctttgta 3050gcagaatata tttgcagcta ttgactttgt aatttaggaa aaatgtataa 3100taagataaaa tctattaaat ttttctcctc taaaaactga aaaaaaaaaa 3150aaaaaaaaaa aaaaaaaaaa 317048259PRTHomo sapiens 48Met Ala Ala Leu Met Arg Ser Lys Asp Ser Ser Cys Cys Leu Leu1 5 10 15Leu Leu Ala Ala Val Leu Met Val Glu Ser Ser Gln Ile Gly Ser 20 25 30Ser Arg Ala Lys Leu Asn Ser Ile Lys Ser Ser Leu Gly Gly Glu 35 40 45Thr Pro Gly Gln Ala Ala Asn Arg Ser Ala Gly Met Tyr Gln Gly 50 55 60Leu Ala Phe Gly Gly Ser Lys Lys Gly Lys Asn Leu Gly Gln Ala 65 70 75Tyr Pro Cys Ser Ser Asp Lys Glu Cys Glu Val Gly Arg Tyr Cys 80 85 90His Ser Pro His Gln Gly Ser Ser Ala Cys Met Val Cys Arg Arg 95 100 105Lys Lys Lys Arg Cys His Arg Asp Gly Met Cys Cys Pro Ser Thr 110 115 120Arg Cys Asn Asn Gly Ile Cys Ile Pro Val Thr Glu Ser Ile Leu 125 130 135Thr Pro His Ile Pro Ala Leu Asp Gly Thr Arg His Arg Asp Arg 140 145 150Asn His Gly His Tyr Ser Asn His Asp Leu Gly Trp Gln Asn Leu 155 160 165Gly Arg Pro His Thr Lys Met Ser His Ile Lys Gly His Glu Gly 170 175 180Asp Pro Cys Leu Arg Ser Ser Asp Cys Ile Glu Gly Phe Cys Cys 185 190 195Ala Arg His Phe Trp Thr Lys Ile Cys Lys Pro Val Leu His Gln 200 205 210Gly Glu Val Cys Thr Lys Gln Arg Lys Lys Gly Ser His Gly Leu 215 220 225Glu Ile Phe Gln Arg Cys Asp Cys Ala Lys Gly Leu Ser Cys Lys 230 235 240Val Trp Lys Asp Ala Thr Tyr Ser Ser Lys Ala Arg Leu His Val 245 250 255Cys Gln Lys Ile492567DNAHomo sapiens 49cgtgggccgg ggtcgcgcag cgggctgtgg gcgcgcccgg aggagcgacc 50gccgcagttc tcgagctcca gctgcattcc ctccgcgtcc gccccacgct 100tctcccgctc cgggccccgc aatggcccag gcagtgtggt cgcgcctcgg 150ccgcatcctc tggcttgcct gcctcctgcc ctgggccccg gcaggggtgg 200ccgcaggcct gtatgaactc aatctcacca ccgatagccc tgccaccacg 250ggagcggtgg tgaccatctc ggccagcctg gtggccaagg acaacggcag 300cctggccctg cccgctgacg cccacctcta ccgcttccac tggatccaca 350ccccgctggt gcttactggc aagatggaga agggtctcag ctccaccatc 400cgtgtggtcg gccacgtgcc cggggaattc ccggtctctg tctgggtcac 450tgccgctgac tgctggatgt gccagcctgt ggccaggggc tttgtggtcc 500tccccatcac agagttcctc gtgggggacc ttgttgtcac ccagaacact 550tccctaccct ggcccagctc ctatctcact aagaccgtcc tgaaagtctc 600cttcctcctc cacgacccga gcaacttcct caagaccgcc ttgtttctct 650acagctggga cttcggggac gggacccaga tggtgactga agactccgtg 700gtctattata actattccat catcgggacc ttcaccgtga agctcaaagt 750ggtggcggag tgggaagagg tggagccgga tgccacgagg gctgtgaagc 800agaagaccgg ggacttctcc gcctcgctga agctgcagga aacccttcga 850ggcatccaag tgttggggcc caccctaatt cagaccttcc aaaagatgac 900cgtgaccttg aacttcctgg

ggagccctcc tctgactgtg tgctggcgtc 950tcaagcctga gtgcctcccg ctggaggaag gggagtgcca ccctgtgtcc 1000gtggccagca cagcgtacaa cctgacccac accttcaggg accctgggga 1050ctactgcttc agcatccggg ccgagaatat catcagcaag acacatcagt 1100accacaagat ccaggtgtgg ccctccagaa tccagccggc tgtctttgct 1150ttcccatgtg ctacacttat cactgtgatg ttggccttca tcatgtacat 1200gaccctgcgg aatgccactc agcaaaagga catggtggag aacccggagc 1250caccctctgg ggtcaggtgc tgctgccaga tgtgctgtgg gcctttcttg 1300ctggagactc catctgagta cctggaaatt gttcgtgaga accacgggct 1350gctcccgccc ctctataagt ctgtcaaaac ttacaccgtg tgagcactcc 1400ccctccccac cccatctcag tgttaactga ctgctgactt ggagtttcca 1450gcagggtggt gtgcaccact gaccaggagg ggttcatttg cgtggggctg 1500ttggcctgga tcatccatcc atctgtacag ttcagccact gccacaagcc 1550cctccctctc tgtcacccct gaccccagcc attcacccat ctgtacagtc 1600cagccactga cataagcccc actcggttac cacccccttg accccctacc 1650tttgaagagg cttcgtgcag gactttgatg cttggggtgt tccgtgttga 1700ctcctaggtg ggcctggctg cccactgccc attcctctca tattggcaca 1750tctgctgtcc attgggggtt ctcagtttcc tcccccagac agccctacct 1800gtgccagaga gctagaaaga aggtcataaa gggttaaaaa tccataacta 1850aaggttgtac acatagatgg gcacactcac agagagaagt gtgcatgtac 1900acacaccaca cacacacaca cacacacaca cacagaaata taaacacatg 1950cgtcacatgg gcatttcaga tgatcagctc tgtatctggt taagtcggtt 2000gctgggatgc accctgcact agagctgaaa ggaaatttga cctccaagca 2050gccctgacag gttctgggcc cgggccctcc ctttgtgctt tgtctctgca 2100gttcttgcgc cctttataag gccatcctag tccctgctgg ctggcagggg 2150cctggatggg gggcaggact aatactgagt gattgcagag tgctttataa 2200atatcacctt attttatcga aacccatctg tgaaactttc actgaggaaa 2250aggccttgca gcggtagaag aggttgagtc aaggccgggc gcggtggctc 2300acgcctgtaa tcccagcact ttgggaggcc gaggcgggtg gatcacgaga 2350tcaggagatc gagaccaccc tggctaacac ggtgaaaccc cgtctctact 2400aaaaaaatac aaaaagttag ccgggcgtgg tggtgggtgc ctgtagtccc 2450agctactcgg gaggctgagg caggagaatg gtgcgaaccc gggaggcgga 2500gcttgcagtg agcccagatg gcgccactgc actccagcct gagtgacaga 2550gcgagactct gtctcca 256750423PRTHomo sapiens 50Met Ala Gln Ala Val Trp Ser Arg Leu Gly Arg Ile Leu Trp Leu1 5 10 15Ala Cys Leu Leu Pro Trp Ala Pro Ala Gly Val Ala Ala Gly Leu 20 25 30Tyr Glu Leu Asn Leu Thr Thr Asp Ser Pro Ala Thr Thr Gly Ala 35 40 45Val Val Thr Ile Ser Ala Ser Leu Val Ala Lys Asp Asn Gly Ser 50 55 60Leu Ala Leu Pro Ala Asp Ala His Leu Tyr Arg Phe His Trp Ile 65 70 75His Thr Pro Leu Val Leu Thr Gly Lys Met Glu Lys Gly Leu Ser 80 85 90Ser Thr Ile Arg Val Val Gly His Val Pro Gly Glu Phe Pro Val 95 100 105Ser Val Trp Val Thr Ala Ala Asp Cys Trp Met Cys Gln Pro Val 110 115 120Ala Arg Gly Phe Val Val Leu Pro Ile Thr Glu Phe Leu Val Gly 125 130 135Asp Leu Val Val Thr Gln Asn Thr Ser Leu Pro Trp Pro Ser Ser 140 145 150Tyr Leu Thr Lys Thr Val Leu Lys Val Ser Phe Leu Leu His Asp 155 160 165Pro Ser Asn Phe Leu Lys Thr Ala Leu Phe Leu Tyr Ser Trp Asp 170 175 180Phe Gly Asp Gly Thr Gln Met Val Thr Glu Asp Ser Val Val Tyr 185 190 195Tyr Asn Tyr Ser Ile Ile Gly Thr Phe Thr Val Lys Leu Lys Val 200 205 210Val Ala Glu Trp Glu Glu Val Glu Pro Asp Ala Thr Arg Ala Val 215 220 225Lys Gln Lys Thr Gly Asp Phe Ser Ala Ser Leu Lys Leu Gln Glu 230 235 240Thr Leu Arg Gly Ile Gln Val Leu Gly Pro Thr Leu Ile Gln Thr 245 250 255Phe Gln Lys Met Thr Val Thr Leu Asn Phe Leu Gly Ser Pro Pro 260 265 270Leu Thr Val Cys Trp Arg Leu Lys Pro Glu Cys Leu Pro Leu Glu 275 280 285Glu Gly Glu Cys His Pro Val Ser Val Ala Ser Thr Ala Tyr Asn 290 295 300Leu Thr His Thr Phe Arg Asp Pro Gly Asp Tyr Cys Phe Ser Ile 305 310 315Arg Ala Glu Asn Ile Ile Ser Lys Thr His Gln Tyr His Lys Ile 320 325 330Gln Val Trp Pro Ser Arg Ile Gln Pro Ala Val Phe Ala Phe Pro 335 340 345Cys Ala Thr Leu Ile Thr Val Met Leu Ala Phe Ile Met Tyr Met 350 355 360Thr Leu Arg Asn Ala Thr Gln Gln Lys Asp Met Val Glu Asn Pro 365 370 375Glu Pro Pro Ser Gly Val Arg Cys Cys Cys Gln Met Cys Cys Gly 380 385 390Pro Phe Leu Leu Glu Thr Pro Ser Glu Tyr Leu Glu Ile Val Arg 395 400 405Glu Asn His Gly Leu Leu Pro Pro Leu Tyr Lys Ser Val Lys Thr 410 415 420Tyr Thr Val 51963DNAHomo sapiens 51ctatgaagaa gcttcctgga aaacaataag caaaggaaaa caaatgtgtc 50ccatctcaca tggttctacc ctactaaaga caggaagatc ataaactgac 100agatactgaa attgtaagag ttggaaacta cattttgcaa agtcattgaa 150ctctgagctc agttgcagta ctcgggaagc catgcaggat gaagatggat 200acatcacctt aaatattaaa actcggaaac cagctctcgt ctccgttggc 250cctgcatcct cctcctggtg gcgtgtgatg gctttgattc tgctgatcct 300gtgcgtgggg atggttgtcg ggctggtggc tctggggatt tggtctgtca 350tgcagcgcaa ttacctacaa gatgagaatg aaaatcgcac aggaactctg 400caacaattag caaagcgctt ctgtcaatat gtggtaaaac aatcagaact 450aaagggcact ttcaaaggtc ataaatgcag cccctgtgac acaaactgga 500gatattatgg agatagctgc tatgggttct tcaggcacaa cttaacatgg 550gaagagagta agcagtactg cactgacatg aatgctactc tcctgaagat 600tgacaaccgg aacattgtgg agtacatcaa agccaggact catttaattc 650gttgggtcgg attatctcgc cagaagtcga atgaggtctg gaagtgggag 700gatggctcgg ttatctcaga aaatatgttt gagtttttgg aagatggaaa 750aggaaatatg aattgtgctt attttcataa tgggaaaatg caccctacct 800tctgtgagaa caaacattat ttaatgtgtg agaggaaggc tggcatgacc 850aaggtggacc aactacctta atgcaaagag gtggacagga taacacagat 900aagggcttta ttgtacaata aaagatatgt atgaatgcat cagtagctga 950aaaaaaaaaa aaa 96352229PRTHomo sapiens 52Met Gln Asp Glu Asp Gly Tyr Ile Thr Leu Asn Ile Lys Thr Arg1 5 10 15Lys Pro Ala Leu Val Ser Val Gly Pro Ala Ser Ser Ser Trp Trp 20 25 30Arg Val Met Ala Leu Ile Leu Leu Ile Leu Cys Val Gly Met Val 35 40 45Val Gly Leu Val Ala Leu Gly Ile Trp Ser Val Met Gln Arg Asn 50 55 60Tyr Leu Gln Asp Glu Asn Glu Asn Arg Thr Gly Thr Leu Gln Gln 65 70 75Leu Ala Lys Arg Phe Cys Gln Tyr Val Val Lys Gln Ser Glu Leu 80 85 90Lys Gly Thr Phe Lys Gly His Lys Cys Ser Pro Cys Asp Thr Asn 95 100 105Trp Arg Tyr Tyr Gly Asp Ser Cys Tyr Gly Phe Phe Arg His Asn 110 115 120Leu Thr Trp Glu Glu Ser Lys Gln Tyr Cys Thr Asp Met Asn Ala 125 130 135Thr Leu Leu Lys Ile Asp Asn Arg Asn Ile Val Glu Tyr Ile Lys 140 145 150Ala Arg Thr His Leu Ile Arg Trp Val Gly Leu Ser Arg Gln Lys 155 160 165Ser Asn Glu Val Trp Lys Trp Glu Asp Gly Ser Val Ile Ser Glu 170 175 180Asn Met Phe Glu Phe Leu Glu Asp Gly Lys Gly Asn Met Asn Cys 185 190 195Ala Tyr Phe His Asn Gly Lys Met His Pro Thr Phe Cys Glu Asn 200 205 210Lys His Tyr Leu Met Cys Glu Arg Lys Ala Gly Met Thr Lys Val 215 220 225Asp Gln Leu Pro533934DNAHomo sapiens 53ccctgacctc cctgagccac actgagctgg aagccgcaga ggtcatcctg 50gagcatgccc accgcgggga gcagacaacc tcccaggtaa gctgggagca 100agacctgaag ctgtttcttc aggagcctgg tgtattttcc cccaccccac 150ctcagcagtt tcagccagca gggactgatc aggtgtgtgt cctggagtgg 200ggagcagaag gcgtggctgg caagagtggc ctggagaaag aggttcagcg 250cttgaccagc cgagctgccc gtgactacaa gatccagaac catgggcatc 300gggtgaggtg ggggggcaca ggtgtcatgt gcaccttctt gtctcagcaa 350gaagagctga gagaggggat cttggagcca ttgagggtgt catggagcta 400cagaggggag ggaaaggtat tttaaggtaa cagtgtggca caatagttaa 450gagcacagtt tttggagcta gaccgacata ggttcaaatt ctcttctgtt 500gcttcctagt tctgtagccc caggtaaggg agtgacttaa cctctctgga 550cttcaatttc ctcatcacta aagtagggcc aataatagca cccacctcat 600agggaagatt aaatgacata atgtatgtga tgcaactagc aaagtaccag 650tcccatagta agtcatgccc cacagtattt ccacccaccc ctgttctctg 700ccttcccaac caggtactgc aacgactgga gcagaggcgg cagcaggctt 750cagagcggga ggctccaagc atagaacaga ggttacagga agtgcgagag 800agcatccgcc gggcacaggt gagccaggtg aagggggctg cccggctggc 850cctgctgcag ggggctggct tagatgtgga gcgctggctg aagccagcca 900tgacccaggc ccaggatgag gtggagcagg agcggcggct cagtgaggct 950cggctgtccc agagggacct ctctccaacc gctgaggatg ctgagctttc 1000tgactttgag gaatgtgagg agacgggaga gctctttgag gagcctgccc 1050cccaagccct ggccacgagg gccctcccct gccctgcaca cgtggtattt 1100cgctatcagg cagggcgtga ggatgagctg acaatcacgg agggtgagtg 1150gctggaggtc atagaggagg gagatgctga cgaatgggtc aaggctcgga 1200accagcacgg cgaggtaggc tttgtccctg agcgatatct caacttcccg 1250gacctctccc tcccagagag cagccaagac agtgacaatc cctgcggggc 1300agagcccaca gcattcctgg cacaggccct gtacagctac accggacaga 1350gtgcagagga gctgagcttc cctgaggggg cactcatccg tctgctgccc 1400cgggcccaag atggagtaga tgacggcttc tggaggggag aatttggggg 1450ccgtgttggg gtcttcccct ccctgctggt ggaagagctg cttggccccc 1500cagggccacc tgaactctct gaccctgaac agatgctgcc gtccccttct 1550cctcccagct tctccccacc tgcacctacc tctgtgttgg atgggccccc 1600tgcacctgtc ctgcctgggg acaaagccct ggacttccct gggttcctgg 1650acatgatggc acctcgactc aggccgatgc gtccaccacc tcccccgccg 1700gctaaagccc cggatcctgg ccacccagat cccctcacct gaaggccagg 1750gaagccttga cccccagtga tgctgctgtc cctatcttca agctgtcaga 1800ccacaccatc aatgatccag agcaacacag ccaaaagctg gaatcgccct 1850tatttccacc ctcacctcca agggtggaaa cttgcccctt cccatttcta 1900gagctggaac ccactccttt ttttcccatt gttctatcat ctctaggacc 1950ggaactacta ccttctcttc tgtcatgacc ctatctaggg tggtgaaatg 2000cctgaaatct ctggggctgg aaaccatcca tcaaggtctc tagtagttct 2050ggcccacctc tttccccacc ctggctccat gacccacccc actctggatg 2100ccagggtcac tggggttggg ctggggagag gaacaggcct tgggaatcag 2150gagctggagc caggatgcga agcagctgta atggtctgag cggatttatt 2200gacaatgaat aaagggcacg aaggccaggc cagggcctgg gcctcttgtg 2250ctaagagggc agggggccta cggtgctatt gctttagggg cccaccacgg 2300gcaggggcct gctcccagct gccacgctct atcatatgga gcgaggtgtt 2350ggggaaggcg gggcaggcag cctgttgcag gcaggggaag gagaagagac 2400tgaggggctg tgacctctcc tgaggccccc agcctgagac tgtgcaactc 2450caggtggaag tagagctggt ccctcagctg gggggcagtg ctgtccagtg 2500gaggggaggg ctttcacgcc cacccacccc ctggccctgc cagctggtag 2550tccatcagca caatgaagga gacttggaga agaggaagaa taacactgtt 2600gcttcctgtt caagctgtgt ccagcttttc ccctggggct ccaggacctt 2650ccctacctcc accaccaaac caagggattt atagcaaagg ctaagcctgc 2700agtttactct gggggttcag ggagccgaaa ggcttaaata gtttaagtag 2750gtgatgggaa gatgagatta cctcatttag ggctcaggca gactcacctc 2800acatactccc tgctccctgt ggtagagaca cctgagagaa aggggagggg 2850tcaacaatga gagaccagga gtaggtccta tcagtgcccc ccagagtaga 2900gagcaataag agcccagccc agtgcagtcc cggctgtgtt ttcctacctg 2950gtgatcagaa gtgtctggtt tgcttggctg cccatttgcc tcttgagtgg 3000gcagccctgg gcttgggccc ctccctccgg ccctcagtgt tggctctgca 3050gaagctctgg ggttcccttc aagtgcacga ggggttaggc tgctgtccct 3100gagtcctcca ttctgtactg gggggctggc taggacctgg ggctgtggcc 3150tctcaggggg cagcctctcc atggcaggca tccctgcctt gggctgccct 3200cccccagacc cctgaccacc ccctgggtcc tgtcccccac cagagcccca 3250gctcctgtct gtgggggagc catcacggtg ttcgtgcagt ccatagcgct 3300tctcaatgtg tgtcacccgg aacctgggag gggagggaac actggggttt 3350aggaccacaa ctcagaggct gcttggccct cccctctgac cagggacatc 3400ctgagtttgg tggctacttc cctctggcct aaggtagggg aggccttctc 3450agattgtggg gcacattgtg tagcctgact tctgctggag ctcccagtcc 3500aggaggaaag agccaaggcc cacttttggg atcaggtgcc tgatcactgg 3550gccccctacc tcagcccccc tttccctgga gcacctgccc cacctgccca 3600cagagaacac agtggtctcc cctgtccggg ggcggctttt tccttccttg 3650gagcgtccct gacggacaag tggaggcctc ttgctgcggc tgcaatggat 3700gcaaggggct gcagagccca ggtgcactgt gtgatgatgg gagggggctc 3750cgtcctgcag gctggaggtg gcatccacac tggacagcag gaggagggga 3800gtgagggtaa catttccatt tcccttcatg ttttgtttct tacgttcttt 3850cagcatgctc cttaaaaccc cagaagcccc aatttcccca agccccattt 3900tttcttgtct ttatctaata aactcaatat taag 393454370PRTHomo sapiens 54Met Gln Leu Ala Lys Tyr Gln Ser His Ser Lys Ser Cys Pro Thr1 5 10 15Val Phe Pro Pro Thr Pro Val Leu Cys Leu Pro Asn Gln Val Leu 20 25 30Gln Arg Leu Glu Gln Arg Arg Gln Gln Ala Ser Glu Arg Glu Ala 35 40 45Pro Ser Ile Glu Gln Arg Leu Gln Glu Val Arg Glu Ser Ile Arg 50 55 60Arg Ala Gln Val Ser Gln Val Lys Gly Ala Ala Arg Leu Ala Leu 65 70 75Leu Gln Gly Ala Gly Leu Asp Val Glu Arg Trp Leu Lys Pro Ala 80 85 90Met Thr Gln Ala Gln Asp Glu Val Glu Gln Glu Arg Arg Leu Ser 95 100 105Glu Ala Arg Leu Ser Gln Arg Asp Leu Ser Pro Thr Ala Glu Asp 110 115 120Ala Glu Leu Ser Asp Phe Glu Glu Cys Glu Glu Thr Gly Glu Leu 125 130 135Phe Glu Glu Pro Ala Pro Gln Ala Leu Ala Thr Arg Ala Leu Pro 140 145 150Cys Pro Ala His Val Val Phe Arg Tyr Gln Ala Gly Arg Glu Asp 155 160 165Glu Leu Thr Ile Thr Glu Gly Glu Trp Leu Glu Val Ile Glu Glu 170 175 180Gly Asp Ala Asp Glu Trp Val Lys Ala Arg Asn Gln His Gly Glu 185 190 195Val Gly Phe Val Pro Glu Arg Tyr Leu Asn Phe Pro Asp Leu Ser 200 205 210Leu Pro Glu Ser Ser Gln Asp Ser Asp Asn Pro Cys Gly Ala Glu 215 220 225Pro Thr Ala Phe Leu Ala Gln Ala Leu Tyr Ser Tyr Thr Gly Gln 230 235 240Ser Ala Glu Glu Leu Ser Phe Pro Glu Gly Ala Leu Ile Arg Leu 245 250 255Leu Pro Arg Ala Gln Asp Gly Val Asp Asp Gly Phe Trp Arg Gly 260 265 270Glu Phe Gly Gly Arg Val Gly Val Phe Pro Ser Leu Leu Val Glu 275 280 285Glu Leu Leu Gly Pro Pro Gly Pro Pro Glu Leu Ser Asp Pro Glu 290 295 300Gln Met Leu Pro Ser Pro Ser Pro Pro Ser Phe Ser Pro Pro Ala 305 310 315Pro Thr Ser Val Leu Asp Gly Pro Pro Ala Pro Val Leu Pro Gly 320 325 330Asp Lys Ala Leu Asp Phe Pro Gly Phe Leu Asp Met Met Ala Pro 335 340 345Arg Leu Arg Pro Met Arg Pro Pro Pro Pro Pro Pro Ala Lys Ala 350 355 360Pro Asp Pro Gly His Pro Asp Pro Leu Thr 365 370551942DNAHomo sapiens 55cccacgcgtc cgcccacgcg tccgggtgcc actcgcgcgc cggccgcgct 50ccgggcttct cttttccctc cgacgcgcca cggctgccca gacattccgg 100ctgccgggtc tggagagctc cccgaacccc tccgcggaga ggagcgaggc 150ggcgccaggg tggcccccgg ggcgcgcttg gtctcggaga agcggggacg 200aggccggagg atgagcgact gagggcgacg cgggcactga cgcgagttgg 250ggccgcgact accggcagct gacagcgcga tgagcgactc cccagagacg 300ccctagcccg gtgtgcgcgc caggcggagc gcgcaggtgg

ggctgggctg 350ttagtggtcc gccccacgcg ggtcgccggc cggcccagga tgggcgctgg 400caacccgggc ccgcgcccgc cgctgctacc cctgcgcccg ctgcgagccc 450ggcgtccggc ccgcgccctg cgctcatgga cggcggctcc cggctggcgg 500cggcgcgccc ccgggctgtg aatgcgactc gcccctcggc cgcgctcccc 550gcccgcccgc ccgccgggac gtggtagggg atgcccagct ccactgcgat 600ggcagttggc gcgctctcca gttccctcct ggtcacctgc tgcctgatgg 650tggctctgtg cagtccgagc atcccgctgg agaagctggc ccaggcacca 700gagcagccgg gccaggagaa gcgtgagcac gccactcggg acggcccggg 750gcgggtgaac gagctcgggc gcccggcgag ggacgagggc ggcagcggcc 800gggactggaa gagcaagagc ggccgtgggc tcgccggccg tgagccgtgg 850agcaagctga agcaggcctg ggtctcccag ggcgggggcg ccaaggccgg 900ggatctgcag gtccggcccc gcggggacac cccgcaggcg gaagccctgg 950ccgcagccgc ccaggacgcg attggcccgg aactcgcgcc cacgcccgag 1000ccacccgagg agtacgtgta cccggactac cgtggcaagg gctgcgtgga 1050cgagagcggc ttcgtgtacg cgatcgggga gaagttcgcg ccgggcccct 1100cggcctgccc gtgcctgtgc accgaggagg ggccgctgtg cgcgcagccc 1150gagtgcccga ggctgcaccc gcgctgcatc cacgtcgaca cgagccagtg 1200ctgcccgcag tgcaaggaga ggaagaacta ctgcgagttc cggggcaaga 1250cctatcagac tttggaggag ttcgtggtgt ctccatgcga gaggtgtcgc 1300tgtgaagcca acggtgaggt gctatgcaca gtgtcagcgt gtccccagac 1350ggagtgtgtg gaccctgtgt acgagcctga tcagtgctgt cccatctgca 1400aaaatggtcc aaactgcttt gcagaaaccg cggtgatccc tgctggcaga 1450gaagtgaaga ctgacgagtg caccatatgc cactgtactt atgaggaagg 1500cacatggaga atcgagcggc aggccatgtg cacgagacat gaatgcaggc 1550aaatgtagac gcttcccaga acacaaactc tgactttttc tagaacattt 1600tactgatgtg aacattctag atgactctgg gaactatcag tcaaagaaga 1650cttttgatga ggaataatgg aaaattgttg gtacttttcc ttttcttgat 1700aacagttact acaacagaag gaaatggata tatttcaaaa catcaacaag 1750aactttgggc ataaaatcct tctctaaata aatgtgctat tttcacagta 1800agtacacaaa agtacactat tatatatcaa atgtatttct ataatccctc 1850cattagagag cttatataag tgttttctat agatgcagat taaaaatgct 1900gtgttgtcaa ccgtcaaaaa aaaaaaaaaa aaaaaaaaaa aa 194256325PRTHomo sapiens 56Met Pro Ser Ser Thr Ala Met Ala Val Gly Ala Leu Ser Ser Ser1 5 10 15Leu Leu Val Thr Cys Cys Leu Met Val Ala Leu Cys Ser Pro Ser 20 25 30Ile Pro Leu Glu Lys Leu Ala Gln Ala Pro Glu Gln Pro Gly Gln 35 40 45Glu Lys Arg Glu His Ala Thr Arg Asp Gly Pro Gly Arg Val Asn 50 55 60Glu Leu Gly Arg Pro Ala Arg Asp Glu Gly Gly Ser Gly Arg Asp 65 70 75Trp Lys Ser Lys Ser Gly Arg Gly Leu Ala Gly Arg Glu Pro Trp 80 85 90Ser Lys Leu Lys Gln Ala Trp Val Ser Gln Gly Gly Gly Ala Lys 95 100 105Ala Gly Asp Leu Gln Val Arg Pro Arg Gly Asp Thr Pro Gln Ala 110 115 120Glu Ala Leu Ala Ala Ala Ala Gln Asp Ala Ile Gly Pro Glu Leu 125 130 135Ala Pro Thr Pro Glu Pro Pro Glu Glu Tyr Val Tyr Pro Asp Tyr 140 145 150Arg Gly Lys Gly Cys Val Asp Glu Ser Gly Phe Val Tyr Ala Ile 155 160 165Gly Glu Lys Phe Ala Pro Gly Pro Ser Ala Cys Pro Cys Leu Cys 170 175 180Thr Glu Glu Gly Pro Leu Cys Ala Gln Pro Glu Cys Pro Arg Leu 185 190 195His Pro Arg Cys Ile His Val Asp Thr Ser Gln Cys Cys Pro Gln 200 205 210Cys Lys Glu Arg Lys Asn Tyr Cys Glu Phe Arg Gly Lys Thr Tyr 215 220 225Gln Thr Leu Glu Glu Phe Val Val Ser Pro Cys Glu Arg Cys Arg 230 235 240Cys Glu Ala Asn Gly Glu Val Leu Cys Thr Val Ser Ala Cys Pro 245 250 255Gln Thr Glu Cys Val Asp Pro Val Tyr Glu Pro Asp Gln Cys Cys 260 265 270Pro Ile Cys Lys Asn Gly Pro Asn Cys Phe Ala Glu Thr Ala Val 275 280 285Ile Pro Ala Gly Arg Glu Val Lys Thr Asp Glu Cys Thr Ile Cys 290 295 300His Cys Thr Tyr Glu Glu Gly Thr Trp Arg Ile Glu Arg Gln Ala 305 310 315Met Cys Thr Arg His Glu Cys Arg Gln Met 320 325572725DNAHomo sapiens 57ggaggcggag gccgcggcga gccgggccga gcagtgaggg ccctagcggg 50gcccgagcgg ggcccggggc ccctaagcca ttcctgaagt catgggctgg 100ccaggacatt ggtgacccgc caatccggta tggacgactg gaagcccagc 150cccctcatca agccctttgg ggctcggaag aagcggagct ggtaccttac 200ctggaagtat aaactgacaa accagcgggc cctgcggaga ttctgtcaga 250caggggccgt gcttttcctg ctggtgactg tcattgtcaa tatcaagttg 300atcctggaca ctcggcgagc catcagtgaa gccaatgaag acccagagcc 350agagcaagac tatgatgagg ccctaggccg cctggagccc ccacggcgca 400gaggcagtgg tccccggcgg gtcctggacg tagaggtgta ttcaagtcgc 450agcaaagtat atgtggcagt ggatggcacc acggtgctgg aggatgaggc 500ccgggagcag ggccggggca tccatgtcat tgtcctcaac caggccacgg 550gccacgtgat ggcaaaacgt gtgtttgaca cgtactcacc tcatgaggat 600gaggccatgg tgctattcct caacatggta gcgcccggcc gagtgctcat 650ctgcactgtc aaggatgagg gctccttcca cctcaaggac acagccaagg 700ctctgctgag gagcctgggc agccaggctg gccctgccct gggctggagg 750gacacatggg ccttcgtggg acgaaaagga ggtcctgtct tcggggagaa 800acattctaag tcacctgccc tctcttcctg gggggaccca gtcctgctga 850agacagatgt gccattgagc tcagcagaag aggcagagtg ccactgggca 900gacacagagc tgaaccgtcg ccgccggcgc ttctgcagca aagttgaggg 950ctatggaagt gtatgcagct gcaaggaccc cacacccatc gagttcagcc 1000ctgacccact cccagacaac aaggtcctca atgtgcctgt ggctgtcatt 1050gcagggaacc gacccaatta cctgtacagg atgctgcgct ctctgctttc 1100agcccagggg gtgtctcctc agatgataac agttttcatt gacggctact 1150atgaggaacc catggatgtg gtggcactgt ttggtctgag gggcatccag 1200catactccca tcagcatcaa gaatgcccgc gtgtctcagc actacaaggc 1250cagcctcact gccactttca acctgtttcc ggaggccaag tttgctgtgg 1300ttctggaaga ggacctggac attgctgtgg attttttcag tttcctgagc 1350caatccatcc acctactgga ggaggatgac agcctgtact gcatctctgc 1400ctggaatgac caggggtatg aacacacggc tgaggaccca gcactactgt 1450accgtgtgga gaccatgcct gggctgggct gggtgctcag gaggtccttg 1500tacaaggagg agcttgagcc caagtggcct acaccggaaa agctctggga 1550ttgggacatg tggatgcgga tgcctgaaca acgccggggc cgagagtgca 1600tcatccctga cgtttcccga tcctaccact ttggcatcgt cggcctcaac 1650atgaatggct actttcacga ggcctacttc aagaagcaca agttcaacac 1700ggttccaggt gtccagctca ggaatgtgga cagtctgaag aaagaagctt 1750atgaagtgga agttcacagg ctgctcagtg aggctgaggt tctggaccac 1800agcaagaacc cttgtgaaga ctctttcctg ccagacacag agggccacac 1850ctacgtggcc tttattcgaa tggagaaaga tgatgacttc accacctgga 1900cccagcttgc caagtgcctc catatctggg acctggatgt gcgtggcaac 1950catcggggcc tgtggagatt gtttcggaag aagaaccact tcctggtggt 2000gggggtcccg gcttccccct actcagtgaa gaagccaccc tcagtcaccc 2050caattttcct ggagccaccc ccaaaggagg agggagcccc aggagcccca 2100gaacagacat gagacctcct ccaggaccct gcggggctgg gtactgtgta 2150cccccaggct ggctagccct tccctccatc ctgtaggatt ttgtagatgc 2200tggtaggggc tggggctacc ttgtttttaa catgagactt aattactaac 2250tccaagggga gggttcccct gctccaacac cccgttcctg agttaaaagt 2300ctatttattt acttccttgt tggagaaggg caggagagta cctgggaatc 2350attacgatcc ctagcagctc atcctgccct ttgaataccc tcactttcca 2400ggcctggctc agaatctaac ctatttattg actgtcctga gggccttgaa 2450aacaggccga acctggaggg cctggatttc tttttgggct ggaatgctgc 2500cctgagggtg gggctggctc ttactcagga aactgctgtg cccaacccat 2550ggacaggccc agctggggcc cacatgctga cacagactca ctcagagacc 2600cttagacact ggaccaggcc tcctctcagc cttctctttg tccagatttc 2650caaagctgga taagttggtc attgattaaa aaaggagaag ccctctggga 2700aaaaaaaaaa aaaaaaaaaa aaaaa 272558660PRTHomo sapiens 58Met Asp Asp Trp Lys Pro Ser Pro Leu Ile Lys Pro Phe Gly Ala1 5 10 15Arg Lys Lys Arg Ser Trp Tyr Leu Thr Trp Lys Tyr Lys Leu Thr 20 25 30Asn Gln Arg Ala Leu Arg Arg Phe Cys Gln Thr Gly Ala Val Leu 35 40 45Phe Leu Leu Val Thr Val Ile Val Asn Ile Lys Leu Ile Leu Asp 50 55 60Thr Arg Arg Ala Ile Ser Glu Ala Asn Glu Asp Pro Glu Pro Glu 65 70 75Gln Asp Tyr Asp Glu Ala Leu Gly Arg Leu Glu Pro Pro Arg Arg 80 85 90Arg Gly Ser Gly Pro Arg Arg Val Leu Asp Val Glu Val Tyr Ser 95 100 105Ser Arg Ser Lys Val Tyr Val Ala Val Asp Gly Thr Thr Val Leu 110 115 120Glu Asp Glu Ala Arg Glu Gln Gly Arg Gly Ile His Val Ile Val 125 130 135Leu Asn Gln Ala Thr Gly His Val Met Ala Lys Arg Val Phe Asp 140 145 150Thr Tyr Ser Pro His Glu Asp Glu Ala Met Val Leu Phe Leu Asn 155 160 165Met Val Ala Pro Gly Arg Val Leu Ile Cys Thr Val Lys Asp Glu 170 175 180Gly Ser Phe His Leu Lys Asp Thr Ala Lys Ala Leu Leu Arg Ser 185 190 195Leu Gly Ser Gln Ala Gly Pro Ala Leu Gly Trp Arg Asp Thr Trp 200 205 210Ala Phe Val Gly Arg Lys Gly Gly Pro Val Phe Gly Glu Lys His 215 220 225Ser Lys Ser Pro Ala Leu Ser Ser Trp Gly Asp Pro Val Leu Leu 230 235 240Lys Thr Asp Val Pro Leu Ser Ser Ala Glu Glu Ala Glu Cys His 245 250 255Trp Ala Asp Thr Glu Leu Asn Arg Arg Arg Arg Arg Phe Cys Ser 260 265 270Lys Val Glu Gly Tyr Gly Ser Val Cys Ser Cys Lys Asp Pro Thr 275 280 285Pro Ile Glu Phe Ser Pro Asp Pro Leu Pro Asp Asn Lys Val Leu 290 295 300Asn Val Pro Val Ala Val Ile Ala Gly Asn Arg Pro Asn Tyr Leu 305 310 315Tyr Arg Met Leu Arg Ser Leu Leu Ser Ala Gln Gly Val Ser Pro 320 325 330Gln Met Ile Thr Val Phe Ile Asp Gly Tyr Tyr Glu Glu Pro Met 335 340 345Asp Val Val Ala Leu Phe Gly Leu Arg Gly Ile Gln His Thr Pro 350 355 360Ile Ser Ile Lys Asn Ala Arg Val Ser Gln His Tyr Lys Ala Ser 365 370 375Leu Thr Ala Thr Phe Asn Leu Phe Pro Glu Ala Lys Phe Ala Val 380 385 390Val Leu Glu Glu Asp Leu Asp Ile Ala Val Asp Phe Phe Ser Phe 395 400 405Leu Ser Gln Ser Ile His Leu Leu Glu Glu Asp Asp Ser Leu Tyr 410 415 420Cys Ile Ser Ala Trp Asn Asp Gln Gly Tyr Glu His Thr Ala Glu 425 430 435Asp Pro Ala Leu Leu Tyr Arg Val Glu Thr Met Pro Gly Leu Gly 440 445 450Trp Val Leu Arg Arg Ser Leu Tyr Lys Glu Glu Leu Glu Pro Lys 455 460 465Trp Pro Thr Pro Glu Lys Leu Trp Asp Trp Asp Met Trp Met Arg 470 475 480Met Pro Glu Gln Arg Arg Gly Arg Glu Cys Ile Ile Pro Asp Val 485 490 495Ser Arg Ser Tyr His Phe Gly Ile Val Gly Leu Asn Met Asn Gly 500 505 510Tyr Phe His Glu Ala Tyr Phe Lys Lys His Lys Phe Asn Thr Val 515 520 525Pro Gly Val Gln Leu Arg Asn Val Asp Ser Leu Lys Lys Glu Ala 530 535 540Tyr Glu Val Glu Val His Arg Leu Leu Ser Glu Ala Glu Val Leu 545 550 555Asp His Ser Lys Asn Pro Cys Glu Asp Ser Phe Leu Pro Asp Thr 560 565 570Glu Gly His Thr Tyr Val Ala Phe Ile Arg Met Glu Lys Asp Asp 575 580 585Asp Phe Thr Thr Trp Thr Gln Leu Ala Lys Cys Leu His Ile Trp 590 595 600Asp Leu Asp Val Arg Gly Asn His Arg Gly Leu Trp Arg Leu Phe 605 610 615Arg Lys Lys Asn His Phe Leu Val Val Gly Val Pro Ala Ser Pro 620 625 630Tyr Ser Val Lys Lys Pro Pro Ser Val Thr Pro Ile Phe Leu Glu 635 640 645Pro Pro Pro Lys Glu Glu Gly Ala Pro Gly Ala Pro Glu Gln Thr 650 655 660592084DNAHomo sapiens 59ggttcctggg cgctctgtta cacaagcaag atacagccag ccccacctaa 50ttttgtttcc ctggcaccct cctgctcagt gcgacattgt cacacttaac 100ccatctgttt tctctaatgc acgacagatt cctttcagac aggacaactg 150tgatatttca gttcctgatt gtaaatacct cctaagcctg aagcttctgt 200tactagccat tgtgagcttc agtttcttca tctgcaaaat gggcataata 250caatctattc ttgccacatc aagggattgt tattccttta aaaaaaaacc 300aataccaaag aagcctacaa tgttggcctt agccaaaatt ctgttgattt 350caacgttgtt ttattcactt ctatcgggga gccatggaaa agaaaatcaa 400gacataaaca caacacagaa cattgcagaa gtttttaaaa caatggaaaa 450taaacctatt tctttggaaa gtgaagcaaa cttaaactca gataaagaaa 500atataaccac ctcaaatctc aaggcgagtc attcccctcc tttgaatcta 550cccaacaaca gccacggaat aacagatttc tccagtaact catcagcaga 600gcattctttg ggcagtctaa aacccacatc taccatttcc acaagccctc 650ccttgatcca tagctttgtt tctaaagtgc cttggaatgc acctatagca 700gatgaagatc ttttgcccat ctcagcacat cccaatgcta cacctgctct 750gtcttcagaa aacttcactt ggtctttggt caatgacacc gtgaaaactc 800ctgataacag ttccattaca gttagcatcc tctcttcaga accaacttct 850ccatctgtga cccccttgat agtggaacca agtggatggc ttaccacaaa 900cagtgatagc ttcactgggt ttacccctta tcaagaaaaa acaactctac 950agcctacctt aaaattcacc aataattcaa aactctttcc aaatacgtca 1000gatccccaaa aagaaaatag aaatacagga atagtattcg gggccatttt 1050aggtgctatt ctgggtgtct cattgcttac tcttgtgggc tacttgttgt 1100gtggaaaaag gaaaacggat tcattttccc atcggcgact ttatgacgac 1150agaaatgaac cagttctgcg attagacaat gcaccggaac cttatgatgt 1200gagttttggg aattctagct actacaatcc aactttgaat gattcagcca 1250tgccagaaag tgaagaaaat gcacgtgatg gcattcctat ggatgacata 1300cctccacttc gtacttctgt atagaactaa cagcaaaaag gcgttaaaca 1350gcaagtgtca tctacatcct agccttttga caaattcatc tttcaaaagg 1400ttacacaaaa ttactgtcac gtggattttg tcaaggagaa tcataaaagc 1450aggagaccag tagcagaaat gtagacagga tgtatcatcc aaaggttttc 1500tttcttacaa tttttggcca tcctgaggca tttactaagt agccttaatt 1550tgtattttag tagtattttc ttagtagaaa atatttgtgg aatcagataa 1600aactaaaaga tttcaccatt acagccctgc ctcataacta aataataaaa 1650attattccac caaaaaattc taaaacaatg aagatgactc tttactgctc 1700tgcctgaagc cctagtacca taattcaaga ttgcattttc ttaaatgaaa 1750attgaaaggg tgctttttaa agaaaatttg acttaaagct aaaaagagga 1800catagcccag agtttctgtt attgggaaat tgaggcaata gaaatgacag 1850acctgtattc tagtacgtta taattttcta gatcagcaca cacatgatca 1900gcccactgag ttatgaagct gacaatgact gcattcaacg gggccatggc 1950aggaaagctg accctaccca ggaaagtaat agcttcttta aaagtcttca 2000aaggttttgg gaattttaac ttgtcttaat atatcttagg cttcaattat 2050ttgggtgcct taaaaactca atgagaatca tggt 208460334PRTHomo sapiens 60Met Leu Ala Leu Ala Lys Ile Leu Leu Ile Ser Thr Leu Phe Tyr1 5 10 15Ser Leu Leu Ser Gly Ser His Gly Lys Glu Asn Gln Asp Ile Asn 20 25 30Thr Thr Gln Asn Ile Ala Glu Val Phe Lys Thr Met Glu Asn Lys 35 40 45Pro Ile Ser Leu Glu Ser Glu Ala Asn Leu Asn Ser Asp Lys Glu 50 55 60Asn Ile Thr Thr Ser Asn Leu Lys Ala Ser His Ser Pro Pro Leu 65 70 75Asn Leu Pro Asn Asn Ser His Gly Ile Thr Asp Phe Ser Ser Asn 80 85 90Ser Ser Ala Glu His Ser Leu Gly Ser Leu Lys Pro Thr Ser Thr 95 100 105Ile Ser Thr Ser Pro Pro Leu Ile His Ser Phe Val Ser Lys Val 110 115 120Pro Trp Asn Ala Pro Ile Ala Asp Glu

Asp Leu Leu Pro Ile Ser 125 130 135Ala His Pro Asn Ala Thr Pro Ala Leu Ser Ser Glu Asn Phe Thr 140 145 150Trp Ser Leu Val Asn Asp Thr Val Lys Thr Pro Asp Asn Ser Ser 155 160 165Ile Thr Val Ser Ile Leu Ser Ser Glu Pro Thr Ser Pro Ser Val 170 175 180Thr Pro Leu Ile Val Glu Pro Ser Gly Trp Leu Thr Thr Asn Ser 185 190 195Asp Ser Phe Thr Gly Phe Thr Pro Tyr Gln Glu Lys Thr Thr Leu 200 205 210Gln Pro Thr Leu Lys Phe Thr Asn Asn Ser Lys Leu Phe Pro Asn 215 220 225Thr Ser Asp Pro Gln Lys Glu Asn Arg Asn Thr Gly Ile Val Phe 230 235 240Gly Ala Ile Leu Gly Ala Ile Leu Gly Val Ser Leu Leu Thr Leu 245 250 255Val Gly Tyr Leu Leu Cys Gly Lys Arg Lys Thr Asp Ser Phe Ser 260 265 270His Arg Arg Leu Tyr Asp Asp Arg Asn Glu Pro Val Leu Arg Leu 275 280 285Asp Asn Ala Pro Glu Pro Tyr Asp Val Ser Phe Gly Asn Ser Ser 290 295 300Tyr Tyr Asn Pro Thr Leu Asn Asp Ser Ala Met Pro Glu Ser Glu 305 310 315Glu Asn Ala Arg Asp Gly Ile Pro Met Asp Asp Ile Pro Pro Leu 320 325 330Arg Thr Ser Val612397DNAHomo sapiens 61agagaaagaa gcgtctccag ctgaagccaa tgcagccctc cggctctccg 50cgaagaagtt ccctgccccg atgagccccc gccgtgcgtc cccgactatc 100cccaggcggg cgtggggcac cgggcccagc gccgacgatc gctgccgttt 150tgcccttggg agtaggatgt ggtgaaagga tggggcttct cccttacggg 200gctcacaatg gccagagaag attccgtgaa gtgtctgcgc tgcctgctct 250acgccctcaa tctgctcttt tggttaatgt ccatcagtgt gttggcagtt 300tctgcttgga tgagggacta cctaaataat gttctcactt taactgcaga 350aacgagggta gaggaagcag tcattttgac ttactttcct gtggttcatc 400cggtcatgat tgctgtttgc tgtttcctta tcattgtggg gatgttagga 450tattgtggaa cggtgaaaag aaatctgttg cttcttgcat ggtactttgg 500aagtttgctt gtcattttct gtgtagaact ggcttgtggc gtttggacat 550atgaacagga acttatggtt ccagtacaat ggtcagatat ggtcactttg 600aaagccagga tgacaaatta tggattacct agatatcggt ggcttactca 650tgcttggaat ttttttcaga gagagtttaa gtgctgtgga gtagtatatt 700tcactgactg gttggaaatg acagagatgg actggccccc agattcctgc 750tgtgttagag aattcccagg atgttccaaa caggcccacc aggaagatct 800cagtgacctt tatcaagagg gttgtgggaa gaaaatgtat tcctttttga 850gaggaaccaa acaactgcag gtgctgaggt ttctgggaat ctccattggg 900gtgacacaaa tcctggccat gattctcacc attactctgc tctgggctct 950gtattatgat agaagggagc ctgggacaga ccaaatgatg tccttgaaga 1000atgacaactc tcagcacctg tcatgtccct cagtagaact gttgaaacca 1050agcctgtcaa gaatctttga acacacatcc atggcaaaca gctttaatac 1100acactttgag atggaggagt tataaaaaga aatgtcacag aagaaaacca 1150caaacttgtt ttattggact tgtgaatttt tgagtacata ctatgtgttt 1200cagaaatatg tagaaataaa aatgttgcca taaaataaca cctaagcata 1250tactattcta tgctttaaaa tgaggatgga aaagtttcat gtcataagtc 1300accacctgga caataattga tgcccttaaa atgctgaaga cagatgtcat 1350acccactgtg tagcctgtgt atgactttta ctgaacacag ttatgttttg 1400aggcagcatg gtttgattag catttccgca tccatgcaaa cgagtcacat 1450atggtgggac tggagccata gtaaaggttg atttacttct accaactagt 1500atataaagta ctaattaaat gctaacatag gaagttagaa aatactaata 1550acttttatta ctcagcgatc tattcttctg atgctaaata aattatatat 1600cagaaaactt tcaatattgg tgactaccta aatgtgattt ttgctggtta 1650ctaaaatatt cttaccactt aaaagagcaa gctaacacat tgtcttaagc 1700tgatcaggga ttttttgtat ataagtctgt gttaaatctg tataattcag 1750tcgatttcag ttctgataat gttaagaata accattatga aaaggaaaat 1800ttgtcctgta tagcatcatt atttttagcc tttcctgtta ataaagcttt 1850actattctgt cctgggctta tattacacat ataactgtta tttaaatact 1900taaccactaa ttttgaaaat taccagtgtg atacatagga atcattattc 1950agaatgtagt ctggtcttta ggaagtatta ataagaaaat ttgcacataa 2000cttagttgat tcagaaagga cttgtatgct gtttttctcc caaatgaaga 2050ctctttttga cactaaacac tttttaaaaa gcttatcttt gccttctcca 2100aacaagaagc aatagtctcc aagtcaatat aaattctaca gaaaatagtg 2150ttctttttct ccagaaaaat gcttgtgaga atcattaaaa catgtgacaa 2200tttagagatt ctttgtttta tttcactgat taatatactg tggcaaatta 2250cacagattat taaatttttt tacaagagta tagtatattt atttgaaatg 2300ggaaaagtgc attttactgt attttgtgta ttttgtttat ttctcagaat 2350atggaaagaa aattaaaatg tgtcaataaa tattttctag agagtaa 239762305PRTHomo sapiens 62Met Ala Arg Glu Asp Ser Val Lys Cys Leu Arg Cys Leu Leu Tyr1 5 10 15Ala Leu Asn Leu Leu Phe Trp Leu Met Ser Ile Ser Val Leu Ala 20 25 30Val Ser Ala Trp Met Arg Asp Tyr Leu Asn Asn Val Leu Thr Leu 35 40 45Thr Ala Glu Thr Arg Val Glu Glu Ala Val Ile Leu Thr Tyr Phe 50 55 60Pro Val Val His Pro Val Met Ile Ala Val Cys Cys Phe Leu Ile 65 70 75Ile Val Gly Met Leu Gly Tyr Cys Gly Thr Val Lys Arg Asn Leu 80 85 90Leu Leu Leu Ala Trp Tyr Phe Gly Ser Leu Leu Val Ile Phe Cys 95 100 105Val Glu Leu Ala Cys Gly Val Trp Thr Tyr Glu Gln Glu Leu Met 110 115 120Val Pro Val Gln Trp Ser Asp Met Val Thr Leu Lys Ala Arg Met 125 130 135Thr Asn Tyr Gly Leu Pro Arg Tyr Arg Trp Leu Thr His Ala Trp 140 145 150Asn Phe Phe Gln Arg Glu Phe Lys Cys Cys Gly Val Val Tyr Phe 155 160 165Thr Asp Trp Leu Glu Met Thr Glu Met Asp Trp Pro Pro Asp Ser 170 175 180Cys Cys Val Arg Glu Phe Pro Gly Cys Ser Lys Gln Ala His Gln 185 190 195Glu Asp Leu Ser Asp Leu Tyr Gln Glu Gly Cys Gly Lys Lys Met 200 205 210Tyr Ser Phe Leu Arg Gly Thr Lys Gln Leu Gln Val Leu Arg Phe 215 220 225Leu Gly Ile Ser Ile Gly Val Thr Gln Ile Leu Ala Met Ile Leu 230 235 240Thr Ile Thr Leu Leu Trp Ala Leu Tyr Tyr Asp Arg Arg Glu Pro 245 250 255Gly Thr Asp Gln Met Met Ser Leu Lys Asn Asp Asn Ser Gln His 260 265 270Leu Ser Cys Pro Ser Val Glu Leu Leu Lys Pro Ser Leu Ser Arg 275 280 285Ile Phe Glu His Thr Ser Met Ala Asn Ser Phe Asn Thr His Phe 290 295 300Glu Met Glu Glu Leu 305632010DNAHomo sapiens 63ggaaaaactg ttctcttctg tggcacagag aaccctgctt caaagcagaa 50gtagcagttc cggagtccag ctggctaaaa ctcatcccag aggataatgg 100caacccatgc cttagaaatc gctgggctgt ttcttggtgg tgttggaatg 150gtgggcacag tggctgtcac tgtcatgcct cagtggagag tgtcggcctt 200cattgaaaac aacatcgtgg tttttgaaaa cttctgggaa ggactgtgga 250tgaattgcgt gaggcaggct aacatcagga tgcagtgcaa aatctatgat 300tccctgctgg ctctttctcc ggacctacag gcagccagag gactgatgtg 350tgctgcttcc gtgatgtcct tcttggcttt catgatggcc atccttggca 400tgaaatgcac caggtgcacg ggggacaatg agaaggtgaa ggctcacatt 450ctgctgacgg ctggaatcat cttcatcatc acgggcatgg tggtgctcat 500ccctgtgagc tgggttgcca atgccatcat cagagatttc tataactcaa 550tagtgaatgt tgcccaaaaa cgtgagcttg gagaagctct ctacttagga 600tggaccacgg cactggtgct gattgttgga ggagctctgt tctgctgcgt 650tttttgttgc aacgaaaaga gcagtagcta cagatactcg ataccttccc 700atcgcacaac ccaaaaaagt tatcacaccg gaaagaagtc accgagcgtc 750tactccagaa gtcagtatgt gtagttgtgt atgttttttt aactttacta 800taaagccatg caaatgacaa aaatctatat tactttctca aaatggaccc 850caaagaaact ttgatttact gttcttaact gcctaatctt aattacagga 900actgtgcatc agctatttat gattctataa gctatttcag cagaatgaga 950tattaaaccc aatgctttga ttgttctaga aagtatagta atttgttttc 1000taaggtggtt caagcatcta ctctttttat catttacttc aaaatgacat 1050tgctaaagac tgcattattt tactactgta atttctccac gacatagcat 1100tatgtacata gatgagtgta acatttatat ctcacataga gacatgctta 1150tatggtttta tttaaaatga aatgccagtc cattacactg aataaataga 1200actcaactat tgcttttcag ggaaatcatg gatagggttg aagaaggtta 1250ctattaattg tttaaaaaca gcttagggat taatgtcctc catttataat 1300gaagattaaa atgaaggctt taatcagcat tgtaaaggaa attgaatggc 1350tttctgatat gctgtttttt agcctaggag ttagaaatcc taacttcttt 1400atcctcttct cccagaggct ttttttttct tgtgtattaa attaacattt 1450ttaaaacgca gatattttgt caaggggctt tgcattcaaa ctgcttttcc 1500agggctatac tcagaagaaa gataaaagtg tgatctaaga aaaagtgatg 1550gttttaggaa agtgaaaata tttttgtttt tgtatttgaa gaagaatgat 1600gcattttgac aagaaatcat atatgtatgg atatatttta ataagtattt 1650gagtacagac tttgaggttt catcaatata aataaaagag cagaaaaata 1700tgtcttggtt ttcatttgct taccaaaaaa acaacaacaa aaaaagttgt 1750cctttgagaa cttcacctgc tcctatgtgg gtacctgagt caaaattgtc 1800atttttgttc tgtgaaaaat aaatttcctt cttgtaccat ttctgtttag 1850ttttactaaa atctgtaaat actgtatttt tctgtttatt ccaaatttga 1900tgaaactgac aatccaattt gaaagtttgt gtcgacgtct gtctagctta 1950aatgaatgtg ttctatttgc tttatacatt tatattaata aattgtacat 2000ttttctaatt 201064225PRTHomo sapiens 64Met Ala Thr His Ala Leu Glu Ile Ala Gly Leu Phe Leu Gly Gly1 5 10 15Val Gly Met Val Gly Thr Val Ala Val Thr Val Met Pro Gln Trp 20 25 30Arg Val Ser Ala Phe Ile Glu Asn Asn Ile Val Val Phe Glu Asn 35 40 45Phe Trp Glu Gly Leu Trp Met Asn Cys Val Arg Gln Ala Asn Ile 50 55 60Arg Met Gln Cys Lys Ile Tyr Asp Ser Leu Leu Ala Leu Ser Pro 65 70 75Asp Leu Gln Ala Ala Arg Gly Leu Met Cys Ala Ala Ser Val Met 80 85 90Ser Phe Leu Ala Phe Met Met Ala Ile Leu Gly Met Lys Cys Thr 95 100 105Arg Cys Thr Gly Asp Asn Glu Lys Val Lys Ala His Ile Leu Leu 110 115 120Thr Ala Gly Ile Ile Phe Ile Ile Thr Gly Met Val Val Leu Ile 125 130 135Pro Val Ser Trp Val Ala Asn Ala Ile Ile Arg Asp Phe Tyr Asn 140 145 150Ser Ile Val Asn Val Ala Gln Lys Arg Glu Leu Gly Glu Ala Leu 155 160 165Tyr Leu Gly Trp Thr Thr Ala Leu Val Leu Ile Val Gly Gly Ala 170 175 180Leu Phe Cys Cys Val Phe Cys Cys Asn Glu Lys Ser Ser Ser Tyr 185 190 195Arg Tyr Ser Ile Pro Ser His Arg Thr Thr Gln Lys Ser Tyr His 200 205 210Thr Gly Lys Lys Ser Pro Ser Val Tyr Ser Arg Ser Gln Tyr Val 215 220 225651114DNAHomo sapiens 65cggacgcgtg ggcggacgcg tgggcggacg cgtgggtctc tgcggggaga 50cgccagcctg cgtctgccat ggggctcggg ttgaggggct ggggacgtcc 100tctgctgact gtggccaccg ccctgatgct gcccgtgaag ccccccgcag 150gctcctgggg ggcccagatc atcgggggcc acgaggtgac cccccactcc 200aggccctaca tggcatccgt gcgcttcggg ggccaacatc actgcggagg 250cttcctgctg cgagcccgct gggtggtctc ggccgcccac tgcttcagcc 300acagagacct ccgcactggc ctggtggtgc tgggcgccca cgtcctgagt 350actgcggagc ccacccagca ggtgtttggc atcgatgctc tcaccacgca 400ccccgactac caccccatga cccacgccaa cgacatctgc ctgctgcggc 450tgaacggctc tgctgtcctg ggccctgcag tggggctgct gaggctgcca 500gggagaaggg ccaggccccc cacagcgggg acacggtgcc gggtggctgg 550ctggggcttc gtgtctgact ttgaggagct gccgcctgga ctgatggagg 600ccaaggtccg agtgctggac ccggacgtct gcaacagctc ctggaagggc 650cacctgacac ttaccatgct ctgcacccgc agtggggaca gccacagacg 700gggcttctgc tcggccgact ccggagggcc cctggtgtgc aggaaccggg 750ctcacggcct cgtttccttc tcgggcctct ggtgcggcga ccccaagacc 800cccgacgtgt acacgcaggt gtccgccttt gtggcctgga tctgggacgt 850ggttcggcgg agcagtcccc agcccggccc cctgcctggg accaccaggc 900ccccaggaga agccgcctga gccacaacct tgcggcatgc aaatgagatg 950gccgctccag gcctggaatg ttccgtggct gggccccacg ggaagcctga 1000tgttcagggt tggggtggga cgggcagcgg tggggcacac ccattccaca 1050tgcaaagggc agaagcaaac ccagtaaaat gttaactgac aaaaaaaaaa 1100aaaaaaaaaa gaaa 111466283PRTHomo sapiens 66Met Gly Leu Gly Leu Arg Gly Trp Gly Arg Pro Leu Leu Thr Val1 5 10 15Ala Thr Ala Leu Met Leu Pro Val Lys Pro Pro Ala Gly Ser Trp 20 25 30Gly Ala Gln Ile Ile Gly Gly His Glu Val Thr Pro His Ser Arg 35 40 45Pro Tyr Met Ala Ser Val Arg Phe Gly Gly Gln His His Cys Gly 50 55 60Gly Phe Leu Leu Arg Ala Arg Trp Val Val Ser Ala Ala His Cys 65 70 75Phe Ser His Arg Asp Leu Arg Thr Gly Leu Val Val Leu Gly Ala 80 85 90His Val Leu Ser Thr Ala Glu Pro Thr Gln Gln Val Phe Gly Ile 95 100 105Asp Ala Leu Thr Thr His Pro Asp Tyr His Pro Met Thr His Ala 110 115 120Asn Asp Ile Cys Leu Leu Arg Leu Asn Gly Ser Ala Val Leu Gly 125 130 135Pro Ala Val Gly Leu Leu Arg Leu Pro Gly Arg Arg Ala Arg Pro 140 145 150Pro Thr Ala Gly Thr Arg Cys Arg Val Ala Gly Trp Gly Phe Val 155 160 165Ser Asp Phe Glu Glu Leu Pro Pro Gly Leu Met Glu Ala Lys Val 170 175 180Arg Val Leu Asp Pro Asp Val Cys Asn Ser Ser Trp Lys Gly His 185 190 195Leu Thr Leu Thr Met Leu Cys Thr Arg Ser Gly Asp Ser His Arg 200 205 210Arg Gly Phe Cys Ser Ala Asp Ser Gly Gly Pro Leu Val Cys Arg 215 220 225Asn Arg Ala His Gly Leu Val Ser Phe Ser Gly Leu Trp Cys Gly 230 235 240Asp Pro Lys Thr Pro Asp Val Tyr Thr Gln Val Ser Ala Phe Val 245 250 255Ala Trp Ile Trp Asp Val Val Arg Arg Ser Ser Pro Gln Pro Gly 260 265 270Pro Leu Pro Gly Thr Thr Arg Pro Pro Gly Glu Ala Ala 275 280672272DNAHomo sapiens 67ccgccgccgc agccgctacc gccgctgcag ccgctttccg cggcctgggc 50ctctcgccgt cagcatgcca cacgccttca agcccgggga cttggtgttc 100gctaagatga agggctaccc tcactggcct gccaggatcg acgacatcgc 150ggatggcgcc gtgaagcccc cacccaacaa gtaccccatc tttttctttg 200gcacacacga aacagccttc ctgggaccca aggacctgtt cccctacgac 250aaatgtaaag acaagtacgg gaagcccaac aagaggaaag gcttcaatga 300agggctgtgg gagatccaga acaaccccca cgccagctac agcgcccctc 350cgccagtgag ctcctccgac agcgaggccc ccgaggccaa ccccgccgac 400ggcagtgacg ctgacgagga cgatgaggac cggggggtca tggccgtcac 450agcggtaacc gccacagctg ccagcgacag gatggagagc gactcagact 500cagacaagag tagcgacaac agtggcctga agaggaagac gcctgcgcta 550aagatgtcgg tctcgaaacg agcccgaaag gcctccagcg acctggatca 600ggccagcgtg tccccatccg aagaggagaa ctcggaaagc tcatctgagt 650cggagaagac cagcgaccag gacttcacac ctgagaagaa agcagcggtc 700cgggcgccac ggaggggccc tctgggggga cggaaaaaaa agaaggcgcc 750gtcagcctcc gactccgact ccaaggccga ttcggacggg gccaagcctg 800agccggtggc catggcgcgg tcggcgtcct cctcctcctc ttcctcctcc 850tcctccgact ccgatgtgtc tgtgaagaag cctccgaggg gcaggaagcc 900agcggagaag cctctcccga agccgcgagg gcggaaaccg aagcctgaac 950ggcctccgtc cagctccagc agtgacagtg acagcgacga ggtggaccgc 1000atcagtgagt ggaagcggcg ggacgaggcg cggaggcgcg agctggaggc 1050ccggcggcgg cgagagcagg aggaggagct gcggcgcctg cgggagcagg 1100agaaggagga gaaggagcgg aggcgcgagc gggccgaccg cggggaggct 1150gagcggggca gcggcggcag cagcggggac gagctcaggg aggacgatga 1200gcccgtcaag aagcggggac gcaagggccg gggccggggt cccccgtcct 1250cctctgactc cgagcccgag gccgagctgg agagagaggc caagaaatca 1300gcgaagaagc cgcagtcctc aagcacagag cccgccagga

aacctggcca 1350gaaggagaag agagtgcggc ccgaggagaa gcaacaagcc aagcccgtga 1400aggtggagcg gacccggaag cggtccgagg gcttctcgat ggacaggaag 1450gtagagaaga agaaagagcc ctccgtggag gagaagctgc agaagctgca 1500cagtgagatc aagtttgccc taaaggtcga cagcccggac gtgaagaggt 1550gcctgaatgc cctagaggag ctgggaaccc tgcaggtgac ctctcagatc 1600ctccagaaga acacagacgt ggtggccacc ttgaagaaga ttcgccgtta 1650caaagcgaac aaggacgtaa tggagaaggc agcagaagtc tatacccggc 1700tcaagtcgcg ggtcctcggc ccaaagatcg aggcggtgca gaaagtgaac 1750aaggctggga tggagaagga gaaggccgag gagaagctgg ccggggagga 1800gctggccggg gaggaggccc cccaggagaa ggcggaggac aagcccagca 1850ccgatctctc agccccagtg aatggcgagg ccacatcaca gaagggggag 1900agcgcagagg acaaggagca cgaggagggt cgggactcgg aggaggggcc 1950aaggtgtggc tcctctgaag acctgcacga cagcgtacgg gagggtcccg 2000acctggacag gcctgggagc gaccggcagg agcgcgagag ggcacggggg 2050gactcggagg ccctggacga ggagagctga gccgcgggca gccaggccca 2100gcccccgccc gagctcaggc tgcccctctc cttccccggc tcgcaggaga 2150gcagagcaga gaactgtggg gaacgctgtg ctgtttgtat ttgttccctt 2200gggttttttt ttcctgccta atttctgtga tttccaacca acatgaaatg 2250actataaacg gttttttaat ga 227268671PRTHomo sapiens 68Met Pro His Ala Phe Lys Pro Gly Asp Leu Val Phe Ala Lys Met1 5 10 15Lys Gly Tyr Pro His Trp Pro Ala Arg Ile Asp Asp Ile Ala Asp 20 25 30Gly Ala Val Lys Pro Pro Pro Asn Lys Tyr Pro Ile Phe Phe Phe 35 40 45Gly Thr His Glu Thr Ala Phe Leu Gly Pro Lys Asp Leu Phe Pro 50 55 60Tyr Asp Lys Cys Lys Asp Lys Tyr Gly Lys Pro Asn Lys Arg Lys 65 70 75Gly Phe Asn Glu Gly Leu Trp Glu Ile Gln Asn Asn Pro His Ala 80 85 90Ser Tyr Ser Ala Pro Pro Pro Val Ser Ser Ser Asp Ser Glu Ala 95 100 105Pro Glu Ala Asn Pro Ala Asp Gly Ser Asp Ala Asp Glu Asp Asp 110 115 120Glu Asp Arg Gly Val Met Ala Val Thr Ala Val Thr Ala Thr Ala 125 130 135Ala Ser Asp Arg Met Glu Ser Asp Ser Asp Ser Asp Lys Ser Ser 140 145 150Asp Asn Ser Gly Leu Lys Arg Lys Thr Pro Ala Leu Lys Met Ser 155 160 165Val Ser Lys Arg Ala Arg Lys Ala Ser Ser Asp Leu Asp Gln Ala 170 175 180Ser Val Ser Pro Ser Glu Glu Glu Asn Ser Glu Ser Ser Ser Glu 185 190 195Ser Glu Lys Thr Ser Asp Gln Asp Phe Thr Pro Glu Lys Lys Ala 200 205 210Ala Val Arg Ala Pro Arg Arg Gly Pro Leu Gly Gly Arg Lys Lys 215 220 225Lys Lys Ala Pro Ser Ala Ser Asp Ser Asp Ser Lys Ala Asp Ser 230 235 240Asp Gly Ala Lys Pro Glu Pro Val Ala Met Ala Arg Ser Ala Ser 245 250 255Ser Ser Ser Ser Ser Ser Ser Ser Ser Asp Ser Asp Val Ser Val 260 265 270Lys Lys Pro Pro Arg Gly Arg Lys Pro Ala Glu Lys Pro Leu Pro 275 280 285Lys Pro Arg Gly Arg Lys Pro Lys Pro Glu Arg Pro Pro Ser Ser 290 295 300Ser Ser Ser Asp Ser Asp Ser Asp Glu Val Asp Arg Ile Ser Glu 305 310 315Trp Lys Arg Arg Asp Glu Ala Arg Arg Arg Glu Leu Glu Ala Arg 320 325 330Arg Arg Arg Glu Gln Glu Glu Glu Leu Arg Arg Leu Arg Glu Gln 335 340 345Glu Lys Glu Glu Lys Glu Arg Arg Arg Glu Arg Ala Asp Arg Gly 350 355 360Glu Ala Glu Arg Gly Ser Gly Gly Ser Ser Gly Asp Glu Leu Arg 365 370 375Glu Asp Asp Glu Pro Val Lys Lys Arg Gly Arg Lys Gly Arg Gly 380 385 390Arg Gly Pro Pro Ser Ser Ser Asp Ser Glu Pro Glu Ala Glu Leu 395 400 405Glu Arg Glu Ala Lys Lys Ser Ala Lys Lys Pro Gln Ser Ser Ser 410 415 420Thr Glu Pro Ala Arg Lys Pro Gly Gln Lys Glu Lys Arg Val Arg 425 430 435Pro Glu Glu Lys Gln Gln Ala Lys Pro Val Lys Val Glu Arg Thr 440 445 450Arg Lys Arg Ser Glu Gly Phe Ser Met Asp Arg Lys Val Glu Lys 455 460 465Lys Lys Glu Pro Ser Val Glu Glu Lys Leu Gln Lys Leu His Ser 470 475 480Glu Ile Lys Phe Ala Leu Lys Val Asp Ser Pro Asp Val Lys Arg 485 490 495Cys Leu Asn Ala Leu Glu Glu Leu Gly Thr Leu Gln Val Thr Ser 500 505 510Gln Ile Leu Gln Lys Asn Thr Asp Val Val Ala Thr Leu Lys Lys 515 520 525Ile Arg Arg Tyr Lys Ala Asn Lys Asp Val Met Glu Lys Ala Ala 530 535 540Glu Val Tyr Thr Arg Leu Lys Ser Arg Val Leu Gly Pro Lys Ile 545 550 555Glu Ala Val Gln Lys Val Asn Lys Ala Gly Met Glu Lys Glu Lys 560 565 570Ala Glu Glu Lys Leu Ala Gly Glu Glu Leu Ala Gly Glu Glu Ala 575 580 585Pro Gln Glu Lys Ala Glu Asp Lys Pro Ser Thr Asp Leu Ser Ala 590 595 600Pro Val Asn Gly Glu Ala Thr Ser Gln Lys Gly Glu Ser Ala Glu 605 610 615Asp Lys Glu His Glu Glu Gly Arg Asp Ser Glu Glu Gly Pro Arg 620 625 630Cys Gly Ser Ser Glu Asp Leu His Asp Ser Val Arg Glu Gly Pro 635 640 645Asp Leu Asp Arg Pro Gly Ser Asp Arg Gln Glu Arg Glu Arg Ala 650 655 660Arg Gly Asp Ser Glu Ala Leu Asp Glu Glu Ser 665 670692340DNAHomo sapiens 69gagcggagta aaatctccac aagctgggaa caaacctcgt cccaactccc 50acccaccggc gtttctccag ctcgatctgg aggctgcttc gccagtgtgg 100gacgcagctg acgcccgctt attagctctc gctgcgtcgc cccggctcag 150aagctccgtg gcggcggcga ccgtgacgag aagcccacgg ccagctcagt 200tctcttctac tttgggagag agagaaagtc agatgcccct tttaaactcc 250ctcttcaaaa ctcatctcct gggtgactga gttaatagag tggatacaac 300cttgctgaag atgaagaata tacaatattg aggatatttt tttctttttt 350ttttcaagtc ttgatttgtg gcttacctca agttaccatt tttcagtcaa 400gtctgtttgt ttgcttcttc agaaatgttt tttacaatct caagaaaaaa 450tatgtcccag aaattgagtt tactgttgct tgtatttgga ctcatttggg 500gattgatgtt actgcactat acttttcaac aaccaagaca tcaaagcagt 550gtcaagttac gtgagcaaat actagactta agcaaaagat atgttaaagc 600tctagcagag gaaaataaga acacagtgga tgtcgagaac ggtgcttcta 650tggcaggata tgcggatctg aaaagaacaa ttgctgtcct tctggatgac 700attttgcaac gattggtgaa gctggagaac aaagttgact atattgttgt 750gaatggctca gcagccaaca ccaccaatgg tactagtggg aatttggtgc 800cagtaaccac aaataaaaga acgaatgtct cgggcagtat cagatagcag 850ttgaaaatca ccttgtgctg ctccatccac tgtggattat atcctatggc 900agaaaagctt tataattgct ggcttaggac agagcaatac tttacaataa 950aagctctaca cattttcaag gagtatgctg gattcatgga actctaattc 1000tgtacataaa aattttaaag ttatttgttt gctttcaggc aagtctgttc 1050aatgctgtac tatgtcctta aagagaattt ggtaacttgg ttgatgtggt 1100aagcagatag gtgagttttg tataaatctt ttgtgtttga gatcaagctg 1150aaatgaaaac actgaaaaac atggattcat ttctataaca catttattta 1200agtatataac acgttttttg gacaagtgaa gaatgtttaa tcattctgtc 1250atttgttctc aatagatgta actgttagac tacggctatt tgaaaaaatg 1300tgcttattgt actatatttt gttattccaa ttatgagcag agaaaggaaa 1350tataatgttg aaaataatgt tttgaaatca tgacccaaag aatgtattga 1400tttgcactat ccttcagaat aactgaaggt taattattgt atatttttaa 1450aaattacact tataagagta taatcttgaa atgggtagca gccactgtcc 1500attacctatc gtaaacattg gggcaattta ataacagcat taaaatagtt 1550gtaaactcta atcttatact tattgaagaa taaaagatat ttttatgatg 1600agagtaacaa taaagtattc atgatttttc acatacatga atgttcattt 1650aaaagtttaa tcctttgagt gtctatgcta tcaggaaagc acattatttc 1700catatttggg ttaattttgc ttttattata ttggtctagg aggaagggac 1750tttggagaat ggaactcttg aggactttag ccaggtgtat ataataaagg 1800tacttttgtg ctgcattaaa ttgcttggaa agtgttaaca ttatattata 1850taagagtatc ctttatgaaa ttttgaattt gtataacaga tgcattagat 1900attcatttta tataatggcc acttaaaata agaacattta aaatataaac 1950tatgaagatt gactatcttt tcaggaaaaa agctgtatat agcacaggga 2000accctaatct tgggtaattc tagtataaaa caaattatac ttttatttaa 2050atttcccttg tagcaaatct aattgccaca tggtgcccta tatttcatag 2100tatttattct ctatagtaac tgcttaagtg cagctagctt ctagatttag 2150actatataga atttagatat tgtattgttc gtcattataa tatgctacca 2200catgtagcaa taattacaat attttattaa aataaatatg tgaaatattg 2250tttcatgaaa gacagatttc caaatctctc ttctcttctc tgtactgtct 2300acctttatgt gaagaaatta attatatgcc attgccaggt 234070140PRTHomo sapiens 70Met Phe Phe Thr Ile Ser Arg Lys Asn Met Ser Gln Lys Leu Ser1 5 10 15Leu Leu Leu Leu Val Phe Gly Leu Ile Trp Gly Leu Met Leu Leu 20 25 30His Tyr Thr Phe Gln Gln Pro Arg His Gln Ser Ser Val Lys Leu 35 40 45Arg Glu Gln Ile Leu Asp Leu Ser Lys Arg Tyr Val Lys Ala Leu 50 55 60Ala Glu Glu Asn Lys Asn Thr Val Asp Val Glu Asn Gly Ala Ser 65 70 75Met Ala Gly Tyr Ala Asp Leu Lys Arg Thr Ile Ala Val Leu Leu 80 85 90Asp Asp Ile Leu Gln Arg Leu Val Lys Leu Glu Asn Lys Val Asp 95 100 105Tyr Ile Val Val Asn Gly Ser Ala Ala Asn Thr Thr Asn Gly Thr 110 115 120Ser Gly Asn Leu Val Pro Val Thr Thr Asn Lys Arg Thr Asn Val 125 130 135Ser Gly Ser Ile Arg 140712379DNAHomo sapiens 71gctgagcgtg tgcgcggtac ggggctctcc tgccttctgg gctccaacgc 50agctctgtgg ctgaactggg tgctcatcac gggaactgct gggctatgga 100atacagatgt ggcagctcag gtagccccaa attgcctgga agaatacatc 150atgtttttcg ataagaagaa attgtaggat ccagtttttt ttttaaccgc 200cccctcccca ccccccaaaa aaactgtaaa gatgcaaaaa cgtaatatcc 250atgaagatcc tattacctag gaagattttg atgttttgct gcgaatgcgg 300tgttgggatt tatttgttct tggagtgttc tgcgtggctg gcaaagaata 350atgttccaaa atcggtccat ctcccaaggg gtccaatttt tcttcctggg 400tgtcagcgag ccctgactca ctacagtgca gctgacaggg gctgtcatgc 450aactggcccc taagccaaag caaaagacct aaggacgacc tttgaacaat 500acaaaggatg ggtttcaatg taattaggct actgagcgga tcagctgtag 550cactggttat agcccccact gtcttactga caatgctttc ttctgccgaa 600cgaggatgcc ctaagggctg taggtgtgaa ggcaaaatgg tatattgtga 650atctcagaaa ttacaggaga taccctcaag tatatctgct ggttgcttag 700gtttgtccct tcgctataac agccttcaaa aacttaagta taatcaattt 750aaagggctca accagctcac ctggctatac cttgaccata accatatcag 800caatattgac gaaaatgctt ttaatggaat acgcagactc aaagagctga 850ttcttagttc caatagaatc tcctattttc ttaacaatac cttcagacct 900gtgacaaatt tacggaactt ggatctgtcc tataatcagc tgcattctct 950gggatctgaa cagtttcggg gcttgcggaa gctgctgagt ttacatttac 1000ggtctaactc cctgagaacc atccctgtgc gaatattcca agactgccgc 1050aacctggaac ttttggacct gggatataac cggatccgaa gtttagccag 1100gaatgtcttt gctggcatga tcagactcaa agaacttcac ctggagcaca 1150atcaattttc caagctcaac ctggcccttt ttccaaggtt ggtcagcctt 1200cagaaccttt acttgcagtg gaataaaatc agtgtcatag gacagaccat 1250gtcctggacc tggagctcct tacaaaggct tgatttatca ggcaatgaga 1300tcgaagcttt cagtggaccc agtgttttcc agtgtgtccc gaatctgcag 1350cgcctcaacc tggattccaa caagctcaca tttattggtc aagagatttt 1400ggattcttgg atatccctca atgacatcag tcttgctggg aatatatggg 1450aatgcagcag aaatatttgc tcccttgtaa actggctgaa aagttttaaa 1500ggtctaaggg agaatacaat tatctgtgcc agtcccaaag agctgcaagg 1550agtaaatgtg atcgatgcag tgaagaacta cagcatctgt ggcaaaagta 1600ctacagagag gtttgatctg gccagggctc tcccaaagcc gacgtttaag 1650cccaagctcc ccaggccgaa gcatgagagc aaaccccctt tgcccccgac 1700ggtgggagcc acagagcccg gcccagagac cgatgctgac gccgagcaca 1750tctctttcca taaaatcatc gcgggcagcg tggcgctttt cctgtccgtg 1800ctcgtcatcc tgctggttat ctacgtgtca tggaagcggt accctgcgag 1850catgaagcag ctgcagcagc gctccctcat gcgaaggcac aggaaaaaga 1900aaagacagtc cctaaagcaa atgactccca gcacccagga attttatgta 1950gattataaac ccaccaacac ggagaccagc gagatgctgc tgaatgggac 2000gggaccctgc acctataaca aatcgggctc cagggagtgt gaggtatgaa 2050ccattgtgat aaaaagagct cttaaaagct gggaaataag tggtgcttta 2100ttgaactctg gtgactatca agggaacgcg atgccccccc tccccttccc 2150tctccctctc actttggtgg caagatcctt ccttgtccgt tttagtgcat 2200tcataatact ggtcattttc ctctcataca taatcaaccc attgaaattt 2250aaataccaca atcaatgtga agcttgaact ccggtttaat ataataccta 2300ttgtataaga ccctttactg attccattaa tgtcgcattt gttttaagat 2350aaaacttctt tcataggtaa aaaaaaaaa 237972513PRTHomo sapiens 72Met Gly Phe Asn Val Ile Arg Leu Leu Ser Gly Ser Ala Val Ala1 5 10 15Leu Val Ile Ala Pro Thr Val Leu Leu Thr Met Leu Ser Ser Ala 20 25 30Glu Arg Gly Cys Pro Lys Gly Cys Arg Cys Glu Gly Lys Met Val 35 40 45Tyr Cys Glu Ser Gln Lys Leu Gln Glu Ile Pro Ser Ser Ile Ser 50 55 60Ala Gly Cys Leu Gly Leu Ser Leu Arg Tyr Asn Ser Leu Gln Lys 65 70 75Leu Lys Tyr Asn Gln Phe Lys Gly Leu Asn Gln Leu Thr Trp Leu 80 85 90Tyr Leu Asp His Asn His Ile Ser Asn Ile Asp Glu Asn Ala Phe 95 100 105Asn Gly Ile Arg Arg Leu Lys Glu Leu Ile Leu Ser Ser Asn Arg 110 115 120Ile Ser Tyr Phe Leu Asn Asn Thr Phe Arg Pro Val Thr Asn Leu 125 130 135Arg Asn Leu Asp Leu Ser Tyr Asn Gln Leu His Ser Leu Gly Ser 140 145 150Glu Gln Phe Arg Gly Leu Arg Lys Leu Leu Ser Leu His Leu Arg 155 160 165Ser Asn Ser Leu Arg Thr Ile Pro Val Arg Ile Phe Gln Asp Cys 170 175 180Arg Asn Leu Glu Leu Leu Asp Leu Gly Tyr Asn Arg Ile Arg Ser 185 190 195Leu Ala Arg Asn Val Phe Ala Gly Met Ile Arg Leu Lys Glu Leu 200 205 210His Leu Glu His Asn Gln Phe Ser Lys Leu Asn Leu Ala Leu Phe 215 220 225Pro Arg Leu Val Ser Leu Gln Asn Leu Tyr Leu Gln Trp Asn Lys 230 235 240Ile Ser Val Ile Gly Gln Thr Met Ser Trp Thr Trp Ser Ser Leu 245 250 255Gln Arg Leu Asp Leu Ser Gly Asn Glu Ile Glu Ala Phe Ser Gly 260 265 270Pro Ser Val Phe Gln Cys Val Pro Asn Leu Gln Arg Leu Asn Leu 275 280 285Asp Ser Asn Lys Leu Thr Phe Ile Gly Gln Glu Ile Leu Asp Ser 290 295 300Trp Ile Ser Leu Asn Asp Ile Ser Leu Ala Gly Asn Ile Trp Glu 305 310 315Cys Ser Arg Asn Ile Cys Ser Leu Val Asn Trp Leu Lys Ser Phe 320 325 330Lys Gly Leu Arg Glu Asn Thr Ile Ile Cys Ala Ser Pro Lys Glu 335 340 345Leu Gln Gly Val Asn Val Ile Asp Ala Val Lys Asn Tyr Ser Ile 350 355 360Cys Gly Lys Ser Thr Thr Glu Arg Phe Asp Leu Ala Arg Ala Leu 365 370 375Pro Lys Pro Thr Phe Lys Pro Lys Leu Pro Arg Pro Lys His Glu 380 385 390Ser Lys Pro Pro Leu Pro Pro Thr Val Gly Ala Thr Glu Pro Gly 395 400 405Pro Glu Thr Asp Ala Asp Ala Glu His Ile Ser Phe His Lys Ile 410 415 420Ile Ala Gly Ser Val Ala Leu Phe Leu Ser Val Leu Val Ile Leu 425 430 435Leu Val Ile Tyr Val Ser Trp Lys Arg Tyr

Pro Ala Ser Met Lys 440 445 450Gln Leu Gln Gln Arg Ser Leu Met Arg Arg His Arg Lys Lys Lys 455 460 465Arg Gln Ser Leu Lys Gln Met Thr Pro Ser Thr Gln Glu Phe Tyr 470 475 480Val Asp Tyr Lys Pro Thr Asn Thr Glu Thr Ser Glu Met Leu Leu 485 490 495Asn Gly Thr Gly Pro Cys Thr Tyr Asn Lys Ser Gly Ser Arg Glu 500 505 510Cys Glu Val 732339DNAHomo sapiens 73ccaaggccag agctgtggac accttatccc actcatcctc atcctcttcc 50tctgataaag cccctaccag tgctgataaa gtctttctcg tgagagccta 100gaggccttaa aaaaaaaagt gcttgaaaga gaaggggaca aaggaacacc 150agtattaaga ggattttcca gtgtttctgg cagttggtcc agaaggatgc 200ctccattcct gcttctcacc tgcctcttca tcacaggcac ctccgtgtca 250cccgtggccc tagatccttg ttctgcttac atcagcctga atgagccctg 300gaggaacact gaccaccagt tggatgagtc tcaaggtcct cctctatgtg 350acaaccatgt gaatggggag tggtaccact tcacgggcat ggcgggagat 400gccatgccta ccttctgcat accagaaaac cactgtggaa cccacgcacc 450tgtctggctc aatggcagcc accccctaga aggcgacggc attgtgcaac 500gccaggcttg tgccagcttc aatgggaact gctgtctctg gaacaccacg 550gtggaagtca aggcttgccc tggaggctac tatgtgtatc gtctgaccaa 600gcccagcgtc tgcttccacg tctactgtgg tcatttttat gacatctgcg 650acgaggactg ccatggcagc tgctcagata ccagcgagtg cacatgcgct 700ccaggaactg tgctaggccc tgacaggcag acatgctttg atgaaaatga 750atgtgagcaa aacaacggtg gctgcagtga gatctgtgtg aacctcaaaa 800actcctaccg ctgtgagtgt ggggttggcc gtgtgctaag aagtgatggc 850aagacttgtg aagacgttga aggatgccac aataacaatg gtggctgcag 900ccactcttgc cttggatctg agaaaggcta ccagtgtgaa tgtccccggg 950gcctggtgct gtctgaggat aaccacactt gccaagtccc tgtgttgtgc 1000aaatcaaatg ccattgaagt gaacatcccc agggagctgg ttggtggcct 1050ggagctcttc ctgaccaaca cctcctgccg aggagtgtcc aacggcaccc 1100atgtcaacat cctcttctct ctcaagacat gtggtacagt ggtcgatgtg 1150gtgaatgaca agattgtggc cagcaacctc gtgacaggtc tacccaagca 1200gaccccgggg agcagcgggg acttcatcat ccgaaccagc aagctgctga 1250tcccggtgac ctgcgagttt ccacgcctgt acaccatttc tgaaggatac 1300gttcccaacc ttcgaaactc cccactggaa atcatgagcc gaaatcatgg 1350gatcttccca ttcactctgg agatcttcaa ggacaatgag tttgaagagc 1400cttaccggga agctctgccc accctcaagc ttcgtgactc cctctacttt 1450ggcattgagc ccgtggtgca cgtgagcggc ttggaaagct tggtggagag 1500ctgctttgcc acccccacct ccaagatcga cgaggtcctg aaatactacc 1550tcatccggga tggctgtgtt tcagatgact cggtaaagca gtacacatcc 1600cgggatcacc tagcaaagca cttccaggtc cctgtcttca agtttgtggg 1650caaagaccac aaggaagtgt ttctgcactg ccgggttctt gtctgtggag 1700tgttggacga gcgttcccgc tgtgcccagg gttgccaccg gcgaatgcgt 1750cgtggggcag gaggagagga ctcagccggt ctacagggcc agacgctaac 1800aggcggcccg atccgcatcg actgggagga ctagttcgta gccatacctc 1850gagtccctgc attggacggc tctgctcttt ggagcttctc cccccaccgc 1900cctctaagaa catctgccaa cagctgggtt cagacttcac actgtgagtt 1950cagactccca gcaccaactc actctgattc tggtccattc agtgggcaca 2000ggtcacagca ctgctgaaca atgtggcctg ggtggggttt catctttcta 2050gggttgaaaa ctaaactgtc cacccagaaa gacactcacc ccatttccct 2100catttctttc ctacacttaa atacctcgtg tatggtgcaa tcagaccaca 2150aaatcagaag ctgggtataa tatttcaagt tacaaaccct agaaaaatta 2200aacagttact gaaattatga cttaaatacc caatgactcc ttaaatatgt 2250aaattatagt tataccttga aatttcaatt caaatgcaga ctaattatag 2300ggaatttgga agtgtatcaa taaaacagta tataatttt 233974545PRTHomo sapiens 74Met Pro Pro Phe Leu Leu Leu Thr Cys Leu Phe Ile Thr Gly Thr1 5 10 15Ser Val Ser Pro Val Ala Leu Asp Pro Cys Ser Ala Tyr Ile Ser 20 25 30Leu Asn Glu Pro Trp Arg Asn Thr Asp His Gln Leu Asp Glu Ser 35 40 45Gln Gly Pro Pro Leu Cys Asp Asn His Val Asn Gly Glu Trp Tyr 50 55 60His Phe Thr Gly Met Ala Gly Asp Ala Met Pro Thr Phe Cys Ile 65 70 75Pro Glu Asn His Cys Gly Thr His Ala Pro Val Trp Leu Asn Gly 80 85 90Ser His Pro Leu Glu Gly Asp Gly Ile Val Gln Arg Gln Ala Cys 95 100 105Ala Ser Phe Asn Gly Asn Cys Cys Leu Trp Asn Thr Thr Val Glu 110 115 120Val Lys Ala Cys Pro Gly Gly Tyr Tyr Val Tyr Arg Leu Thr Lys 125 130 135Pro Ser Val Cys Phe His Val Tyr Cys Gly His Phe Tyr Asp Ile 140 145 150Cys Asp Glu Asp Cys His Gly Ser Cys Ser Asp Thr Ser Glu Cys 155 160 165Thr Cys Ala Pro Gly Thr Val Leu Gly Pro Asp Arg Gln Thr Cys 170 175 180Phe Asp Glu Asn Glu Cys Glu Gln Asn Asn Gly Gly Cys Ser Glu 185 190 195Ile Cys Val Asn Leu Lys Asn Ser Tyr Arg Cys Glu Cys Gly Val 200 205 210Gly Arg Val Leu Arg Ser Asp Gly Lys Thr Cys Glu Asp Val Glu 215 220 225Gly Cys His Asn Asn Asn Gly Gly Cys Ser His Ser Cys Leu Gly 230 235 240Ser Glu Lys Gly Tyr Gln Cys Glu Cys Pro Arg Gly Leu Val Leu 245 250 255Ser Glu Asp Asn His Thr Cys Gln Val Pro Val Leu Cys Lys Ser 260 265 270Asn Ala Ile Glu Val Asn Ile Pro Arg Glu Leu Val Gly Gly Leu 275 280 285Glu Leu Phe Leu Thr Asn Thr Ser Cys Arg Gly Val Ser Asn Gly 290 295 300Thr His Val Asn Ile Leu Phe Ser Leu Lys Thr Cys Gly Thr Val 305 310 315Val Asp Val Val Asn Asp Lys Ile Val Ala Ser Asn Leu Val Thr 320 325 330Gly Leu Pro Lys Gln Thr Pro Gly Ser Ser Gly Asp Phe Ile Ile 335 340 345Arg Thr Ser Lys Leu Leu Ile Pro Val Thr Cys Glu Phe Pro Arg 350 355 360Leu Tyr Thr Ile Ser Glu Gly Tyr Val Pro Asn Leu Arg Asn Ser 365 370 375Pro Leu Glu Ile Met Ser Arg Asn His Gly Ile Phe Pro Phe Thr 380 385 390Leu Glu Ile Phe Lys Asp Asn Glu Phe Glu Glu Pro Tyr Arg Glu 395 400 405Ala Leu Pro Thr Leu Lys Leu Arg Asp Ser Leu Tyr Phe Gly Ile 410 415 420Glu Pro Val Val His Val Ser Gly Leu Glu Ser Leu Val Glu Ser 425 430 435Cys Phe Ala Thr Pro Thr Ser Lys Ile Asp Glu Val Leu Lys Tyr 440 445 450Tyr Leu Ile Arg Asp Gly Cys Val Ser Asp Asp Ser Val Lys Gln 455 460 465Tyr Thr Ser Arg Asp His Leu Ala Lys His Phe Gln Val Pro Val 470 475 480Phe Lys Phe Val Gly Lys Asp His Lys Glu Val Phe Leu His Cys 485 490 495Arg Val Leu Val Cys Gly Val Leu Asp Glu Arg Ser Arg Cys Ala 500 505 510Gln Gly Cys His Arg Arg Met Arg Arg Gly Ala Gly Gly Glu Asp 515 520 525Ser Ala Gly Leu Gln Gly Gln Thr Leu Thr Gly Gly Pro Ile Arg 530 535 540Ile Asp Trp Glu Asp 545752524DNAHomo sapiens 75cgccaagcat gcagtaaagg ctgaaaatct gggtcacagc tgaggaagac 50ctcagacatg gagtccagga tgtggcctgc gctgctgctg tcccacctcc 100tccctctctg gccactgctg ttgctgcccc tcccaccgcc tgctcagggc 150tcttcatcct cccctcgaac cccaccagcc ccagcccgcc ccccgtgtgc 200caggggaggc ccctcggccc cacgtcatgt gtgcgtgtgg gagcgagcac 250ctccaccaag ccgatctcct cgggtcccaa gatcacgtcg gcaagtcctg 300cctggcactg cacccccagc caccccatca ggctttgagg aggggccgcc 350ctcatcccaa tacccctggg ctatcgtgtg gggtcccacc gtgtctcgag 400aggatggagg ggaccccaac tctgccaatc ccggatttct ggactatggt 450tttgcagccc ctcatgggct cgcaacccca caccccaact cagactccat 500gcgaggtgat ggagatgggc ttatccttgg agaggcacct gccaccctgc 550ggccattcct gttcgggggc cgtggggaag gtgtggaccc ccagctctat 600gtcacaatta ccatctccat catcattgtt ctcgtggcca ctggcatcat 650cttcaagttc tgctgggacc gcagccagaa gcgacgcaga ccctcagggc 700agcaaggtgc cctgaggcag gaggagagcc agcagccact gacagacctg 750tccccggctg gagtcactgt gctgggggcc ttcggggact cacctacccc 800cacccctgac catgaggagc cccgaggggg accccggcct gggatgcccc 850accccaaggg ggctccagcc ttccagttga accggtgagg gcaggggcaa 900tgggatggga gggcaaagag ggaaggcaac ttaggtcttc agagctgggg 950tgggggtgcc ctctggatgg gtagtgagga ggcaggcgtg gcctcccaca 1000gcccctggcc ctcccaaggg ggctggacca gctcctctct gggaggcacc 1050cttccttctc ccagtctctc aggatctgtg tcctattctc tgctgcccat 1100aactccaact ctgccctctt tggttttttc tcatgccacc ttgtctaaga 1150caactctgcc ctcttaacct tgattccccc tctttgtctt gaacttcccc 1200ttctattctg gcctacccct tggttcctga ctgtgccctt tccctcttcc 1250tctcaggatt cccctggtga atctgtgatg cccccaatgt tggggtgcag 1300ccaagcagga ggccaagggg ccggcacagc ccccatccca ctgagggtgg 1350ggcagctgtg gggagctggg gccacagggg ctcctggctc ctgccccttg 1400cacaccaccc ggaacactcc ccagccccac gggcaatcct atctgctcgc 1450cctcctgcag gtgggggcct cacatatctg tgacttcggg tccctgtccc 1500cacccttgtg cactcacatg aaagccttgc acactcacct ccaccttcac 1550aggccatttg cacacgctcc tgcaccctct ccccgtccat accgctccgc 1600tcagctgact ctcatgttct ctcgtctcac atttgcactc tctccttccc 1650acattctgtg ctcagctcac tcagtggtca gcgtttcctg cacactttac 1700ctctcatgtg cgtttcccgg cctgatgttg tggtggtgtg cggcgtgctc 1750actctctccc tcatgaacac ccacccacct cgtttccgca gcccctgcgt 1800gctgctccag aggtgggtgg gaggtgagct gggggctcct tgggccctca 1850tcggtcatgg tctcgtccca ttccacacca tttgtttctc tgtctcccca 1900tcctactcca aggatgccgg catcaccctg agggctcccc cttgggaatg 1950gggtagtgag gccccagact tcacccccag cccactgcta aaatctgttt 2000tctgacagat gggttttggg gagtcgcctg ctgcactaca tgagaaaggg 2050actcccattt gcccttccct ttctcctaca gtcccttttg tcttgtctgt 2100cctggctgtc tgtgtgtgtg ccattctctg gacttcagag ccccctgagc 2150cagtcctccc ttcccagcct ccctttgggc ctccctaact ccacctaggc 2200tgccagggac cggagtcagc tggttcaagg ccatcgggag ctctgcctcc 2250aagtctaccc ttcccttccc ggactccctc ctgtcccctc ctttcctccc 2300tccttccttc cactctcctt ccttttgctt ccctgccctt tccccctcct 2350caggttcttc cctccttctc actggttttt ccaccttcct ccttcccttc 2400ttccctggct cctaggctgt gatatatatt tttgtattat ctctttcttc 2450ttcttgtggt gatcatcttg aattactgtg ggatgtaagt ttcaaaattt 2500tcaaataaag cctttgcaag ataa 252476276PRTHomo sapiens 76Met Glu Ser Arg Met Trp Pro Ala Leu Leu Leu Ser His Leu Leu1 5 10 15Pro Leu Trp Pro Leu Leu Leu Leu Pro Leu Pro Pro Pro Ala Gln 20 25 30Gly Ser Ser Ser Ser Pro Arg Thr Pro Pro Ala Pro Ala Arg Pro 35 40 45Pro Cys Ala Arg Gly Gly Pro Ser Ala Pro Arg His Val Cys Val 50 55 60Trp Glu Arg Ala Pro Pro Pro Ser Arg Ser Pro Arg Val Pro Arg 65 70 75Ser Arg Arg Gln Val Leu Pro Gly Thr Ala Pro Pro Ala Thr Pro 80 85 90Ser Gly Phe Glu Glu Gly Pro Pro Ser Ser Gln Tyr Pro Trp Ala 95 100 105Ile Val Trp Gly Pro Thr Val Ser Arg Glu Asp Gly Gly Asp Pro 110 115 120Asn Ser Ala Asn Pro Gly Phe Leu Asp Tyr Gly Phe Ala Ala Pro 125 130 135His Gly Leu Ala Thr Pro His Pro Asn Ser Asp Ser Met Arg Gly 140 145 150Asp Gly Asp Gly Leu Ile Leu Gly Glu Ala Pro Ala Thr Leu Arg 155 160 165Pro Phe Leu Phe Gly Gly Arg Gly Glu Gly Val Asp Pro Gln Leu 170 175 180Tyr Val Thr Ile Thr Ile Ser Ile Ile Ile Val Leu Val Ala Thr 185 190 195Gly Ile Ile Phe Lys Phe Cys Trp Asp Arg Ser Gln Lys Arg Arg 200 205 210Arg Pro Ser Gly Gln Gln Gly Ala Leu Arg Gln Glu Glu Ser Gln 215 220 225Gln Pro Leu Thr Asp Leu Ser Pro Ala Gly Val Thr Val Leu Gly 230 235 240Ala Phe Gly Asp Ser Pro Thr Pro Thr Pro Asp His Glu Glu Pro 245 250 255Arg Gly Gly Pro Arg Pro Gly Met Pro His Pro Lys Gly Ala Pro 260 265 270Ala Phe Gln Leu Asn Arg 275772737DNAHomo sapiens 77ggctgcgccc aggccggcgg gcccagcagc tgcgaaccgc cggcgcacca 50cctgtttccg cgcccgggga cttccccggc ggggctcaga agtgtggggt 100cggtcgcttg gcttcccctg gcgtcagcga cccagggtaa cctcctccac 150tgctgcgtgc cgtgcaggcc tgcctgtgtg agagccacgt gtgccgcgct 200ctgggcacag ccttggaaag tcaggaccgc gacggcagca gagcagaaac 250cttacagaaa catgaagccc tcaaccatct gctactcagt tattcggggc 300tgacggcggc ttctagaaca tccaggtgtt ctgcagatgc gagaactcat 350cctgtagtca ccagatggag tcccaaacag ccaagcagat gtaaggcctg 400tgctgtggct ctgaggccct gaatacagaa gggtcacttt cttagtggcc 450aaagagcagt tgttgacatt gatgtctaat tattgaacac gaccagtcat 500tttactgagc tgcagtgagg aaacactgac catagaagat caagccaaat 550gagggattgc aaatttcctg attcttttga attaggattc cagatggggg 600cctcatttct acagccccca acattcctat agccgttatc actgccatca 650ccactgccac cagcatcttc ttgcagattc cacccctgct ccccagagac 700ttcctgcttt gaaagtgagc agaaaggaag ctctcagaaa aatctctagt 750ggtggctgcc gtcgctccag acaatcggaa tcctgccttc accaccatgg 800gctggctttt tctaaaggtt ttgttggcgg gagtgagttt ctcaggattt 850ctttatcctc ttgtggattt ttgcatcagt gggaaaacaa gaggacagaa 900gccaaacttt gtgattattt tggccgatga catggggtgg ggtgacctgg 950gagcaaactg ggcagaaaca aaggacactg ccaaccttga taagatggct 1000tcggagggaa tgaggtttgt ggatttccat gcagctgcct ccacctgctc 1050accctcccgg gcttccttgc tcaccggccg gcttggcctt cgcaatggag 1100tcacacgcaa ctttgcagtc acttctgtgg gaggccttcc gctcaacgag 1150accaccttgg cagaggtgct gcagcaggcg ggttacgtca ctgggataat 1200aggcaaatgg catcttggac accacggctc ttatcacccc aacttccgtg 1250gttttgatta ctactttgga atcccatata gccatgatat gggctgtact 1300gatactccag gctacaacca ccctccttgt ccagcgtgtc cacagggtga 1350tggaccatca aggaaccttc aaagagactg ttacactgac gtggccctcc 1400ctctttatga aaacctcaac attgtggagc agccggtgaa cttgagcagc 1450cttgcccaga agtatgctga gaaagcaacc cagttcatcc agcgtgcaag 1500caccagcggg aggcccttcc tgctctatgt ggctctggcc cacatgcacg 1550tgcccttacc tgtgactcag ctaccagcag cgccacgggg cagaagcctg 1600tatggtgcag ggctctggga gatggacagt ctggtgggcc agatcaagga 1650caaagttgac cacacagtga aggaaaacac attcctctgg tttacaggag 1700acaatggccc gtgggctcag aagtgtgagc tagcgggcag tgtgggtccc 1750ttcactggat tttggcaaac tcgtcaaggg ggaagtccag ccaagcagac 1800gacctgggaa ggagggcacc gggtcccagc actggcttac tggcctggca 1850gagttccagt taatgtcacc agcactgcct tgttaagcgt gctggacatt 1900tttccaactg tggtagccct ggcccaggcc agcttacctc aaggacggcg 1950ctttgatggt gtggacgtct ccgaggtgct ctttggccgg tcacagcctg 2000ggcacagggt gctgttccac cccaacagcg gggcagctgg agagtttgga 2050gccctgcaga ctgtccgcct ggagcgttac aaggccttct acattaccgg 2100tggagccagg gcgtgtgatg ggagcatggt gcctgagctg cagcataagt 2150ttcctctgat tttcaacctg gaagacgata ccgcagaagc tgtgccccta 2200gaaagaggtg gtgcggagta ccaggctgtg ctgcccgagg tcagaaaggt 2250tcttgcagac gtcctccaag acattgccaa cgacaacatc tccagcgcag 2300attacactca ggacccttca gtaactccct gctgtaatcc ctaccaaatt 2350gcctgccgct gtcaagccgc ataacagacc aatttttatt ccacgaggag 2400gagtacctgg aaattaggca agtttgcttc caaatttcat ttttaccctc 2450tttacaaaca cacgctttag tttagtcttg gagtttagtt ttggagttag 2500ccttgcatat cccttctgta tcctgtcccc cctccacgcc gacccgagag 2550cagctgagct gcgctggctc tgggcaggga gtgtgcctta atgggaagca 2600cacgggcttt ggagtcaggc acaggtgcca gctccagctt ttgaacttgg 2650gcaattgttt aacctaacct gcaagttgat tttgagggtt aaataaaggc 2700atacatgaaa atgcctggca actttaaaaa aaaaaaa

273778525PRTHomo sapiens 78Met Gly Trp Leu Phe Leu Lys Val Leu Leu Ala Gly Val Ser Phe1 5 10 15Ser Gly Phe Leu Tyr Pro Leu Val Asp Phe Cys Ile Ser Gly Lys 20 25 30Thr Arg Gly Gln Lys Pro Asn Phe Val Ile Ile Leu Ala Asp Asp 35 40 45Met Gly Trp Gly Asp Leu Gly Ala Asn Trp Ala Glu Thr Lys Asp 50 55 60Thr Ala Asn Leu Asp Lys Met Ala Ser Glu Gly Met Arg Phe Val 65 70 75Asp Phe His Ala Ala Ala Ser Thr Cys Ser Pro Ser Arg Ala Ser 80 85 90Leu Leu Thr Gly Arg Leu Gly Leu Arg Asn Gly Val Thr Arg Asn 95 100 105Phe Ala Val Thr Ser Val Gly Gly Leu Pro Leu Asn Glu Thr Thr 110 115 120Leu Ala Glu Val Leu Gln Gln Ala Gly Tyr Val Thr Gly Ile Ile 125 130 135Gly Lys Trp His Leu Gly His His Gly Ser Tyr His Pro Asn Phe 140 145 150Arg Gly Phe Asp Tyr Tyr Phe Gly Ile Pro Tyr Ser His Asp Met 155 160 165Gly Cys Thr Asp Thr Pro Gly Tyr Asn His Pro Pro Cys Pro Ala 170 175 180Cys Pro Gln Gly Asp Gly Pro Ser Arg Asn Leu Gln Arg Asp Cys 185 190 195Tyr Thr Asp Val Ala Leu Pro Leu Tyr Glu Asn Leu Asn Ile Val 200 205 210Glu Gln Pro Val Asn Leu Ser Ser Leu Ala Gln Lys Tyr Ala Glu 215 220 225Lys Ala Thr Gln Phe Ile Gln Arg Ala Ser Thr Ser Gly Arg Pro 230 235 240Phe Leu Leu Tyr Val Ala Leu Ala His Met His Val Pro Leu Pro 245 250 255Val Thr Gln Leu Pro Ala Ala Pro Arg Gly Arg Ser Leu Tyr Gly 260 265 270Ala Gly Leu Trp Glu Met Asp Ser Leu Val Gly Gln Ile Lys Asp 275 280 285Lys Val Asp His Thr Val Lys Glu Asn Thr Phe Leu Trp Phe Thr 290 295 300Gly Asp Asn Gly Pro Trp Ala Gln Lys Cys Glu Leu Ala Gly Ser 305 310 315Val Gly Pro Phe Thr Gly Phe Trp Gln Thr Arg Gln Gly Gly Ser 320 325 330Pro Ala Lys Gln Thr Thr Trp Glu Gly Gly His Arg Val Pro Ala 335 340 345Leu Ala Tyr Trp Pro Gly Arg Val Pro Val Asn Val Thr Ser Thr 350 355 360Ala Leu Leu Ser Val Leu Asp Ile Phe Pro Thr Val Val Ala Leu 365 370 375Ala Gln Ala Ser Leu Pro Gln Gly Arg Arg Phe Asp Gly Val Asp 380 385 390Val Ser Glu Val Leu Phe Gly Arg Ser Gln Pro Gly His Arg Val 395 400 405Leu Phe His Pro Asn Ser Gly Ala Ala Gly Glu Phe Gly Ala Leu 410 415 420Gln Thr Val Arg Leu Glu Arg Tyr Lys Ala Phe Tyr Ile Thr Gly 425 430 435Gly Ala Arg Ala Cys Asp Gly Ser Met Val Pro Glu Leu Gln His 440 445 450Lys Phe Pro Leu Ile Phe Asn Leu Glu Asp Asp Thr Ala Glu Ala 455 460 465Val Pro Leu Glu Arg Gly Gly Ala Glu Tyr Gln Ala Val Leu Pro 470 475 480Glu Val Arg Lys Val Leu Ala Asp Val Leu Gln Asp Ile Ala Asn 485 490 495Asp Asn Ile Ser Ser Ala Asp Tyr Thr Gln Asp Pro Ser Val Thr 500 505 510Pro Cys Cys Asn Pro Tyr Gln Ile Ala Cys Arg Cys Gln Ala Ala 515 520 525792639DNAHomo sapiens 79cgcggccggg ccgccggggt gagcgtgccg aggcggctgt ggcgcaggct 50tccagccccc accatgccgt ggcccctgct gctgctgctg gccgtgagtg 100gggcccagac aacccggcca tgcttccccg ggtgccaatg cgaggtggag 150accttcggcc ttttcgacag cttcagcctg actcgggtgg attgtagcgg 200cctgggcccc cacatcatgc cggtgcccat ccctctggac acagcccact 250tggacctgtc ctccaaccgg ctggagatgg tgaatgagtc ggtgttggcg 300gggccgggct acacgacgtt ggctggcctg gatctcagcc acaacctgct 350caccagcatc tcacccactg ccttctcccg ccttcgctac ctggagtcgc 400ttgacctcag ccacaatggc ctgacagccc tgccagccga gagcttcacc 450agctcacccc tgagcgacgt gaaccttagc cacaaccagc tccgggaggt 500ctcagtgtct gccttcacga cgcacagtca gggccgggca ctacacgtgg 550acctctccca caacctcatt caccgcctcg tgccccaccc cacgagggcc 600ggcctgcctg cgcccaccat tcagagcctg aacctggcct ggaaccggct 650ccatgccgtg cccaacctcc gagacttgcc cctgcgctac ctgagcctgg 700atgggaaccc tctagctgtc attggtccgg gtgccttcgc ggggctggga 750ggccttacac acctgtctct ggccagcctg cagaggctcc ctgagctggc 800gcccagtggc ttccgtgagc taccgggcct gcaggtcctg gacctgtcgg 850gcaaccccaa gcttaactgg gcaggagctg aggtgttttc aggcctgagc 900tccctgcagg agctggacct ttcgggcacc aacctggtgc ccctgcctga 950ggcgctgctc ctccacctcc cggcactgca gagcgtcagc gtgggccagg 1000atgtgcggtg ccggcgcctg gtgcgggagg gcacctaccc ccggaggcct 1050ggctccagcc ccaaggtgcc cctgcactgc gtagacaccc gggaatctgc 1100tgccaggggc cccaccatct tgtgacaaat ggtgtggccc agggccacat 1150aacagactgc tgtcctgggc tgcctcaggt cccgagtaac ttatgttcaa 1200tgtgccaaca ccagtgggga gcccgcaggc ctatgtggca gcgtcaccac 1250aggagttgtg ggcctaggag aggctttgga cctgggagcc acacctagga 1300gcaaagtctc acccctttgt ctacgttgct tccccaaacc atgagcagag 1350ggacttcgat gccaaaccag actcgggtcc cctcctgctt cccttcccca 1400cttatccccc aagtgccttc cctcatgcct gggccggcct gacccgcaat 1450gggcagaggg tgggtgggac cccctgctgc agggcagagt tcaggtccac 1500tgggctgagt gtccccttgg gcccatggcc cagtcactca ggggcgagtt 1550tcttttctaa catagccctt tctttgccat gaggccatga ggcccgcttc 1600atccttttct atttccctag aaccttaatg gtagaaggaa ttgcaaagaa 1650tcaagtccac ccttctcatg tgacagatgg ggaaactgag gccttgagaa 1700ggaaaaaggc taatctaagt tcctgcgggc agtggcatga ctggagcaca 1750gcctcctgcc tcccagcccg gacccaatgc actttcttgt ctcctctaat 1800aagccccacc ctccccgcct gggctcccct tgctgccctt gcctgttccc 1850cattagcaca ggagtagcag cagcaggaca ggcaagagcc tcacaagtgg 1900gactctgggc ctctgaccag ctgtgcggca tgggctaagt cactctgccc 1950ttcggagcct ctggaagctt agggcacatt ggttccagcc tagccagttt 2000ctcaccctgg gttggggtcc cccagcatcc agactggaaa cctacccatt 2050ttcccctgag catcctctag atgctgcccc aaggagttgc tgcagttctg 2100gagcctcatc tggctgggat ctccaagggg cctcctggat tcagtcccca 2150ctggccctga gcacgacagc ccttcttacc ctcccaggaa tgccgtgaaa 2200ggagacaagg tctgcccgac ccatgtctat gctctacccc cagggcagca 2250tctcagcttc cgaaccctgg gctgtttcct tagtcttcat tttataaaag 2300ttgttgcctt tttaacggag tgtcactttc aaccggcctc ccctacccct 2350gctggccggg gatggagaca tgtcatttgt aaaagcagaa aaaggttgca 2400tttgttcact tttgtaatat tgtcctgggc ctgtgttggg gtgttggggg 2450aagctgggca tcagtggcca catgggcatc aggggctggc cccacagaga 2500ccccacaggg cagtgagctc tgtcttcccc cacctgccta gcccatcatc 2550tatctaaccg gtccttgatt taataaacac tataaaaggt ttaaaaaaaa 2600aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaa 263980353PRTHomo sapiens 80Met Pro Trp Pro Leu Leu Leu Leu Leu Ala Val Ser Gly Ala Gln1 5 10 15Thr Thr Arg Pro Cys Phe Pro Gly Cys Gln Cys Glu Val Glu Thr 20 25 30Phe Gly Leu Phe Asp Ser Phe Ser Leu Thr Arg Val Asp Cys Ser 35 40 45Gly Leu Gly Pro His Ile Met Pro Val Pro Ile Pro Leu Asp Thr 50 55 60Ala His Leu Asp Leu Ser Ser Asn Arg Leu Glu Met Val Asn Glu 65 70 75Ser Val Leu Ala Gly Pro Gly Tyr Thr Thr Leu Ala Gly Leu Asp 80 85 90Leu Ser His Asn Leu Leu Thr Ser Ile Ser Pro Thr Ala Phe Ser 95 100 105Arg Leu Arg Tyr Leu Glu Ser Leu Asp Leu Ser His Asn Gly Leu 110 115 120Thr Ala Leu Pro Ala Glu Ser Phe Thr Ser Ser Pro Leu Ser Asp 125 130 135Val Asn Leu Ser His Asn Gln Leu Arg Glu Val Ser Val Ser Ala 140 145 150Phe Thr Thr His Ser Gln Gly Arg Ala Leu His Val Asp Leu Ser 155 160 165His Asn Leu Ile His Arg Leu Val Pro His Pro Thr Arg Ala Gly 170 175 180Leu Pro Ala Pro Thr Ile Gln Ser Leu Asn Leu Ala Trp Asn Arg 185 190 195Leu His Ala Val Pro Asn Leu Arg Asp Leu Pro Leu Arg Tyr Leu 200 205 210Ser Leu Asp Gly Asn Pro Leu Ala Val Ile Gly Pro Gly Ala Phe 215 220 225Ala Gly Leu Gly Gly Leu Thr His Leu Ser Leu Ala Ser Leu Gln 230 235 240Arg Leu Pro Glu Leu Ala Pro Ser Gly Phe Arg Glu Leu Pro Gly 245 250 255Leu Gln Val Leu Asp Leu Ser Gly Asn Pro Lys Leu Asn Trp Ala 260 265 270Gly Ala Glu Val Phe Ser Gly Leu Ser Ser Leu Gln Glu Leu Asp 275 280 285Leu Ser Gly Thr Asn Leu Val Pro Leu Pro Glu Ala Leu Leu Leu 290 295 300His Leu Pro Ala Leu Gln Ser Val Ser Val Gly Gln Asp Val Arg 305 310 315Cys Arg Arg Leu Val Arg Glu Gly Thr Tyr Pro Arg Arg Pro Gly 320 325 330Ser Ser Pro Lys Val Pro Leu His Cys Val Asp Thr Arg Glu Ser 335 340 345Ala Ala Arg Gly Pro Thr Ile Leu 350811572DNAHomo sapiens 81cgggccagcc tggggcggcc ggccaggaac cacccgttaa ggtgtcttct 50ctttagggat ggtgaggttg gaaaaagact cctgtaaccc tcctccagga 100tgaaccacct gccagaagac atggagaacg ctctcaccgg gagccagagc 150tcccatgctt ctctgcgcaa tatccattcc atcaacccca cacaactcat 200ggccaggatt gagtcctatg aaggaaggga aaagaaaggc atatctgatg 250tcaggaggac tttctgtttg tttgtcacct ttgacctctt attcgtaaca 300ttactgtgga taatagagtt aaatgtgaat ggaggcattg agaacacatt 350agagaaggag gtgatgcagt atgactacta ttcttcatat tttgatatat 400ttcttctggc agtttttcga tttaaagtgt taatacttgc atatgctgtg 450tgcagactgc gccattggtg ggcaatagcg ttgacaacgg cagtgaccag 500tgccttttta ctagcaaaag tgatcctttc gaagcttttc tctcaagggg 550cttttggcta tgtgctgccc atcatttcat tcatccttgc ctggattgag 600acgtggttcc tggatttcaa agtgttacct caagaagcag aagaagaaaa 650cagactcctg atagttcagg atgcttcaga gagggcagca cttatacctg 700gtggtctttc tgatggtcag ttttattccc ctcctgaatc cgaagcagga 750tctgaagaag ctgaagaaaa acaggacagt gagaaaccac ttttagaact 800atgagtacta cttttgttaa atgtgaaaaa ccctcacaga aagtcatcga 850ggcaaaaaga ggcaggcagt ggagtctccc tgtcgacagt aaagttgaaa 900tggtgacgtc cactgctggc tttattgaac agctaataaa gatttattta 950ttgtaatacc tcacaaacgt tgtaccatat ccatgcacat ttagttgcct 1000gcctgtggct ggtaaggtaa tgtcatgatt catcctctct tcagtgagac 1050tgagcctgat gtgttaacaa ataggtgaag aaagtcttgt gctgtattcc 1100taatcaaaag acttaatata ttgaagtaac acttttttag taagcaagat 1150acctttttat ttcaattcac agaatggaat ttttttgttt catgtctcag 1200atttattttg tatttctttt ttaacactct acatttccct tgttttttaa 1250ctcatgcaca tgtgctcttt gtacagtttt aaaaagtgta ataaaatctg 1300acatgtcaat gtggctagtt ttatttttct tgttttgcat tatgtgtatg 1350gcctgaagtg ttggacttgc aaaaggggaa gaaaggaatt gcgaatacat 1400gtaaaatgtc accagacatt tgtattattt ttatcatgaa atcatgtttt 1450tctctgattg ttctgaaatg ttctaaatac tcttattttg aatgcacaaa 1500atgacttaaa ccattcatat catgtttcct ttgcgttcag ccaatttcaa 1550ttaaaatgaa ctaaattaaa aa 157282234PRTHomo sapiens 82Met Asn His Leu Pro Glu Asp Met Glu Asn Ala Leu Thr Gly Ser1 5 10 15Gln Ser Ser His Ala Ser Leu Arg Asn Ile His Ser Ile Asn Pro 20 25 30Thr Gln Leu Met Ala Arg Ile Glu Ser Tyr Glu Gly Arg Glu Lys 35 40 45Lys Gly Ile Ser Asp Val Arg Arg Thr Phe Cys Leu Phe Val Thr 50 55 60Phe Asp Leu Leu Phe Val Thr Leu Leu Trp Ile Ile Glu Leu Asn 65 70 75Val Asn Gly Gly Ile Glu Asn Thr Leu Glu Lys Glu Val Met Gln 80 85 90Tyr Asp Tyr Tyr Ser Ser Tyr Phe Asp Ile Phe Leu Leu Ala Val 95 100 105Phe Arg Phe Lys Val Leu Ile Leu Ala Tyr Ala Val Cys Arg Leu 110 115 120Arg His Trp Trp Ala Ile Ala Leu Thr Thr Ala Val Thr Ser Ala 125 130 135Phe Leu Leu Ala Lys Val Ile Leu Ser Lys Leu Phe Ser Gln Gly 140 145 150Ala Phe Gly Tyr Val Leu Pro Ile Ile Ser Phe Ile Leu Ala Trp 155 160 165Ile Glu Thr Trp Phe Leu Asp Phe Lys Val Leu Pro Gln Glu Ala 170 175 180Glu Glu Glu Asn Arg Leu Leu Ile Val Gln Asp Ala Ser Glu Arg 185 190 195Ala Ala Leu Ile Pro Gly Gly Leu Ser Asp Gly Gln Phe Tyr Ser 200 205 210Pro Pro Glu Ser Glu Ala Gly Ser Glu Glu Ala Glu Glu Lys Gln 215 220 225Asp Ser Glu Lys Pro Leu Leu Glu Leu 230831882DNAHomo sapiens 83ccgtcatccc cctgcagcca cccttcccag agtcctttgc ccaggccacc 50ccaggcttct tggcagccct gccgggccac ttgtcttcat gtctgccagg 100gggaggtggg aaggaggtgg gaggagggcg tgcagaggca gtctgggctt 150ggccagagct cagggtgctg agcgtgtgac cagcagtgag cagaggccgg 200ccatggccag cctggggctg ctgctcctgc tcttactgac agcactgcca 250ccgctgtggt cctcctcact gcctgggctg gacactgctg aaagtaaagc 300caccattgca gacctgatcc tgtctgcgct ggagagagcc accgtcttcc 350tagaacagag gctgcctgaa atcaacctgg atggcatggt gggggtccga 400gtgctggaag agcagctaaa aagtgtccgg gagaagtggg cccaggagcc 450cctgctgcag ccgctgagcc tgcgcgtggg gatgctgggg gagaagctgg 500aggctgccat ccagagatcc ctccactacc tcaagctgag tgatcccaag 550tacctaagag agttccagct gaccctccag cccgggtttt ggaagctccc 600acatgcctgg atccacactg atgcctcctt ggtgtacccc acgttcgggc 650cccaggactc attctcagag gagagaagtg acgtgtgcct ggtgcagctg 700ctgggaaccg ggacggacag cagcgagccc tgcggcctct cagacctctg 750caggagcctc atgaccaagc ccggctgctc aggctactgc ctgtcccacc 800aactgctctt cttcctctgg gccagaatga ggggatgcac acagggacca 850ctccaacaga gccaggacta tatcaacctc ttctgcgcca acatgatgga 900cttgaaccgc agagctgagg ccatcggata cgcctaccct acccgggaca 950tcttcatgga aaacatcatg ttctgtggaa tgggcggctt ctccgacttc 1000tacaagctcc ggtggctgga ggccattctc agctggcaga aacagcagga 1050aggatgcttc ggggagcctg atgctgaaga tgaagaatta tctaaagcta 1100ttcaatatca gcagcatttt tcgaggagag tgaagaggcg agaaaaacaa 1150tttccagatt ctcgctctgt tgctcaggct ggagtacagt ggcgcaatct 1200cggctcactg caacctttgc ctcctgggtt caagcaattc tcttgcctca 1250tcctcccgag tagctgggac tacaggagcg tgccaccata cctggctaat 1300ttttatattt ttttagtaga gacagggttt catcatgttg ctcatgctgg 1350tctcgaactc ctgatctcaa gagatccgcc cacctcaggc tcccaaagtg 1400tgggattata ggtgtgagcc accgtgtctg gctgaaaagc actttcaaag 1450agactgtgtt gaataaaggg ccaaggttct tgccacccag cactcatggg 1500ggctctctcc cctagatggc tgctcctccc acaacacagc cacagcagtg 1550gcagccctgg gtggcttcct atacatcctg gcagaatacc ccccagcaaa 1600cagagagcca cacccatcca caccgccacc accaagcagc cgctgagacg 1650gacggttcca tgccagctgc ctggaggagg aacagacccc tttagtcctc 1700atcccttaga tcctggaggg cacggatcac atcctgggaa gaaggcatct 1750ggaggataag caaagccacc ccgacaccca atcttggaag ccctgagtag 1800gcagggccag ggtaggtggg ggccgggagg gacccaggtg tgaacggatg 1850aataaagttc aactgcaact gaaaaaaaaa aa 188284440PRTHomo sapiens 84Met Ser Ala Arg Gly Arg Trp Glu Gly Gly Gly Arg Arg Ala Cys1 5 10 15Arg Gly Ser Leu Gly Leu Ala Arg Ala Gln Gly Ala Glu Arg Val 20 25 30Thr Ser Ser Glu Gln Arg Pro Ala Met Ala Ser Leu Gly Leu Leu 35 40 45Leu Leu Leu Leu Leu Thr Ala Leu Pro Pro Leu Trp Ser Ser Ser 50

55 60Leu Pro Gly Leu Asp Thr Ala Glu Ser Lys Ala Thr Ile Ala Asp 65 70 75Leu Ile Leu Ser Ala Leu Glu Arg Ala Thr Val Phe Leu Glu Gln 80 85 90Arg Leu Pro Glu Ile Asn Leu Asp Gly Met Val Gly Val Arg Val 95 100 105Leu Glu Glu Gln Leu Lys Ser Val Arg Glu Lys Trp Ala Gln Glu 110 115 120Pro Leu Leu Gln Pro Leu Ser Leu Arg Val Gly Met Leu Gly Glu 125 130 135Lys Leu Glu Ala Ala Ile Gln Arg Ser Leu His Tyr Leu Lys Leu 140 145 150Ser Asp Pro Lys Tyr Leu Arg Glu Phe Gln Leu Thr Leu Gln Pro 155 160 165Gly Phe Trp Lys Leu Pro His Ala Trp Ile His Thr Asp Ala Ser 170 175 180Leu Val Tyr Pro Thr Phe Gly Pro Gln Asp Ser Phe Ser Glu Glu 185 190 195Arg Ser Asp Val Cys Leu Val Gln Leu Leu Gly Thr Gly Thr Asp 200 205 210Ser Ser Glu Pro Cys Gly Leu Ser Asp Leu Cys Arg Ser Leu Met 215 220 225Thr Lys Pro Gly Cys Ser Gly Tyr Cys Leu Ser His Gln Leu Leu 230 235 240Phe Phe Leu Trp Ala Arg Met Arg Gly Cys Thr Gln Gly Pro Leu 245 250 255Gln Gln Ser Gln Asp Tyr Ile Asn Leu Phe Cys Ala Asn Met Met 260 265 270Asp Leu Asn Arg Arg Ala Glu Ala Ile Gly Tyr Ala Tyr Pro Thr 275 280 285Arg Asp Ile Phe Met Glu Asn Ile Met Phe Cys Gly Met Gly Gly 290 295 300Phe Ser Asp Phe Tyr Lys Leu Arg Trp Leu Glu Ala Ile Leu Ser 305 310 315Trp Gln Lys Gln Gln Glu Gly Cys Phe Gly Glu Pro Asp Ala Glu 320 325 330Asp Glu Glu Leu Ser Lys Ala Ile Gln Tyr Gln Gln His Phe Ser 335 340 345Arg Arg Val Lys Arg Arg Glu Lys Gln Phe Pro Asp Ser Arg Ser 350 355 360Val Ala Gln Ala Gly Val Gln Trp Arg Asn Leu Gly Ser Leu Gln 365 370 375Pro Leu Pro Pro Gly Phe Lys Gln Phe Ser Cys Leu Ile Leu Pro 380 385 390Ser Ser Trp Asp Tyr Arg Ser Val Pro Pro Tyr Leu Ala Asn Phe 395 400 405Tyr Ile Phe Leu Val Glu Thr Gly Phe His His Val Ala His Ala 410 415 420Gly Leu Glu Leu Leu Ile Ser Arg Asp Pro Pro Thr Ser Gly Ser 425 430 435Gln Ser Val Gly Leu 440851094DNAHomo sapiens 85ggtctgagtg cagagctgct gtcatggcgg ccgctctgtg gggcttcttt 50cccgtcctgc tgctgctgct gctatcgggg gatgtccaga gctcggaggt 100gcccggggct gctgctgagg gatcgggagg gagtggggtc ggcataggag 150atcgcttcaa gattgagggg cgtgcagttg ttccaggggt gaagcctcag 200gactggatct cggcggcccg agtgctggta gacggagaag agcacgtcgg 250tttccttaag acagatggga gttttgtggt tcatgatata ccttctggat 300cttatgtagt ggaagttgta tctccagctt acagatttga tcccgttcga 350gtggatatca cttcgaaagg aaaaatgaga gcaagatatg tgaattacat 400caaaacatca gaggttgtca gactgcccta tcctctccaa atgaaatctt 450caggtccacc ttcttacttt attaaaaggg aatcgtgggg ctggacagac 500tttctaatga acccaatggt tatgatgatg gttcttcctt tattgatatt 550tgtgcttctg cctaaagtgg tcaacacaag tgatcctgac atgagacggg 600aaatggagca gtcaatgaat atgctgaatt ccaaccatga gttgcctgat 650gtttctgagt tcatgacaag actcttctct tcaaaatcat ctggcaaatc 700tagcagcggc agcagtaaaa caggcaaaag tggggctggc aaaaggaggt 750agtcaggccg tccagagctg gcatttgcac aaacacggca acactgggtg 800gcatccaagt cttggaaaac cgtgtgaagc aactactata aacttgagtc 850atcccgacgt tgatctctta caactgtgta tgttaacttt ttagcacatg 900ttttgtactt ggtacacgag aaaacccagc tttcatcttt tgtctgtatg 950aggtcaatat tgatgtcact gaattaatta cagtgtccta tagaaaatgc 1000cattaataaa ttatatgaac tactatacat tatgtatatt aattaaaaca 1050tcttaatcca gaaatcaaaa aaaaaaaaaa aaaaaaaaaa aaaa 109486242PRTHomo sapiens 86Met Ala Ala Ala Leu Trp Gly Phe Phe Pro Val Leu Leu Leu Leu1 5 10 15Leu Leu Ser Gly Asp Val Gln Ser Ser Glu Val Pro Gly Ala Ala 20 25 30Ala Glu Gly Ser Gly Gly Ser Gly Val Gly Ile Gly Asp Arg Phe 35 40 45Lys Ile Glu Gly Arg Ala Val Val Pro Gly Val Lys Pro Gln Asp 50 55 60Trp Ile Ser Ala Ala Arg Val Leu Val Asp Gly Glu Glu His Val 65 70 75Gly Phe Leu Lys Thr Asp Gly Ser Phe Val Val His Asp Ile Pro 80 85 90Ser Gly Ser Tyr Val Val Glu Val Val Ser Pro Ala Tyr Arg Phe 95 100 105Asp Pro Val Arg Val Asp Ile Thr Ser Lys Gly Lys Met Arg Ala 110 115 120Arg Tyr Val Asn Tyr Ile Lys Thr Ser Glu Val Val Arg Leu Pro 125 130 135Tyr Pro Leu Gln Met Lys Ser Ser Gly Pro Pro Ser Tyr Phe Ile 140 145 150Lys Arg Glu Ser Trp Gly Trp Thr Asp Phe Leu Met Asn Pro Met 155 160 165Val Met Met Met Val Leu Pro Leu Leu Ile Phe Val Leu Leu Pro 170 175 180Lys Val Val Asn Thr Ser Asp Pro Asp Met Arg Arg Glu Met Glu 185 190 195Gln Ser Met Asn Met Leu Asn Ser Asn His Glu Leu Pro Asp Val 200 205 210Ser Glu Phe Met Thr Arg Leu Phe Ser Ser Lys Ser Ser Gly Lys 215 220 225Ser Ser Ser Gly Ser Ser Lys Thr Gly Lys Ser Gly Ala Gly Lys 230 235 240Arg Arg871234DNAHomo sapiens 87caggatgcag ggccgcgtgg cagggagctg cgctcctctg ggcctgctcc 50tggtctgtct tcatctccca ggcctctttg cccggagcat cggtgttgtg 100gaggagaaag tttcccaaaa cttcgggacc aacttgcctc agctcggaca 150accttcctcc actggcccct ctaactctga acatccgcag cccgctctgg 200accctaggtc taatgacttg gcaagggttc ctctgaagct cagcgtgcct 250ccatcagatg gcttcccacc tgcaggaggt tctgcagtgc agaggtggcc 300tccatcgtgg gggctgcctg ccatggattc ctggccccct gaggatcctt 350ggcagatgat ggctgctgcg gctgaggacc gcctggggga agcgctgcct 400gaagaactct cttacctctc cagtgctgcg gccctcgctc cgggcagtgg 450ccctttgcct ggggagtctt ctcccgatgc cacaggcctc tcacctgagg 500cttcactcct ccaccaggac tcggagtcca gacgactgcc ccgttctaat 550tcactgggag ccgggggaaa aatcctttcc caacgccctc cctggtctct 600catccacagg gttctgcctg atcacccctg gggtaccctg aatcccagtg 650tgtcctgggg aggtggaggc cctgggactg gttggggaac gaggcccatg 700ccacaccctg agggaatctg gggtatcaat aatcaacccc caggtaccag 750ctggggaaat attaatcggt atccaggagg cagctgggga aatattaatc 800ggtatccagg aggcagctgg gggaatatta atcggtatcc aggaggcagc 850tgggggaata ttcatctata cccaggtatc aataacccat ttcctcctgg 900agttctccgc cctcctggct cttcttggaa catcccagct ggcttcccta 950atcctccaag ccctaggttg cagtggggct agagcacgat agagggaaac 1000ccaacattgg gagttagagt cctgctcccg ccccttgctg tgtgggctca 1050atccaggccc tgttaacatg tttccagcac tatccccact tttcagtgcc 1100tcccctgctc atctccaata aaataaaagc acttatgaaa aaaaaaaaaa 1150aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 1200aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaa 123488325PRTHomo sapiens 88Met Gln Gly Arg Val Ala Gly Ser Cys Ala Pro Leu Gly Leu Leu1 5 10 15Leu Val Cys Leu His Leu Pro Gly Leu Phe Ala Arg Ser Ile Gly 20 25 30Val Val Glu Glu Lys Val Ser Gln Asn Phe Gly Thr Asn Leu Pro 35 40 45Gln Leu Gly Gln Pro Ser Ser Thr Gly Pro Ser Asn Ser Glu His 50 55 60Pro Gln Pro Ala Leu Asp Pro Arg Ser Asn Asp Leu Ala Arg Val 65 70 75Pro Leu Lys Leu Ser Val Pro Pro Ser Asp Gly Phe Pro Pro Ala 80 85 90Gly Gly Ser Ala Val Gln Arg Trp Pro Pro Ser Trp Gly Leu Pro 95 100 105Ala Met Asp Ser Trp Pro Pro Glu Asp Pro Trp Gln Met Met Ala 110 115 120Ala Ala Ala Glu Asp Arg Leu Gly Glu Ala Leu Pro Glu Glu Leu 125 130 135Ser Tyr Leu Ser Ser Ala Ala Ala Leu Ala Pro Gly Ser Gly Pro 140 145 150Leu Pro Gly Glu Ser Ser Pro Asp Ala Thr Gly Leu Ser Pro Glu 155 160 165Ala Ser Leu Leu His Gln Asp Ser Glu Ser Arg Arg Leu Pro Arg 170 175 180Ser Asn Ser Leu Gly Ala Gly Gly Lys Ile Leu Ser Gln Arg Pro 185 190 195Pro Trp Ser Leu Ile His Arg Val Leu Pro Asp His Pro Trp Gly 200 205 210Thr Leu Asn Pro Ser Val Ser Trp Gly Gly Gly Gly Pro Gly Thr 215 220 225Gly Trp Gly Thr Arg Pro Met Pro His Pro Glu Gly Ile Trp Gly 230 235 240Ile Asn Asn Gln Pro Pro Gly Thr Ser Trp Gly Asn Ile Asn Arg 245 250 255Tyr Pro Gly Gly Ser Trp Gly Asn Ile Asn Arg Tyr Pro Gly Gly 260 265 270Ser Trp Gly Asn Ile Asn Arg Tyr Pro Gly Gly Ser Trp Gly Asn 275 280 285Ile His Leu Tyr Pro Gly Ile Asn Asn Pro Phe Pro Pro Gly Val 290 295 300Leu Arg Pro Pro Gly Ser Ser Trp Asn Ile Pro Ala Gly Phe Pro 305 310 315Asn Pro Pro Ser Pro Arg Leu Gln Trp Gly 320 325893671DNAHomo sapiens 89gccgccggcc cgggctggag ccgagcgcag cagccaccgc cgccgccgcg 50ccagaagttt gggttgaacc ggagctgccg ggaggaaact tttttctttt 100ttccccctcc ctcccgggag gaggaggagg aggaggaggg gaagctgccg 150ccggcgccaa ggctcgtggg ctcggggtcg gcgcggcccg cagaaggggc 200gggggcctcg ccccgcgagg ggaggcgcgc cccgggggcc ccgagagggg 250cggtgaggac cgcgggctgc tggtgcggcg gcggcggcgc gtgtgccccg 300cgcaggggag ggcgcccgcc ccgctcccgg cccggctgcg aggaggaggc 350ggcggcggcg caggaggatg tacttggtgg cgggggacag ggggttggcc 400ggctgcgggc acctcctggt ctcgctgctg gggctgctgc tgctgctggc 450gcgctccggc acccgggcgc tggtctgcct gccctgtgac gagtccaagt 500gcgaggagcc caggaactgc ccggggagca tcgtgcaggg cgtctgcggc 550tgctgctaca cgtgcgccag ccagaggaac gagagctgcg gcggcacctt 600cgggatttac ggaacctgcg accgggggct gcgttgtgtc atccgccccc 650cgctcaatgg cgactccctc accgagtacg aagcgggcgt ttgcgaagat 700gagaactgga ctgatgacca actgcttggt tttaaaccat gcaatgaaaa 750ccttattgct ggctgcaata taatcaatgg gaaatgtgaa tgtaacacca 800ttcgaacctg cagcaatccc tttgagtttc caagtcagga tatgtgcctt 850tcagctttaa agagaattga agaagagaag ccagattgct ccaaggcccg 900ctgtgaagtc cagttctctc cacgttgtcc tgaagattct gttctgatcg 950agggttatgc tcctcctggg gagtgctgtc ccttacccag ccgctgcgtg 1000tgcaaccccg caggctgtct gcgcaaagtc tgccagccgg gaaacctgaa 1050catactagtg tcaaaagcct cagggaagcc gggagagtgc tgtgacctct 1100atgagtgcaa accagttttc ggcgtggact gcaggactgt ggaatgccct 1150cctgttcagc agaccgcgtg tcccccggac agctatgaaa ctcaagtcag 1200actaactgca gatggttgct gtactttgcc aacaagatgc gagtgtctct 1250ctggcttatg tggtttcccc gtgtgtgagg tgggatccac tccccgcata 1300gtctctcgtg gcgatgggac acctggaaag tgctgtgatg tctttgaatg 1350tgttaatgat acaaagccag cctgcgtatt taacaatgtg gaatattatg 1400atggagacat gtttcgaatg gacaactgtc ggttctgtcg atgccaaggg 1450ggcgttgcca tctgcttcac tgcccagtgt ggtgagataa actgcgagag 1500gtactacgtg cccgaaggag agtgctgccc agtgtgtgaa gatccagtgt 1550atccttttaa taatcccgct ggctgctatg ccaatggcct gatccttgcc 1600cacggagacc ggtggcggga agacgactgc acattctgcc agtgcgtcaa 1650cggtgaacgc cactgcgttg cgaccgtctg cggacagacc tgcacaaacc 1700ctgtgaaagt gcctggggag tgttgccctg tgtgcgaaga accaaccatc 1750atcacagttg atccacctgc atgtggggag ttatcaaact gcactctgac 1800agggaaggac tgcattaatg gtttcaaacg cgatcacaat ggttgtcgga 1850cctgtcagtg cataaacacc gaggaactat gttcagaacg taaacaaggc 1900tgcaccttga actgtccctt cggtttcctt actgatgccc aaaactgtga 1950gatctgtgag tgccgcccaa ggcccaagaa gtgcagaccc ataatctgtg 2000acaagtattg tccacttgga ttgctgaaga ataagcacgg ctgtgacatc 2050tgtcgctgta agaaatgtcc agagctctca tgcagtaaga tctgcccctt 2100gggtttccag caggacagtc acggctgtct tatctgcaag tgcagagagg 2150cctctgcttc agctgggcca cccatcctgt cgggcacttg tctcaccgtg 2200gatggtcatc atcataaaaa tgaggagagc tggcacgatg ggtgccggga 2250atgctactgt ctcaatggac gggaaatgtg tgccctgatc acctgcccgg 2300tgcctgcctg tggcaacccc accattcacc ctggacagtg ctgcccatca 2350tgtgcagatg actttgtggt gcagaagcca gagctcagta ctccctccat 2400ttgccacgcc cctggaggag aatactttgt ggaaggagaa acgtggaaca 2450ttgactcctg tactcagtgc acctgccaca gcggacgggt gctgtgtgag 2500acagaggtgt gcccaccgct gctctgccag aacccctcac gcacccagga 2550ttcctgctgc ccacagtgta cagatcaacc ttttcggcct tccttgtccc 2600gcaataacag cgtacctaat tactgcaaaa atgatgaagg ggatatattc 2650ctggcagctg agtcctggaa gcctgacgtt tgtaccagct gcatctgcat 2700tgatagcgta attagctgtt tctctgagtc ctgcccttct gtatcctgtg 2750aaagacctgt cttgagaaaa ggccagtgtt gtccctactg catagaagac 2800acaattccaa agaaggtggt gtgccacttc agtgggaagg cctatgccga 2850cgaggagcgg tgggaccttg acagctgcac ccactgctac tgcctgcagg 2900gccagaccct ctgctcgacc gtcagctgcc cccctctgcc ctgtgttgag 2950cccatcaacg tggaaggaag ttgctgccca atgtgtccag aaatgtatgt 3000cccagaacca accaatatac ccattgagaa gacaaaccat cgaggagagg 3050ttgacctgga ggttcccctg tggcccacgc ctagtgaaaa tgatatcgtc 3100catctcccta gagatatggg tcacctccag gtagattaca gagataacag 3150gctgcaccca agtgaagatt cttcactgga ctccattgcc tcagttgtgg 3200ttcccataat tatatgcctc tctattataa tagcattcct attcatcaat 3250cagaagaaac agtggatacc actgctttgc tggtatcgaa caccaactaa 3300gccttcttcc ttaaataatc agctagtatc tgtggactgc aagaaaggaa 3350ccagagtcca ggtggacagt tcccagagaa tgctaagaat tgcagaacca 3400gatgcaagat tcagtggctt ctacagcatg caaaaacaga accatctaca 3450ggcagacaat ttctaccaaa cagtgtgaag aaaggcaact aggatgaggt 3500ttcaaaagac ggaagacgac taaatctgct ctaaaaagta aactagaatt 3550tgtgcacttg cttagtggat tgtattggat tgtgacttga tgtacagcgc 3600taagacctta ctgggatggg ctctgtctac agcaatgtgc agaacaagca 3650ttcccacttt tcctcaaaaa a 3671901036PRTHomo sapiens 90Met Tyr Leu Val Ala Gly Asp Arg Gly Leu Ala Gly Cys Gly His1 5 10 15Leu Leu Val Ser Leu Leu Gly Leu Leu Leu Leu Leu Ala Arg Ser 20 25 30Gly Thr Arg Ala Leu Val Cys Leu Pro Cys Asp Glu Ser Lys Cys 35 40 45Glu Glu Pro Arg Asn Cys Pro Gly Ser Ile Val Gln Gly Val Cys 50 55 60Gly Cys Cys Tyr Thr Cys Ala Ser Gln Arg Asn Glu Ser Cys Gly 65 70 75Gly Thr Phe Gly Ile Tyr Gly Thr Cys Asp Arg Gly Leu Arg Cys 80 85 90Val Ile Arg Pro Pro Leu Asn Gly Asp Ser Leu Thr Glu Tyr Glu 95 100 105Ala Gly Val Cys Glu Asp Glu Asn Trp Thr Asp Asp Gln Leu Leu 110 115 120Gly Phe Lys Pro Cys Asn Glu Asn Leu Ile Ala Gly Cys Asn Ile 125 130 135Ile Asn Gly Lys Cys Glu Cys Asn Thr Ile Arg Thr Cys Ser Asn 140 145 150Pro Phe Glu Phe Pro Ser Gln Asp Met Cys Leu Ser Ala Leu Lys 155 160 165Arg Ile Glu Glu Glu Lys Pro Asp Cys Ser Lys Ala Arg Cys Glu 170 175 180Val Gln Phe Ser Pro Arg Cys Pro Glu Asp Ser Val Leu Ile Glu 185 190 195Gly Tyr Ala Pro Pro Gly Glu Cys Cys Pro Leu Pro Ser Arg Cys 200 205 210Val Cys Asn Pro Ala Gly Cys Leu Arg Lys Val Cys Gln Pro Gly 215 220 225Asn Leu Asn Ile Leu Val Ser Lys Ala Ser Gly Lys Pro Gly Glu

230 235 240Cys Cys Asp Leu Tyr Glu Cys Lys Pro Val Phe Gly Val Asp Cys 245 250 255Arg Thr Val Glu Cys Pro Pro Val Gln Gln Thr Ala Cys Pro Pro 260 265 270Asp Ser Tyr Glu Thr Gln Val Arg Leu Thr Ala Asp Gly Cys Cys 275 280 285Thr Leu Pro Thr Arg Cys Glu Cys Leu Ser Gly Leu Cys Gly Phe 290 295 300Pro Val Cys Glu Val Gly Ser Thr Pro Arg Ile Val Ser Arg Gly 305 310 315Asp Gly Thr Pro Gly Lys Cys Cys Asp Val Phe Glu Cys Val Asn 320 325 330Asp Thr Lys Pro Ala Cys Val Phe Asn Asn Val Glu Tyr Tyr Asp 335 340 345Gly Asp Met Phe Arg Met Asp Asn Cys Arg Phe Cys Arg Cys Gln 350 355 360Gly Gly Val Ala Ile Cys Phe Thr Ala Gln Cys Gly Glu Ile Asn 365 370 375Cys Glu Arg Tyr Tyr Val Pro Glu Gly Glu Cys Cys Pro Val Cys 380 385 390Glu Asp Pro Val Tyr Pro Phe Asn Asn Pro Ala Gly Cys Tyr Ala 395 400 405Asn Gly Leu Ile Leu Ala His Gly Asp Arg Trp Arg Glu Asp Asp 410 415 420Cys Thr Phe Cys Gln Cys Val Asn Gly Glu Arg His Cys Val Ala 425 430 435Thr Val Cys Gly Gln Thr Cys Thr Asn Pro Val Lys Val Pro Gly 440 445 450Glu Cys Cys Pro Val Cys Glu Glu Pro Thr Ile Ile Thr Val Asp 455 460 465Pro Pro Ala Cys Gly Glu Leu Ser Asn Cys Thr Leu Thr Gly Lys 470 475 480Asp Cys Ile Asn Gly Phe Lys Arg Asp His Asn Gly Cys Arg Thr 485 490 495Cys Gln Cys Ile Asn Thr Glu Glu Leu Cys Ser Glu Arg Lys Gln 500 505 510Gly Cys Thr Leu Asn Cys Pro Phe Gly Phe Leu Thr Asp Ala Gln 515 520 525Asn Cys Glu Ile Cys Glu Cys Arg Pro Arg Pro Lys Lys Cys Arg 530 535 540Pro Ile Ile Cys Asp Lys Tyr Cys Pro Leu Gly Leu Leu Lys Asn 545 550 555Lys His Gly Cys Asp Ile Cys Arg Cys Lys Lys Cys Pro Glu Leu 560 565 570Ser Cys Ser Lys Ile Cys Pro Leu Gly Phe Gln Gln Asp Ser His 575 580 585Gly Cys Leu Ile Cys Lys Cys Arg Glu Ala Ser Ala Ser Ala Gly 590 595 600Pro Pro Ile Leu Ser Gly Thr Cys Leu Thr Val Asp Gly His His 605 610 615His Lys Asn Glu Glu Ser Trp His Asp Gly Cys Arg Glu Cys Tyr 620 625 630Cys Leu Asn Gly Arg Glu Met Cys Ala Leu Ile Thr Cys Pro Val 635 640 645Pro Ala Cys Gly Asn Pro Thr Ile His Pro Gly Gln Cys Cys Pro 650 655 660Ser Cys Ala Asp Asp Phe Val Val Gln Lys Pro Glu Leu Ser Thr 665 670 675Pro Ser Ile Cys His Ala Pro Gly Gly Glu Tyr Phe Val Glu Gly 680 685 690Glu Thr Trp Asn Ile Asp Ser Cys Thr Gln Cys Thr Cys His Ser 695 700 705Gly Arg Val Leu Cys Glu Thr Glu Val Cys Pro Pro Leu Leu Cys 710 715 720Gln Asn Pro Ser Arg Thr Gln Asp Ser Cys Cys Pro Gln Cys Thr 725 730 735Asp Gln Pro Phe Arg Pro Ser Leu Ser Arg Asn Asn Ser Val Pro 740 745 750Asn Tyr Cys Lys Asn Asp Glu Gly Asp Ile Phe Leu Ala Ala Glu 755 760 765Ser Trp Lys Pro Asp Val Cys Thr Ser Cys Ile Cys Ile Asp Ser 770 775 780Val Ile Ser Cys Phe Ser Glu Ser Cys Pro Ser Val Ser Cys Glu 785 790 795Arg Pro Val Leu Arg Lys Gly Gln Cys Cys Pro Tyr Cys Ile Glu 800 805 810Asp Thr Ile Pro Lys Lys Val Val Cys His Phe Ser Gly Lys Ala 815 820 825Tyr Ala Asp Glu Glu Arg Trp Asp Leu Asp Ser Cys Thr His Cys 830 835 840Tyr Cys Leu Gln Gly Gln Thr Leu Cys Ser Thr Val Ser Cys Pro 845 850 855Pro Leu Pro Cys Val Glu Pro Ile Asn Val Glu Gly Ser Cys Cys 860 865 870Pro Met Cys Pro Glu Met Tyr Val Pro Glu Pro Thr Asn Ile Pro 875 880 885Ile Glu Lys Thr Asn His Arg Gly Glu Val Asp Leu Glu Val Pro 890 895 900Leu Trp Pro Thr Pro Ser Glu Asn Asp Ile Val His Leu Pro Arg 905 910 915Asp Met Gly His Leu Gln Val Asp Tyr Arg Asp Asn Arg Leu His 920 925 930Pro Ser Glu Asp Ser Ser Leu Asp Ser Ile Ala Ser Val Val Val 935 940 945Pro Ile Ile Ile Cys Leu Ser Ile Ile Ile Ala Phe Leu Phe Ile 950 955 960Asn Gln Lys Lys Gln Trp Ile Pro Leu Leu Cys Trp Tyr Arg Thr 965 970 975Pro Thr Lys Pro Ser Ser Leu Asn Asn Gln Leu Val Ser Val Asp 980 985 990Cys Lys Lys Gly Thr Arg Val Gln Val Asp Ser Ser Gln Arg Met 995 1000 1005Leu Arg Ile Ala Glu Pro Asp Ala Arg Phe Ser Gly Phe Tyr Ser 1010 1015 1020Met Gln Lys Gln Asn His Leu Gln Ala Asp Asn Phe Tyr Gln Thr 1025 1030 1035Val 911671DNAHomo sapiens 91gcaaaaggaa gggagggaag cactccatca tctcactggg aagaacggca 50cgggcatacc tgcagctact ggggttccac tgggcttgag ggtcgatttt 100tcaccttttg aaggacaaga tgcattggaa gatgttgctg cttctgctgt 150tgtattacaa tgctgaggct tctatgtgcc acaggtggag cagggctgtg 200ctcttccctg ccgcccaccg gccaaagagg tcctcatcac tgccattgaa 250cccagtcctg cagacctccc tggaggaggt ggagctgctc tacgagttcc 300tgctggccga acttgagatc agccctgacc tgcagatctc catcaaggac 350gaggagctgg cctccttgcg gaaggcctca gacttccgca ccgtctgcaa 400caacgtcatc cccaagagca tcccagacat ccgccggctc agcgccagcc 450tctccagcca ccctggcatc ctcaagaaag aagactttga aaggacagtg 500ctgaccctgg cctacacagc ctaccgcaca gccctgtccc acggccatca 550gaaggacatc tgggcgcagt ccctcgttag cctcttccag gccctgaggc 600acgacttgat gcgctcctca cagccgggag tacctccctg agagactggc 650ccacaccagg acctcagagc agggaccagc acagtaatcc agaaagtctt 700cattctctac tccatttaca gagaccagca acaaaacact taccgctgac 750acagagcagc agagatcaaa cagtaacccc gatgctcttt tctccttgta 800gtttcctgga agacacatct gattcatgcc atcatgtgac ctgggctgga 850agaaagggct ggaatggtca ttcaagacgc ctccatgggc agaatggttt 900gcctatggca ggcagaattc tgatatgctt caacccagag cagtggccac 950acactcaaga gtgagaacag gcgtgagcca ccgtgcctgg cccaggatct 1000aaaaactttc taagtttcct ccatcgttgg catcctcaca gctatctcca 1050atgtcactca agagacatca acagacattt aactgctgca gacttcattg 1100ctctgtcacc tcaccttgaa tctaacaaat caaagtattt ctgcaggtcc 1150aatggtctaa aatcaaatgc ttgttaaatg actttttaca acacccctta 1200ctttcctaat ccatttcaat cttatttttt ttattgtggt aaaaaacaca 1250tcacgtaaaa tgtaccatct taaccatttt taagcatatg gtacagcagt 1300gttaactcca tgcatgttgt gaaacagacc cccggaactt tctcatcttg 1350taattctgaa gttctatacc caccgaacaa ctcctctttt ccccttcccc 1400ctgcctgccc cagctcttgg caccattatt ctgctttctg tttttgagag 1450tctgactact taagatacct catacaagcg ggatctggct tacatttctt 1500gagcattgta ttctggaaaa gtgtttcctt cctctgaaaa atgggtagag 1550ttctgaagga gaactactgg tcttattgta cacttgctgt acctattttt 1600atttaacaaa tattcatcta tggtataata aagatgtcat ggttggaaaa 1650aaaaaaaaaa aaaaaaaaaa a 167192173PRTHomo sapiens 92Met His Trp Lys Met Leu Leu Leu Leu Leu Leu Tyr Tyr Asn Ala1 5 10 15Glu Ala Ser Met Cys His Arg Trp Ser Arg Ala Val Leu Phe Pro 20 25 30Ala Ala His Arg Pro Lys Arg Ser Ser Ser Leu Pro Leu Asn Pro 35 40 45Val Leu Gln Thr Ser Leu Glu Glu Val Glu Leu Leu Tyr Glu Phe 50 55 60Leu Leu Ala Glu Leu Glu Ile Ser Pro Asp Leu Gln Ile Ser Ile 65 70 75Lys Asp Glu Glu Leu Ala Ser Leu Arg Lys Ala Ser Asp Phe Arg 80 85 90Thr Val Cys Asn Asn Val Ile Pro Lys Ser Ile Pro Asp Ile Arg 95 100 105Arg Leu Ser Ala Ser Leu Ser Ser His Pro Gly Ile Leu Lys Lys 110 115 120Glu Asp Phe Glu Arg Thr Val Leu Thr Leu Ala Tyr Thr Ala Tyr 125 130 135Arg Thr Ala Leu Ser His Gly His Gln Lys Asp Ile Trp Ala Gln 140 145 150Ser Leu Val Ser Leu Phe Gln Ala Leu Arg His Asp Leu Met Arg 155 160 165Ser Ser Gln Pro Gly Val Pro Pro 170931312DNAHomo sapiens 93caccatgcct ggggggtgct cccggggccc cgccgccggg gacgggcgtc 50tgcggctggc gcgactagcg ctggtactcc tgggctgggt ctcctcgtct 100tctcccacct cctcggcatc ctccttctcc tcctcggcgc cgttcctggc 150ttccgccgtg tccgcccagc ccccgctgcc ggaccagtgc cccgcgctgt 200gcgagtgctc cgaggcagcg cgcacagtca agtgcgttaa ccgcaatctg 250accgaggtgc ccacggacct gcccgcctac gtgcgcaacc tcttccttac 300cggcaaccag ctggccgtgc tccctgccgg cgccttcgcc cgccggccgc 350cgctggcgga gctggccgcg ctcaacctca gcggcagccg cctggacgag 400gtgcgcgcgg gcgccttcga gcatctgccc agcctgcgcc agctcgacct 450cagccacaac ccactggccg acctcagtcc cttcgctttc tcgggcagca 500atgccagcgt ctcggccccc agtccccttg tggaactgat cctgaaccac 550atcgtgcccc ctgaagatga gcggcagaac cggagcttcg agggcatggt 600ggtggcggcc ctgctggcgg gccgtgcact gcaggggctc cgccgcttgg 650agctggccag caaccacttc ctttacctgc cgcgggatgt gctggcccaa 700ctgcccagcc tcaggcacct ggacttaagt aataattcgc tggtgagcct 750gacctacgtg tccttccgca acctgacaca tctagaaagc ctccacctgg 800aggacaatgc cctcaaggtc cttcacaatg gcaccctggc tgagttgcaa 850ggtctacccc acattagggt tttcctggac aacaatccct gggtctgcga 900ctgccacatg gcagacatgg tgacctggct caaggaaaca gaggtagtgc 950agggcaaaga ccggctcacc tgtgcatatc cggaaaaaat gaggaatcgg 1000gtcctcttgg aactcaacag tgctgacctg gactgtgacc cgattcttcc 1050cccatccctg caaacctctt atgtcttcct gggtattgtt ttagccctga 1100taggcgctat tttcctcctg gttttgtatt tgaaccgcaa ggggataaaa 1150aagtggatgc ataacatcag agatgcctgc agggatcaca tggaagggta 1200tcattacaga tatgaaatca atgcggaccc cagattaaca aacctcagtt 1250ctaactcgga tgtctgagaa atattagagg acagaccaag gacaactctg 1300catgagatgt ag 131294420PRTHomo sapiens 94Met Pro Gly Gly Cys Ser Arg Gly Pro Ala Ala Gly Asp Gly Arg1 5 10 15Leu Arg Leu Ala Arg Leu Ala Leu Val Leu Leu Gly Trp Val Ser 20 25 30Ser Ser Ser Pro Thr Ser Ser Ala Ser Ser Phe Ser Ser Ser Ala 35 40 45Pro Phe Leu Ala Ser Ala Val Ser Ala Gln Pro Pro Leu Pro Asp 50 55 60Gln Cys Pro Ala Leu Cys Glu Cys Ser Glu Ala Ala Arg Thr Val 65 70 75Lys Cys Val Asn Arg Asn Leu Thr Glu Val Pro Thr Asp Leu Pro 80 85 90Ala Tyr Val Arg Asn Leu Phe Leu Thr Gly Asn Gln Leu Ala Val 95 100 105Leu Pro Ala Gly Ala Phe Ala Arg Arg Pro Pro Leu Ala Glu Leu 110 115 120Ala Ala Leu Asn Leu Ser Gly Ser Arg Leu Asp Glu Val Arg Ala 125 130 135Gly Ala Phe Glu His Leu Pro Ser Leu Arg Gln Leu Asp Leu Ser 140 145 150His Asn Pro Leu Ala Asp Leu Ser Pro Phe Ala Phe Ser Gly Ser 155 160 165Asn Ala Ser Val Ser Ala Pro Ser Pro Leu Val Glu Leu Ile Leu 170 175 180Asn His Ile Val Pro Pro Glu Asp Glu Arg Gln Asn Arg Ser Phe 185 190 195Glu Gly Met Val Val Ala Ala Leu Leu Ala Gly Arg Ala Leu Gln 200 205 210Gly Leu Arg Arg Leu Glu Leu Ala Ser Asn His Phe Leu Tyr Leu 215 220 225Pro Arg Asp Val Leu Ala Gln Leu Pro Ser Leu Arg His Leu Asp 230 235 240Leu Ser Asn Asn Ser Leu Val Ser Leu Thr Tyr Val Ser Phe Arg 245 250 255Asn Leu Thr His Leu Glu Ser Leu His Leu Glu Asp Asn Ala Leu 260 265 270Lys Val Leu His Asn Gly Thr Leu Ala Glu Leu Gln Gly Leu Pro 275 280 285His Ile Arg Val Phe Leu Asp Asn Asn Pro Trp Val Cys Asp Cys 290 295 300His Met Ala Asp Met Val Thr Trp Leu Lys Glu Thr Glu Val Val 305 310 315Gln Gly Lys Asp Arg Leu Thr Cys Ala Tyr Pro Glu Lys Met Arg 320 325 330Asn Arg Val Leu Leu Glu Leu Asn Ser Ala Asp Leu Asp Cys Asp 335 340 345Pro Ile Leu Pro Pro Ser Leu Gln Thr Ser Tyr Val Phe Leu Gly 350 355 360Ile Val Leu Ala Leu Ile Gly Ala Ile Phe Leu Leu Val Leu Tyr 365 370 375Leu Asn Arg Lys Gly Ile Lys Lys Trp Met His Asn Ile Arg Asp 380 385 390Ala Cys Arg Asp His Met Glu Gly Tyr His Tyr Arg Tyr Glu Ile 395 400 405Asn Ala Asp Pro Arg Leu Thr Asn Leu Ser Ser Asn Ser Asp Val 410 415 420953719DNAHomo sapiens 95ggcttctaca gtccacaaca cccaccagcc ccaggcccag cagaatgagc 50ccagtgagtg ccggggctcc cagtttggct gttgctatga caacgtggcc 100actgcagccg gtcctcttgg ggaaggctgt gtgggccagc ccagccatgc 150ctaccccgtg cggtgcctgc tgcccagtgc ccatggctct tgtgcagact 200gggctgcccg ctggtacttc gttgcctctg tgggccaatg taaccgcttc 250tggtatggcg gctgccatgg caatgccaat aactttgcct cggagcaaga 300gtgcatgagc agctgccagg gatctctcca tgggccccgt cgtccccagc 350ctggggcttc tggaaggagc acccacacgg atggtggcgg cagcagtcct 400gcaggcgagc aggaacccag ccagcacagg acaggggccg cggtgcagag 450aaagccctgg ccttctggtg gtctctggcg gcaagaccaa cagcctgggc 500caggggaggc cccccacacc caggcctttg gagaatggcc atgggggcag 550gagcttgggt ccagggcccc tggactgggt ggagatgccg gatcaccagc 600gccacccttc cacagctcct cctacagatc tcacttccca cctctccagg 650attagcttgg caggtgtgga gccctcgttg gtgcaggcag ccctggggca 700gttggtgcgg ctctcctgct cagacgacac tgccccggaa tcccaggctg 750cctggcagaa agatggccag cccatctcct ctgacaggca caggctgcag 800ttcgacggat ccctgatcat ccaccccctg caggcagagg acgcgggcac 850ctacagctgt ggcagcaccc ggccaggccg cgactcccag aagatccaac 900tccgcattat agggggtgac atggccgtgc tgtctgaggc tgagctgagc 950cgcttccctc agcccaggga cccagctcag gactttggcc aagcgggggc 1000tgctgggccc ctgggggcca tcccctcttc acacccacag cctgcaaaca 1050ggctgcgttt ggaccagaac cagccccggg tggtggatgc cagtccaggc 1100cagcggatcc ggatgacctg ccgtgccgaa ggcttcccgc ccccagccat 1150cgagtggcag agagatgggc agcctgtctc ttctcccaga caccagctgc 1200agcctgatgg ctccctggtc attagccgag tggctgtaga agatggcggc 1250ttctacacct gtgtcgcttt caatgggcag gaccgagacc agcgatgggt 1300ccagctcaga gttctggggg agctgacaat ctcaggactg ccccctactg 1350tgacagtgcc agagggtgat acggccaggc tattgtgtgt ggtagcagga 1400gaaagtgtga acatcaggtg gtccaggaac gggctacctg tgcaggctga 1450tggccaccgt gtccaccagt ccccagatgg cacgctgctc atttacaact 1500tgcgggccag ggatgagggc tcctacatgt gcagtgccta ccaggggagc 1550caggcagtca gccgcagcac cgaggtgaag gtggtctcac cagcacccac 1600cgcccagccc agggaccctg gcagggactg cgtcgaccag ccagagctgg 1650ccaactgtga tttgatcctg caggcccagc tttgtggcaa tgagtattac 1700tccagcttct gctgtgccag ctgttcacgt ttccagcctc acgctcagcc 1750catctggcag tagggatgaa ggctagttcc agccccagtc caaaatagtt 1800catagggcta gggagaaagg aagatggact cttggcttcc tctctctggc 1850tggcaaaggg agttatcttc tggaatacat tagctctttc

aaaaacccac 1900ccagtgttta gcctcaacgg cagccagtta ccagcttctc tctgtagcct 1950tcagcagtgt ttgcatctct gacataacca caggctgctg ttttcaagaa 2000gagcaatctg tttggataag aaaaaccttt actttacagc ttccctttat 2050aatttgttac acaggaatag ttaaatgcat ttgtttgttt gttttttgag 2100acggagtttc actcttgttg cccaggctgg agggcaatgg cgcgatctca 2150gctcactgca acctccgtct cctgggttct tgattctcct gtgtcagcct 2200tctgagtagc tgggattaca gatgcctatc accatgcctg ggtaattttt 2250gtatttttag ttgagatggg gtttcgccat gttggccagg ctggtctcga 2300acttctgacc tcagatgatc tgcccgcctc agcctcccaa agtgctggga 2350ttacaggcat gagccaccac gcccagccat caatgcattt tttttatttt 2400ttttttgaga cagagtttcg cacttcttgc ccaggctgga gtacaatggt 2450gcgatcttgg ctcactgcaa cctccacctc ctgggttcaa gcgcttctcc 2500agcctcagcc tcctgagtag ctgggattac aggtatgtgc caccatgcct 2550ggctaatttt gtatttttgg tggagacggg gtttctccat gttggtcaga 2600ctggtcttga actcccgacc tcaggtaatc cgcccgcctc cgcctcccaa 2650aatgctggga ttagaggtgt gagccactgt gcccagccca tcaatgtgtt 2700ttaaagctag ctgtcagggt tccacttaat ttaaagctgg gcagggagat 2750gtgtaatgat ttcaaagtta acacctgttt gttttctaaa gggcatgcca 2800agtcctgctg tatcagggaa gtattctgtg ctaaaatcag cgatggttca 2850ttgctctagt ctctctcacc cttctaggca gtgcatcagt cagctctaaa 2900tctggtgcag agggttaaca gcataaccct tgttggcaaa atggaataga 2950tgttaagacc tcaaataggg atttgggatg aaacagctgc agttagcact 3000gttatctgag catgaaagaa ctggaaacgc tccttacgtc gagatgttgg 3050accttgaagc cctcctgagg ccaacatgca aatctggctg tgacggttca 3100tctgacacct gtgtaaagct gaccagcctg ctctgtacag tgacaatgag 3150gagcccctct cttccttaag taggaatctg tgaagcaaaa tgtttgctgc 3200caaagacaaa tcagactgtc agtcattaaa aacagcatta gcaggatgag 3250gatagcaatg gggaagggtt gtgggcaatg cagtaacagg gaaatggctt 3300cagaaatggt ttgagttgga agacaacatt cttcatctct caggacttct 3350aattccttga tgctaaaaga agaggcatgg attctatgag cttccaagtc 3400cctttccact ttaaccttct acaaatcttt cagaggactg cctagtagca 3450aaggttattc ctggacacag gaaagacggg cattacaggg accaaagctc 3500tgaaaggtga cttttattac caacacactg gctggaaaag ggacaaacca 3550catcacgggt gagtgatact tctcagtctt ctctactcat tcaacaaagg 3600aaatgtgggc tggggcagag gtcttttttc atttaatact ggaaaaatat 3650tgaagagcat ccatgttcac ttatggctgg ttttgctata gaaattggaa 3700aataaaggcc acttttttg 371996477PRTHomo sapiens 96Met Gly Pro Val Val Pro Ser Leu Gly Leu Leu Glu Gly Ala Pro1 5 10 15Thr Arg Met Val Ala Ala Ala Val Leu Gln Ala Ser Arg Asn Pro 20 25 30Ala Ser Thr Gly Gln Gly Pro Arg Cys Arg Glu Ser Pro Gly Leu 35 40 45Leu Val Val Ser Gly Gly Lys Thr Asn Ser Leu Gly Gln Gly Arg 50 55 60Pro Pro Thr Pro Arg Pro Leu Glu Asn Gly His Gly Gly Arg Ser 65 70 75Leu Gly Pro Gly Pro Leu Asp Trp Val Glu Met Pro Asp His Gln 80 85 90Arg His Pro Ser Thr Ala Pro Pro Thr Asp Leu Thr Ser His Leu 95 100 105Ser Arg Ile Ser Leu Ala Gly Val Glu Pro Ser Leu Val Gln Ala 110 115 120Ala Leu Gly Gln Leu Val Arg Leu Ser Cys Ser Asp Asp Thr Ala 125 130 135Pro Glu Ser Gln Ala Ala Trp Gln Lys Asp Gly Gln Pro Ile Ser 140 145 150Ser Asp Arg His Arg Leu Gln Phe Asp Gly Ser Leu Ile Ile His 155 160 165Pro Leu Gln Ala Glu Asp Ala Gly Thr Tyr Ser Cys Gly Ser Thr 170 175 180Arg Pro Gly Arg Asp Ser Gln Lys Ile Gln Leu Arg Ile Ile Gly 185 190 195Gly Asp Met Ala Val Leu Ser Glu Ala Glu Leu Ser Arg Phe Pro 200 205 210Gln Pro Arg Asp Pro Ala Gln Asp Phe Gly Gln Ala Gly Ala Ala 215 220 225Gly Pro Leu Gly Ala Ile Pro Ser Ser His Pro Gln Pro Ala Asn 230 235 240Arg Leu Arg Leu Asp Gln Asn Gln Pro Arg Val Val Asp Ala Ser 245 250 255Pro Gly Gln Arg Ile Arg Met Thr Cys Arg Ala Glu Gly Phe Pro 260 265 270Pro Pro Ala Ile Glu Trp Gln Arg Asp Gly Gln Pro Val Ser Ser 275 280 285Pro Arg His Gln Leu Gln Pro Asp Gly Ser Leu Val Ile Ser Arg 290 295 300Val Ala Val Glu Asp Gly Gly Phe Tyr Thr Cys Val Ala Phe Asn 305 310 315Gly Gln Asp Arg Asp Gln Arg Trp Val Gln Leu Arg Val Leu Gly 320 325 330Glu Leu Thr Ile Ser Gly Leu Pro Pro Thr Val Thr Val Pro Glu 335 340 345Gly Asp Thr Ala Arg Leu Leu Cys Val Val Ala Gly Glu Ser Val 350 355 360Asn Ile Arg Trp Ser Arg Asn Gly Leu Pro Val Gln Ala Asp Gly 365 370 375His Arg Val His Gln Ser Pro Asp Gly Thr Leu Leu Ile Tyr Asn 380 385 390Leu Arg Ala Arg Asp Glu Gly Ser Tyr Met Cys Ser Ala Tyr Gln 395 400 405Gly Ser Gln Ala Val Ser Arg Ser Thr Glu Val Lys Val Val Ser 410 415 420Pro Ala Pro Thr Ala Gln Pro Arg Asp Pro Gly Arg Asp Cys Val 425 430 435Asp Gln Pro Glu Leu Ala Asn Cys Asp Leu Ile Leu Gln Ala Gln 440 445 450Leu Cys Gly Asn Glu Tyr Tyr Ser Ser Phe Cys Cys Ala Ser Cys 455 460 465Ser Arg Phe Gln Pro His Ala Gln Pro Ile Trp Gln 470 475973979DNAHomo sapiens 97ggcggcggga gcagcgaagg gggcggcagg gatcctccag gctgccggct 50gggaaggcgt gggcgacccg gtgtgtggcg cgcccagagc cccgcgtttc 100agccctaggg aaggaagcca gttgagggaa gttctccatg aatgtacgtc 150acaatgatga tgaccgacca aatccctctg gaactgccac cattgctgaa 200cggagaggta gccatgatgc cccacttggt gaatggagat gcagctcagc 250atgttattct cgttcaagtt aatccaggtg agactttcac aataagagca 300gaggatggaa cacttcagtg cattcaagga cctgctgaag ttcccatgat 350gtcacccaat ggatccattc ctcccattca tgtgcctcca ggttatatct 400cacaggtgat tgaagatagt actggagtcc gccgggtggt ggtcacaccc 450cagtctcctg agtgttatcc cccaagctac ccctcagcca tgtctccaac 500ccatcatctc cctccctatc tgactcacca tccacatttt attcataact 550cacacacggc ttactaccca cctgttaccg gacctggaga tatgccgcct 600cagttttttc cccagcatca tcttccccac acaatatatg gtgagcaaga 650aattatacca ttttatggaa tgtcaagcta catcacccga gaagaccagt 700acagcaagcc tccgcacaaa aaactgaaag accgccagat cgatcgccag 750aaccgcctca acagccctcc ttcttctatc tacaaaagca gctgcacaac 800agtatacaat ggctatggga agggccatag tggtggaagt ggcggaggcg 850gcagcggtag tggtcccgga attaagaaaa cagagcgacg agcaagaagc 900agcccaaagt cgaatgattc agacttgcaa gaatatgagt tggaagtaaa 950gagggtgcaa gacattcttt cgggaataga gaaaccacag gtttctaata 1000ttcaggcaag agcagttgtg ttgtcctggg ctccccctgt tggactttcc 1050tgtggacccc acagtggtct ttccttcccc tacagttacg aggtggcctt 1100atcagacaaa ggacgagatg gaaaatacaa gataatttac agtggagaag 1150aattagaatg taacctgaaa gatcttagac cagcaacaga ttatcatgtg 1200agggtgtatg ccatgtacaa ttccgtaaag ggatcctgct ccgagcctgt 1250tagcttcacc acccacagct gtgcacccga gtgtcctttc ccccctaagc 1300tggcacatag gagcaaaagt tcactaaccc tgcagtggaa ggcaccaatt 1350gacaacggtt caaaaatcac caactacctt ttagagtggg atgagggaaa 1400aagaaatagt ggtttcagac agtgcttctt cgggagccag aagcactgca 1450agttgacaaa gctttgtccg gcaatggggt acacattcag gctggccgct 1500cgaaacgaca ttggcaccag tggttatagc caagaggtgg tgtgctacac 1550attaggaaat atccctcaga tgccttctgc actaaggctg gttcgagctg 1600gcatcacatg ggtcacgttg cagtggagta agccagaagg ctgttcaccc 1650gaggaagtga tcacctacac cttggaaatt caggaggatg aaaatgataa 1700ccttttccac ccaaaataca ctggagagga tttaacctgt actgtgaaaa 1750atctcaaaag aagcacacag tataaattca ggctgactgc ttctaatacg 1800gaaggaaaaa gctgtccaag cgaagttctt gtttgtacga cgagtcctga 1850caggcctgga cctcctacca gaccgcttgt caaaggccca gttacatctc 1900atggctttag tgtcaaatgg gatcccccta aggacaatgg tggttcagaa 1950atcctcaagt acttgctaga gattactgat ggaaattctg aagcgaatca 2000gtgggaagtg gcctacagtg ggtcggctac cgaatacacc ttcacccact 2050tgaaaccagg cactttgtac aaactccgag catgctgcat cagtaccggc 2100ggacacagcc agtgttctga aagtctccct gttcgcacac taagcattgc 2150accaggtcaa tgtcgaccac cgagggtttt gggtagacca aagcacaaag 2200aagtccactt agagtgggat gttcctgcat cggaaagtgg ctgtgaggtc 2250tcagagtaca gcgtggagat gacggagccc gaagacgtag cctcggaagt 2300gtaccatggc ccagagctgg agtgcaccgt cggcaacctg cttcctggaa 2350ccgtgtatcg cttccgggtg agggctctga atgatggagg gtatggtccc 2400tattctgatg tctcagaaat taccactgct gcagggcctc ctggacaatg 2450caaagcacct tgtatttctt gtacacctga tggatgtgtc ttagtgggtt 2500gggagagtcc tgatagttct ggtgctgaca tctcagagta caggttggaa 2550tggggagaag atgaagaatc cttagaactc atttatcatg ggacagacac 2600ccgttttgaa ataagagacc tgttgcctgc tgcacagtat tgctgtagac 2650tacaggcctt caatcaagca ggggcagggc cgtacagtga acttgtcctt 2700tgccagacgc cagcgtctgc ccctgacccc gtctccactc tctgtgtcct 2750ggaggaggag ccccttgatg cctaccctga ttcaccttct gcgtgccttg 2800tactgaactg ggaagagccg tgcaataacg gatctgaaat ccttgcttac 2850accattgatc taggagacac tagcattacc gtgggcaaca ccaccatgca 2900tgttatgaaa gatctccttc cagaaaccac ctaccggatc agaattcagg 2950ctataaatga aattggagct ggaccattta gtcagttcat taaagcaaaa 3000actcggccat taccaccctt gcctcctagg ctagaatgtg ctgctgctgg 3050tcctcagagc ctgaagctaa aatggggaga cagtaactcc aagacacatg 3100ctgctgagga cattgtgtac acactacagc tggaggacag aaacaagagg 3150tttatttcaa tctacagagg acccagccac acctacaagg tccagagact 3200gacggaattc acatgctact ccttcagaat ccaggcagca agcgaggctg 3250gagaagggcc cttctcagaa acctatacct tcagcacaac caaaagtgtc 3300ccccccacca tcaaagcacc tcgagtaaca cagttagaag taaattcatg 3350tgaaatttta tgggagacgg taccatcaat gaaaggtgac cctgttaact 3400acattctgca ggtattggtt ggaagagaat ctgagtacaa acaggtgtac 3450aagggagaag aagccacatt ccaaatctca ggcctccaga ccaacacaga 3500ctacaggttc cgcgtatgtg cgtgtcgtcg ctgtttagac acctctcagg 3550agctaagcgg agccttcagc ccctctgcgg cttttgtatt acaacgaagt 3600gaggtcatgc ttacagggga catggggagc ttagatgatc ccaaaatgaa 3650gagcatgatg cctactgatg aacagtttgc agccatcatt gtgcttggct 3700ttgcaacttt gtccatttta tttgccttta tattacagta cttcttaatg 3750aagtaaaccc aacaaaacta gaggtatgaa ttaatgctac acattttaat 3800acacacattt attcagatac tccccttttt aaagcccttt tgttttttga 3850tttatatact ctgttttaca gatttagcta gaaaaaaaat gtcagtgttt 3900tggtgcacct ttttgaaatg caaaactagg aaaaggttaa actggatttt 3950tttttaaaaa aaaaaaaaaa aaaaaaaaa 3979981204PRTHomo sapiens 98Met Tyr Val Thr Met Met Met Thr Asp Gln Ile Pro Leu Glu Leu1 5 10 15Pro Pro Leu Leu Asn Gly Glu Val Ala Met Met Pro His Leu Val 20 25 30Asn Gly Asp Ala Ala Gln His Val Ile Leu Val Gln Val Asn Pro 35 40 45Gly Glu Thr Phe Thr Ile Arg Ala Glu Asp Gly Thr Leu Gln Cys 50 55 60Ile Gln Gly Pro Ala Glu Val Pro Met Met Ser Pro Asn Gly Ser 65 70 75Ile Pro Pro Ile His Val Pro Pro Gly Tyr Ile Ser Gln Val Ile 80 85 90Glu Asp Ser Thr Gly Val Arg Arg Val Val Val Thr Pro Gln Ser 95 100 105Pro Glu Cys Tyr Pro Pro Ser Tyr Pro Ser Ala Met Ser Pro Thr 110 115 120His His Leu Pro Pro Tyr Leu Thr His His Pro His Phe Ile His 125 130 135Asn Ser His Thr Ala Tyr Tyr Pro Pro Val Thr Gly Pro Gly Asp 140 145 150Met Pro Pro Gln Phe Phe Pro Gln His His Leu Pro His Thr Ile 155 160 165Tyr Gly Glu Gln Glu Ile Ile Pro Phe Tyr Gly Met Ser Ser Tyr 170 175 180Ile Thr Arg Glu Asp Gln Tyr Ser Lys Pro Pro His Lys Lys Leu 185 190 195Lys Asp Arg Gln Ile Asp Arg Gln Asn Arg Leu Asn Ser Pro Pro 200 205 210Ser Ser Ile Tyr Lys Ser Ser Cys Thr Thr Val Tyr Asn Gly Tyr 215 220 225Gly Lys Gly His Ser Gly Gly Ser Gly Gly Gly Gly Ser Gly Ser 230 235 240Gly Pro Gly Ile Lys Lys Thr Glu Arg Arg Ala Arg Ser Ser Pro 245 250 255Lys Ser Asn Asp Ser Asp Leu Gln Glu Tyr Glu Leu Glu Val Lys 260 265 270Arg Val Gln Asp Ile Leu Ser Gly Ile Glu Lys Pro Gln Val Ser 275 280 285Asn Ile Gln Ala Arg Ala Val Val Leu Ser Trp Ala Pro Pro Val 290 295 300Gly Leu Ser Cys Gly Pro His Ser Gly Leu Ser Phe Pro Tyr Ser 305 310 315Tyr Glu Val Ala Leu Ser Asp Lys Gly Arg Asp Gly Lys Tyr Lys 320 325 330Ile Ile Tyr Ser Gly Glu Glu Leu Glu Cys Asn Leu Lys Asp Leu 335 340 345Arg Pro Ala Thr Asp Tyr His Val Arg Val Tyr Ala Met Tyr Asn 350 355 360Ser Val Lys Gly Ser Cys Ser Glu Pro Val Ser Phe Thr Thr His 365 370 375Ser Cys Ala Pro Glu Cys Pro Phe Pro Pro Lys Leu Ala His Arg 380 385 390Ser Lys Ser Ser Leu Thr Leu Gln Trp Lys Ala Pro Ile Asp Asn 395 400 405Gly Ser Lys Ile Thr Asn Tyr Leu Leu Glu Trp Asp Glu Gly Lys 410 415 420Arg Asn Ser Gly Phe Arg Gln Cys Phe Phe Gly Ser Gln Lys His 425 430 435Cys Lys Leu Thr Lys Leu Cys Pro Ala Met Gly Tyr Thr Phe Arg 440 445 450Leu Ala Ala Arg Asn Asp Ile Gly Thr Ser Gly Tyr Ser Gln Glu 455 460 465Val Val Cys Tyr Thr Leu Gly Asn Ile Pro Gln Met Pro Ser Ala 470 475 480Leu Arg Leu Val Arg Ala Gly Ile Thr Trp Val Thr Leu Gln Trp 485 490 495Ser Lys Pro Glu Gly Cys Ser Pro Glu Glu Val Ile Thr Tyr Thr 500 505 510Leu Glu Ile Gln Glu Asp Glu Asn Asp Asn Leu Phe His Pro Lys 515 520 525Tyr Thr Gly Glu Asp Leu Thr Cys Thr Val Lys Asn Leu Lys Arg 530 535 540Ser Thr Gln Tyr Lys Phe Arg Leu Thr Ala Ser Asn Thr Glu Gly 545 550 555Lys Ser Cys Pro Ser Glu Val Leu Val Cys Thr Thr Ser Pro Asp 560 565 570Arg Pro Gly Pro Pro Thr Arg Pro Leu Val Lys Gly Pro Val Thr 575 580 585Ser His Gly Phe Ser Val Lys Trp Asp Pro Pro Lys Asp Asn Gly 590 595 600Gly Ser Glu Ile Leu Lys Tyr Leu Leu Glu Ile Thr Asp Gly Asn 605 610 615Ser Glu Ala Asn Gln Trp Glu Val Ala Tyr Ser Gly Ser Ala Thr 620 625 630Glu Tyr Thr Phe Thr His Leu Lys Pro Gly Thr Leu Tyr Lys Leu 635 640 645Arg Ala Cys Cys Ile Ser Thr Gly Gly His Ser Gln Cys Ser Glu 650 655 660Ser Leu Pro Val Arg Thr Leu Ser Ile Ala Pro Gly Gln Cys Arg 665 670 675Pro Pro Arg Val Leu Gly Arg Pro Lys His Lys Glu Val His Leu 680 685 690Glu Trp Asp Val Pro Ala Ser Glu Ser Gly Cys Glu Val Ser Glu 695 700 705Tyr Ser Val Glu Met Thr Glu Pro Glu Asp Val Ala Ser Glu Val 710 715 720Tyr His Gly Pro Glu Leu Glu Cys Thr Val Gly Asn Leu Leu Pro 725 730 735Gly Thr Val Tyr Arg Phe Arg Val Arg Ala Leu Asn Asp Gly Gly 740 745 750Tyr Gly Pro Tyr Ser Asp

Val Ser Glu Ile Thr Thr Ala Ala Gly 755 760 765Pro Pro Gly Gln Cys Lys Ala Pro Cys Ile Ser Cys Thr Pro Asp 770 775 780Gly Cys Val Leu Val Gly Trp Glu Ser Pro Asp Ser Ser Gly Ala 785 790 795Asp Ile Ser Glu Tyr Arg Leu Glu Trp Gly Glu Asp Glu Glu Ser 800 805 810Leu Glu Leu Ile Tyr His Gly Thr Asp Thr Arg Phe Glu Ile Arg 815 820 825Asp Leu Leu Pro Ala Ala Gln Tyr Cys Cys Arg Leu Gln Ala Phe 830 835 840Asn Gln Ala Gly Ala Gly Pro Tyr Ser Glu Leu Val Leu Cys Gln 845 850 855Thr Pro Ala Ser Ala Pro Asp Pro Val Ser Thr Leu Cys Val Leu 860 865 870Glu Glu Glu Pro Leu Asp Ala Tyr Pro Asp Ser Pro Ser Ala Cys 875 880 885Leu Val Leu Asn Trp Glu Glu Pro Cys Asn Asn Gly Ser Glu Ile 890 895 900Leu Ala Tyr Thr Ile Asp Leu Gly Asp Thr Ser Ile Thr Val Gly 905 910 915Asn Thr Thr Met His Val Met Lys Asp Leu Leu Pro Glu Thr Thr 920 925 930Tyr Arg Ile Arg Ile Gln Ala Ile Asn Glu Ile Gly Ala Gly Pro 935 940 945Phe Ser Gln Phe Ile Lys Ala Lys Thr Arg Pro Leu Pro Pro Leu 950 955 960Pro Pro Arg Leu Glu Cys Ala Ala Ala Gly Pro Gln Ser Leu Lys 965 970 975Leu Lys Trp Gly Asp Ser Asn Ser Lys Thr His Ala Ala Glu Asp 980 985 990Ile Val Tyr Thr Leu Gln Leu Glu Asp Arg Asn Lys Arg Phe Ile 995 1000 1005Ser Ile Tyr Arg Gly Pro Ser His Thr Tyr Lys Val Gln Arg Leu 1010 1015 1020Thr Glu Phe Thr Cys Tyr Ser Phe Arg Ile Gln Ala Ala Ser Glu 1025 1030 1035Ala Gly Glu Gly Pro Phe Ser Glu Thr Tyr Thr Phe Ser Thr Thr 1040 1045 1050Lys Ser Val Pro Pro Thr Ile Lys Ala Pro Arg Val Thr Gln Leu 1055 1060 1065Glu Val Asn Ser Cys Glu Ile Leu Trp Glu Thr Val Pro Ser Met 1070 1075 1080Lys Gly Asp Pro Val Asn Tyr Ile Leu Gln Val Leu Val Gly Arg 1085 1090 1095Glu Ser Glu Tyr Lys Gln Val Tyr Lys Gly Glu Glu Ala Thr Phe 1100 1105 1110Gln Ile Ser Gly Leu Gln Thr Asn Thr Asp Tyr Arg Phe Arg Val 1115 1120 1125Cys Ala Cys Arg Arg Cys Leu Asp Thr Ser Gln Glu Leu Ser Gly 1130 1135 1140Ala Phe Ser Pro Ser Ala Ala Phe Val Leu Gln Arg Ser Glu Val 1145 1150 1155Met Leu Thr Gly Asp Met Gly Ser Leu Asp Asp Pro Lys Met Lys 1160 1165 1170Ser Met Met Pro Thr Asp Glu Gln Phe Ala Ala Ile Ile Val Leu 1175 1180 1185Gly Phe Ala Thr Leu Ser Ile Leu Phe Ala Phe Ile Leu Gln Tyr 1190 1195 1200Phe Leu Met Lys992065DNAHomo sapiens 99cccaaagagg tgaggagccg gcagcggggg cggctgtaac tgtgaggaag 50gctgcagagt ggcgacgtct acgccgtagg ttggaggctg tggggggtgg 100ccgggcgcca gctcccaggc cgcagaagtg acctgcggtg gagttccctc 150ctcgctgctg gagaacggag ggagaaggtt gctggccggg tgaaagtgcc 200tccctctgct tgacggggct gaggggcccg aagtctaggg cgtccgtagt 250cgccccggcc tccgtgaagc cccaggtcta gagatatgac ccgagagtgc 300ccatctccgg ccccggggcc tggggctccg ctgagtggat cggtgctggc 350agaggcggca gtagtgtttg cagtggtgct gagcatccac gcaaccgtat 400gggaccgata ctcgtggtgc gccgtggccc tcgcagtgca ggccttctac 450gtccaataca agtgggaccg gctgctacag cagggaagcg ccgtcttcca 500gttccgaatg tccgcaaaca gtggcctatt gcccgcctcc atggtcatgc 550ctttgcttgg actagtcatg aaggagcggt gccagactgc tgggaacccg 600ttctttgagc gttttggcat tgtggtggca gccactggca tggcagtggc 650cctcttctca tcagtgttgg cgctcggcat cactcgccca gtgccaacca 700acacttgtgt catcttgggc ttggctggag gtgttatcat ttatatcatg 750aagcactcgt tgagcgtggg ggaggtgatc gaagtcctgg aagtccttct 800gatcttcgtt tatctcaaca tgatcctgct gtacctgctg ccccgctgct 850tcacccctgg tgaggcactg ctggtattgg gtggcattag ctttgtcctc 900aaccagctca tcaagcgctc tctgacactg gtggaaagtc agggggaccc 950agtggacttc ttcctgctgg tggtggtagt agggatggta ctcatgggca 1000ttttcttcag cactctgttt gtcttcatgg actcaggcac ctgggcctcc 1050tccatcttct tccacctcat gacctgtgtg ctgagccttg gtgtggtcct 1100accctggctg caccggctca tccgcaggaa tcccctgctc tggcttcttc 1150agtttctctt ccagacagac acccgcatct acctcctagc ctattggtct 1200ctgctggcca ccttggcctg cctggtggtg ctgtaccaga atgccaagcg 1250gtcatcttcc gagtccaaga agcaccaggc ccccaccatc gcccgaaagt 1300atttccacct cattgtggta gccacctaca tcccaggtat catctttgac 1350cggccactgc tctatgtagc cgccactgta tgcctggcgg tcttcatctt 1400cctggagtat gtgcgctact tccgcatcaa gcctttgggt cacactctac 1450ggagcttcct gtcccttttt ctggatgaac gagacagtgg accactcatt 1500ctgacacaca tctacctgct cctgggcatg tctcttccca tctggctgat 1550ccccagaccc tgcacacaga agggtagcct gggaggagcc agggccctcg 1600tcccctatgc cggtgtcctg gctgtgggtg tgggtgatac tgtggcctcc 1650atcttcggta gcaccatggg ggagatccgc tggcctggaa ccaaaaagac 1700ttttgagggg accatgacat ctatatttgc gcagatcatt tctgtagctc 1750tgatcttaat ctttgacagt ggagtggacc taaactacag ttatgcttgg 1800attttggggt ccatcagcac tgtgtccctc ctggaagcat acactacaca 1850gatagacaat ctccttctgc ctctctacct cctgatattg ctgatggcct 1900agctgttaca gtgcagcagc agtgacggag gaaacagaca tggggagggt 1950gaacagtccc cacagcagac agctacttgg gcatgaagag ccaaggtgtg 2000aaaagcagat ttgatttttc agttgattca gatttaaaat aaaaagcaaa 2050gctctcctag ttcta 2065100538PRTHomo sapiens 100Met Thr Arg Glu Cys Pro Ser Pro Ala Pro Gly Pro Gly Ala Pro1 5 10 15Leu Ser Gly Ser Val Leu Ala Glu Ala Ala Val Val Phe Ala Val 20 25 30Val Leu Ser Ile His Ala Thr Val Trp Asp Arg Tyr Ser Trp Cys 35 40 45Ala Val Ala Leu Ala Val Gln Ala Phe Tyr Val Gln Tyr Lys Trp 50 55 60Asp Arg Leu Leu Gln Gln Gly Ser Ala Val Phe Gln Phe Arg Met 65 70 75Ser Ala Asn Ser Gly Leu Leu Pro Ala Ser Met Val Met Pro Leu 80 85 90Leu Gly Leu Val Met Lys Glu Arg Cys Gln Thr Ala Gly Asn Pro 95 100 105Phe Phe Glu Arg Phe Gly Ile Val Val Ala Ala Thr Gly Met Ala 110 115 120Val Ala Leu Phe Ser Ser Val Leu Ala Leu Gly Ile Thr Arg Pro 125 130 135Val Pro Thr Asn Thr Cys Val Ile Leu Gly Leu Ala Gly Gly Val 140 145 150Ile Ile Tyr Ile Met Lys His Ser Leu Ser Val Gly Glu Val Ile 155 160 165Glu Val Leu Glu Val Leu Leu Ile Phe Val Tyr Leu Asn Met Ile 170 175 180Leu Leu Tyr Leu Leu Pro Arg Cys Phe Thr Pro Gly Glu Ala Leu 185 190 195Leu Val Leu Gly Gly Ile Ser Phe Val Leu Asn Gln Leu Ile Lys 200 205 210Arg Ser Leu Thr Leu Val Glu Ser Gln Gly Asp Pro Val Asp Phe 215 220 225Phe Leu Leu Val Val Val Val Gly Met Val Leu Met Gly Ile Phe 230 235 240Phe Ser Thr Leu Phe Val Phe Met Asp Ser Gly Thr Trp Ala Ser 245 250 255Ser Ile Phe Phe His Leu Met Thr Cys Val Leu Ser Leu Gly Val 260 265 270Val Leu Pro Trp Leu His Arg Leu Ile Arg Arg Asn Pro Leu Leu 275 280 285Trp Leu Leu Gln Phe Leu Phe Gln Thr Asp Thr Arg Ile Tyr Leu 290 295 300Leu Ala Tyr Trp Ser Leu Leu Ala Thr Leu Ala Cys Leu Val Val 305 310 315Leu Tyr Gln Asn Ala Lys Arg Ser Ser Ser Glu Ser Lys Lys His 320 325 330Gln Ala Pro Thr Ile Ala Arg Lys Tyr Phe His Leu Ile Val Val 335 340 345Ala Thr Tyr Ile Pro Gly Ile Ile Phe Asp Arg Pro Leu Leu Tyr 350 355 360Val Ala Ala Thr Val Cys Leu Ala Val Phe Ile Phe Leu Glu Tyr 365 370 375Val Arg Tyr Phe Arg Ile Lys Pro Leu Gly His Thr Leu Arg Ser 380 385 390Phe Leu Ser Leu Phe Leu Asp Glu Arg Asp Ser Gly Pro Leu Ile 395 400 405Leu Thr His Ile Tyr Leu Leu Leu Gly Met Ser Leu Pro Ile Trp 410 415 420Leu Ile Pro Arg Pro Cys Thr Gln Lys Gly Ser Leu Gly Gly Ala 425 430 435Arg Ala Leu Val Pro Tyr Ala Gly Val Leu Ala Val Gly Val Gly 440 445 450Asp Thr Val Ala Ser Ile Phe Gly Ser Thr Met Gly Glu Ile Arg 455 460 465Trp Pro Gly Thr Lys Lys Thr Phe Glu Gly Thr Met Thr Ser Ile 470 475 480Phe Ala Gln Ile Ile Ser Val Ala Leu Ile Leu Ile Phe Asp Ser 485 490 495Gly Val Asp Leu Asn Tyr Ser Tyr Ala Trp Ile Leu Gly Ser Ile 500 505 510Ser Thr Val Ser Leu Leu Glu Ala Tyr Thr Thr Gln Ile Asp Asn 515 520 525Leu Leu Leu Pro Leu Tyr Leu Leu Ile Leu Leu Met Ala 530 5351012506DNAHomo sapiens 101cactgcccgt ccgctcttca gcagccggtc gcgggcggtg gaaaagcgag 50tgaagagagc gcgacggcgg cggcggcggc ggcgcagcta ttgctggacg 100gccagtggga gagcgaggcc tgagcctctg cgtctaggat caaaatggtt 150tcaatcccag aatactatga aggcaagaac gtcctcctca caggagctac 200cggttttcta gggaaggtgc ttctggaaaa gttgctgagg tcttgtccta 250aggtgaattc agtatatgtt ttggtgaggc agaaagctgg acagacacca 300caagagcgag tggaagaagt ccttagtggc aagctttttg acagattgag 350agatgaaaat ccagatttta gagagaaaat tatagcaatc aacagcgaac 400tcacccaacc taaactggct ctcagtgaag aagataaaga ggtgatcata 450gattctacca atattatatt ccactgtgca gctacagtaa ggtttaatga 500aaatttaaga gatgctgttc agttaaatgt gattgcaacg cgacagctta 550ttctccttgc acaacaaatg aagaatctgg aagtgttcat gcatgtatca 600acagcatatg cctactgtaa tcgcaagcat attgatgaag tagtctatcc 650accacctgtg gatcccaaga agctgattga ttctttagag tggatggatg 700atggcctagt aaatgatatc acgccaaaat tgataggaga cagacctaat 750acatacatat acacaaaagc attggcagaa tatgttgtac aacaagaagg 800agcaaaacta aatgtggcaa ttgtaaggcc atcgattgtt ggtgccagtt 850ggaaagaacc ttttccagga tggattgata actttaatgg accaagtggt 900ctctttattg cggcagggaa aggaattctt cgaacaatac gtgcctccaa 950caatgccctt gcagatcttg ttcctgtaga tgtagttgtc aacatgagtc 1000ttgcggcagc ctggtattcc ggagttaata gaccaagaaa catcatggtg 1050tataattgta caacaggcag cactaatcct ttccactggg gtgaagttga 1100gtaccatgta atttccactt tcaagaggaa tcctctcgaa caggccttca 1150gacggcccaa tgtaaatcta acctccaatc atcttttata tcattactgg 1200attgctgtaa gccataaggc cccagcattc ctgtatgata tctacctcag 1250gatgactgga agaagcccaa ggatgatgaa aacaataact cgtcttcaca 1300aagctatggt gtttcttgaa tatttcacaa gtaattcttg ggtttggaat 1350actgagaatg tcaatatgtt aatgaatcaa ctaaaccctg aagataaaaa 1400gaccttcaat attgatgtac ggcagttaca ttgggcagaa tatatagaga 1450actactgctt gggaactaag aagtacgtat tgaatgaaga aatgtctggc 1500ctccctgcag ccagaaaaca tctgaacaag ttgcggaata tacgttatgg 1550ttttaatact atccttgtga tcctcatctg gcgcattttt attgcaagat 1600cacaaatggc aagaaatatc tggtactttg tggttagtct gtgttacaag 1650tttttgtcat acttccgagc atccagcact atgagatact gaagaccaag 1700gattcagcat tagaacatct atacatatgg tgatctaaat gtacaaaatg 1750taaaatgtat aagtcatctc actttttgtc aagacattaa accatcttag 1800atcggagtgt gaagtaaatt atggtatatt ttatgtaaca ttttaatgtt 1850tatgctcata aaacttagtg aacacactgt gttatgccag ctcaaatcta 1900cagtagccac caaaaccatg acttaatatt ttgagcccta gaagaaaggg 1950gtgtgctgag gacaagagtg gggaaatagg aacactgacc agtataactg 2000tgcaattctg gaacatatta attaaaataa tatgccttaa catatagtga 2050atttctaatt ctaatgttca gtgcaatgga agacatttat ttggacagta 2100tactagcaaa gttggtagat atttgattct tcattttttg tttttttcat 2150tagttgaagt gggttttagt tttgtttaaa attataacca gcgtattttc 2200acatcattct gtaagttaaa tgatatcaaa catgaaagag atgttctcat 2250ttttcttttt ctgattaaac gtctgatgca tatcattttt ctataagtaa 2300tcagttgctt ttaaaatcag aaggctatat tattctaatg accctattcg 2350atctaaatgg gtttgagaat ccatatcagc aacatacgtg ttttttgaca 2400gaaagtgaaa acaaattccg taaaactgtt agtatcaaaa agaataggaa 2450tacagttttc ttttccacat tatgatcaaa taaaaatctt gtgagattgt 2500taaaaa 2506102515PRTHomo sapiens 102Met Val Ser Ile Pro Glu Tyr Tyr Glu Gly Lys Asn Val Leu Leu1 5 10 15Thr Gly Ala Thr Gly Phe Leu Gly Lys Val Leu Leu Glu Lys Leu 20 25 30Leu Arg Ser Cys Pro Lys Val Asn Ser Val Tyr Val Leu Val Arg 35 40 45Gln Lys Ala Gly Gln Thr Pro Gln Glu Arg Val Glu Glu Val Leu 50 55 60Ser Gly Lys Leu Phe Asp Arg Leu Arg Asp Glu Asn Pro Asp Phe 65 70 75Arg Glu Lys Ile Ile Ala Ile Asn Ser Glu Leu Thr Gln Pro Lys 80 85 90Leu Ala Leu Ser Glu Glu Asp Lys Glu Val Ile Ile Asp Ser Thr 95 100 105Asn Ile Ile Phe His Cys Ala Ala Thr Val Arg Phe Asn Glu Asn 110 115 120Leu Arg Asp Ala Val Gln Leu Asn Val Ile Ala Thr Arg Gln Leu 125 130 135Ile Leu Leu Ala Gln Gln Met Lys Asn Leu Glu Val Phe Met His 140 145 150Val Ser Thr Ala Tyr Ala Tyr Cys Asn Arg Lys His Ile Asp Glu 155 160 165Val Val Tyr Pro Pro Pro Val Asp Pro Lys Lys Leu Ile Asp Ser 170 175 180Leu Glu Trp Met Asp Asp Gly Leu Val Asn Asp Ile Thr Pro Lys 185 190 195Leu Ile Gly Asp Arg Pro Asn Thr Tyr Ile Tyr Thr Lys Ala Leu 200 205 210Ala Glu Tyr Val Val Gln Gln Glu Gly Ala Lys Leu Asn Val Ala 215 220 225Ile Val Arg Pro Ser Ile Val Gly Ala Ser Trp Lys Glu Pro Phe 230 235 240Pro Gly Trp Ile Asp Asn Phe Asn Gly Pro Ser Gly Leu Phe Ile 245 250 255Ala Ala Gly Lys Gly Ile Leu Arg Thr Ile Arg Ala Ser Asn Asn 260 265 270Ala Leu Ala Asp Leu Val Pro Val Asp Val Val Val Asn Met Ser 275 280 285Leu Ala Ala Ala Trp Tyr Ser Gly Val Asn Arg Pro Arg Asn Ile 290 295 300Met Val Tyr Asn Cys Thr Thr Gly Ser Thr Asn Pro Phe His Trp 305 310 315Gly Glu Val Glu Tyr His Val Ile Ser Thr Phe Lys Arg Asn Pro 320 325 330Leu Glu Gln Ala Phe Arg Arg Pro Asn Val Asn Leu Thr Ser Asn 335 340 345His Leu Leu Tyr His Tyr Trp Ile Ala Val Ser His Lys Ala Pro 350 355 360Ala Phe Leu Tyr Asp Ile Tyr Leu Arg Met Thr Gly Arg Ser Pro 365 370 375Arg Met Met Lys Thr Ile Thr Arg Leu His Lys Ala Met Val Phe 380 385 390Leu Glu Tyr Phe Thr Ser Asn Ser Trp Val Trp Asn Thr Glu Asn 395 400 405Val Asn Met Leu Met Asn Gln Leu Asn Pro Glu Asp Lys Lys Thr 410 415 420Phe Asn Ile Asp Val Arg Gln Leu His Trp Ala Glu Tyr Ile Glu 425 430 435Asn Tyr Cys Leu Gly Thr Lys Lys Tyr Val Leu Asn Glu Glu Met 440 445 450Ser Gly Leu Pro Ala Ala Arg Lys His Leu Asn Lys

Leu Arg Asn 455 460 465Ile Arg Tyr Gly Phe Asn Thr Ile Leu Val Ile Leu Ile Trp Arg 470 475 480Ile Phe Ile Ala Arg Ser Gln Met Ala Arg Asn Ile Trp Tyr Phe 485 490 495Val Val Ser Leu Cys Tyr Lys Phe Leu Ser Tyr Phe Arg Ala Ser 500 505 510Ser Thr Met Arg Tyr 5151031515DNAHomo sapiens 103ccggcgatgt cgctcgtgct gctaagcctg gccgcgctgt gcaggagcgc 50cgtaccccga gagccgaccg ttcaatgtgg ctctgaaact gggccatctc 100cagagtggat gctacaacat gatctaatcc ccggagactt gagggacctc 150cgagtagaac ctgttacaac tagtgttgca acaggggact attcaatttt 200gatgaatgta agctgggtac tccgggcaga tgccagcatc cgcttgttga 250aggccaccaa gatttgtgtg acgggcaaaa gcaacttcca gtcctacagc 300tgtgtgaggt gcaattacac agaggccttc cagactcaga ccagaccctc 350tggtggtaaa tggacatttt cctacatcgg cttccctgta gagctgaaca 400cagtctattt cattggggcc cataatattc ctaatgcaaa tatgaatgaa 450gatggccctt ccatgtctgt gaatttcacc tcaccaggct gcctagacca 500cataatgaaa tataaaaaaa agtgtgtcaa ggccggaagc ctgtgggatc 550cgaacatcac tgcttgtaag aagaatgagg agacagtaga agtgaacttc 600acaaccactc ccctgggaaa cagatacatg gctcttatcc aacacagcac 650tatcatcggg ttttctcagg tgtttgagcc acaccagaag aaacaaacgc 700gagcttcagt ggtgattcca gtgactgggg atagtgaagg tgctacggtg 750cagctgactc catattttcc tacttgtggc agcgactgca tccgacataa 800aggaacagtt gtgctctgcc cacaaacagg cgtccctttc cctctggata 850acaacaaaag caagccggga ggctggctgc ctctcctcct gctgtctctg 900ctggtggcca catgggtgct ggtggcaggg atctatctaa tgtggaggca 950cgaaaggatc aagaagactt ccttttctac caccacacta ctgcccccca 1000ttaaggttct tgtggtttac ccatctgaaa tatgtttcca tcacacaatt 1050tgttacttca ctgaatttct tcaaaaccat tgcagaagtg aggtcatcct 1100tgaaaagtgg cagaaaaaga aaatagcaga gatgggtcca gtgcagtggc 1150ttgccactca aaagaaggca gcagacaaag tcgtcttcct tctttccaat 1200gacgtcaaca gtgtgtgcga tggtacctgt ggcaagagcg agggcagtcc 1250cagtgagaac tctcaagacc tcttccccct tgcctttaac cttttctgca 1300gtgatctaag aagccagatt catctgcaca aatacgtggt ggtctacttt 1350agagagattg atacaaaaga cgattacaat gctctcagtg tctgccccaa 1400gtaccacctc atgaaggatg ccactgcttt ctgtgcagaa cttctccatg 1450tcaagcagca ggtgtcagca ggaaaaagat cacaagcctg ccacgatggc 1500tgctgctcct tgtag 1515104502PRTHomo sapiens 104Met Ser Leu Val Leu Leu Ser Leu Ala Ala Leu Cys Arg Ser Ala1 5 10 15Val Pro Arg Glu Pro Thr Val Gln Cys Gly Ser Glu Thr Gly Pro 20 25 30Ser Pro Glu Trp Met Leu Gln His Asp Leu Ile Pro Gly Asp Leu 35 40 45Arg Asp Leu Arg Val Glu Pro Val Thr Thr Ser Val Ala Thr Gly 50 55 60Asp Tyr Ser Ile Leu Met Asn Val Ser Trp Val Leu Arg Ala Asp 65 70 75Ala Ser Ile Arg Leu Leu Lys Ala Thr Lys Ile Cys Val Thr Gly 80 85 90Lys Ser Asn Phe Gln Ser Tyr Ser Cys Val Arg Cys Asn Tyr Thr 95 100 105Glu Ala Phe Gln Thr Gln Thr Arg Pro Ser Gly Gly Lys Trp Thr 110 115 120Phe Ser Tyr Ile Gly Phe Pro Val Glu Leu Asn Thr Val Tyr Phe 125 130 135Ile Gly Ala His Asn Ile Pro Asn Ala Asn Met Asn Glu Asp Gly 140 145 150Pro Ser Met Ser Val Asn Phe Thr Ser Pro Gly Cys Leu Asp His 155 160 165Ile Met Lys Tyr Lys Lys Lys Cys Val Lys Ala Gly Ser Leu Trp 170 175 180Asp Pro Asn Ile Thr Ala Cys Lys Lys Asn Glu Glu Thr Val Glu 185 190 195Val Asn Phe Thr Thr Thr Pro Leu Gly Asn Arg Tyr Met Ala Leu 200 205 210Ile Gln His Ser Thr Ile Ile Gly Phe Ser Gln Val Phe Glu Pro 215 220 225His Gln Lys Lys Gln Thr Arg Ala Ser Val Val Ile Pro Val Thr 230 235 240Gly Asp Ser Glu Gly Ala Thr Val Gln Leu Thr Pro Tyr Phe Pro 245 250 255Thr Cys Gly Ser Asp Cys Ile Arg His Lys Gly Thr Val Val Leu 260 265 270Cys Pro Gln Thr Gly Val Pro Phe Pro Leu Asp Asn Asn Lys Ser 275 280 285Lys Pro Gly Gly Trp Leu Pro Leu Leu Leu Leu Ser Leu Leu Val 290 295 300Ala Thr Trp Val Leu Val Ala Gly Ile Tyr Leu Met Trp Arg His 305 310 315Glu Arg Ile Lys Lys Thr Ser Phe Ser Thr Thr Thr Leu Leu Pro 320 325 330Pro Ile Lys Val Leu Val Val Tyr Pro Ser Glu Ile Cys Phe His 335 340 345His Thr Ile Cys Tyr Phe Thr Glu Phe Leu Gln Asn His Cys Arg 350 355 360Ser Glu Val Ile Leu Glu Lys Trp Gln Lys Lys Lys Ile Ala Glu 365 370 375Met Gly Pro Val Gln Trp Leu Ala Thr Gln Lys Lys Ala Ala Asp 380 385 390Lys Val Val Phe Leu Leu Ser Asn Asp Val Asn Ser Val Cys Asp 395 400 405Gly Thr Cys Gly Lys Ser Glu Gly Ser Pro Ser Glu Asn Ser Gln 410 415 420Asp Leu Phe Pro Leu Ala Phe Asn Leu Phe Cys Ser Asp Leu Arg 425 430 435Ser Gln Ile His Leu His Lys Tyr Val Val Val Tyr Phe Arg Glu 440 445 450Ile Asp Thr Lys Asp Asp Tyr Asn Ala Leu Ser Val Cys Pro Lys 455 460 465Tyr His Leu Met Lys Asp Ala Thr Ala Phe Cys Ala Glu Leu Leu 470 475 480His Val Lys Gln Gln Val Ser Ala Gly Lys Arg Ser Gln Ala Cys 485 490 495His Asp Gly Cys Cys Ser Leu 5001054060DNAHomo sapiens 105gcagctcacc cttcgcagcc gcgatggggg aagacgacgc cgcgcttcgg 50gctggcagca gggggctctc cgacccgtgg gcagactcag tgggagtgcg 100accccgcacc acggagcgcc acatcgccgt acacaagcgg cttgtgctgg 150ccttcgctgt gtccctcgtg gcattgctcg cggtcacaat gctcgctgtg 200ctgctcagcc tgcgcttcga cgagtgcggg gcgagtgcca cgccaggcgc 250cgacggtggc ccctcaggct ttccggagcg cggcggcaac gggagcctcc 300ctggatcggc ccggcgcaac caccacgcag gcggggactc ctggcagccc 350gaggcgggtg gggtggccag tccggggacc acgtcggccc agccgccgtc 400ggaggaggag cgggagccgt gggagccgtg gacgcagctg cgcctgtcgg 450gccacctgaa gccgctgcac tacaatctga tgctcaccgc cttcatggag 500aacttcacct tctccgggga ggtcaacgtg gagatcgcgt gccggaacgc 550cacccgctac gtagtgctgc acgcttcccg agtggcggtg gagaaagtgc 600agctggccga ggaccgggcg ttcggggctg tccctgtagc cggttttttc 650ctctacccgc aaacccaggt cttagtggtg gtgctgaata ggacactgga 700cgcgcagagg aattacaatc tgaagattat ctacaacgcg ctcatcgaga 750atgagctcct gggcttcttc cgcagctcct atgtgctcca cggggagaga 800agattccttg gtgttactca gttttcgcct acacatgcca gaaaggcatt 850tccttgtttt gatgagccaa tctacaaggc tactttcaaa atcagcatca 900agcatcaagc aacctattta tctttatcta atatgccagt ggaaacttcc 950gtgtttgagg aagatggatg ggttacggat cacttttcac agacccctct 1000catgtccaca tattatttag cctgggcaat ttgcaacttc acatacagag 1050aaactaccac caagagtggg gttgtagtac gattatatgc aagacctgat 1100gctatcagaa gaggatccgg ggactatgct ctccatataa caaagagatt 1150aatagaattt tatgaagact actttaaagt gccctattcc ttgccaaaac 1200tagatctttt agctgtgcct aagcatccgt atgctgctat ggagaactgg 1250ggactaagta tttttgtgga acaaagaata ctgctggatc ccagtgtttc 1300atctatttct tatttgctgg atgtcaccat ggtcattgtt catgagatat 1350gtcaccagtg gtttggtgac cttgtgacgc ctgtgtggtg ggaagacgtg 1400tggctgaagg aagggtttgc tcactacttt gaatttgttg gtacagacta 1450cctctatcct ggctggaaca tggaaaagca gaggtttctg accgatgttc 1500tgcatgaagt gatgctgctg gacggtttgg ccagttccca tccagtatca 1550caggaagtgc tgcaggcaac agatattgac agggtgtttg actggatcgc 1600atataaaaag ggtgctgctt taataagaat gctggctaat tttatgggcc 1650attcagtttt ccagaggggt ttgcaagatt atttaaccat tcataagtat 1700ggtaatgcag ccagaaatga tctctggaat acattatcgg aggctttaaa 1750aagaaatggg aaatatgtaa atatacaaga agtaatggat cagtggacac 1800tccagatggg ttatcctgtt atcaccatct tgggaaacac aacagcagaa 1850aatagaataa taattaccca acagcatttt atctatgata tcagtgctaa 1900aactaaagca cttaaacttc agaataacag ttacctgtgg cagattccat 1950taactattgt ggtaggaaat agaagccatg tgtcttcaga agcaattatt 2000tgggtgtcta acaaatcaga gcaccacaga ataacttatt tggacaaagg 2050aagctggctg ctggggaaca tcaatcaaac tggctatttt agagtcaact 2100atgacctaag gaactggaga ttattaattg atcaattaat ccggaatcat 2150gaggttcttt ctgtcagtaa ccgagcgggc ttgatcgatg atgccttcag 2200cctagccagg gctggctatt tgcctcagaa tattcctctg gagattatca 2250gatacctgtc tgaggagaag gattttcttc cttggcatgc tgccagccga 2300gctctttatc ctctagataa attactggac cgcatggaaa actacaacat 2350tttcaatgaa tatattttaa agcaagttgc aacaacatat atcaagcttg 2400ggtggccgaa aaataatttt aatggatctc ttgttcaagc atcctaccaa 2450catgaagaac tacgtagaga agttataatg ctggcctgca gttttggcaa 2500caagcactgt caccaacagg catcaacact tatttcagat tggatttcca 2550gcaacaggaa cagaatacca ctaaatgtta gagacatcgt atactgtaca 2600ggagtgtcac tactggatga ggatgtctgg gaattcatat ggatgaaatt 2650ccattccacc acagcagttt ctgagaagaa aatattattg gaagccttaa 2700cttgcagtga tgacaggaat ttattaaaca ggcttctaaa tctgtcactg 2750aattctgagg tggtgctgga tcaagatgca attgatgtca taatccatgt 2800agctcgaaat ccacatggtc gagaccttgc ctggaagttt ttcagggata 2850aatggaagat attaaatacc aggtatggag aagcattgtt tatgtattcc 2900aaactcatca gtggtgtcac agaatttctt aatactgaag gtgaactcaa 2950agagctcaag aacttcatga aaaactatga tggggtagct gctgcttctt 3000tctcacgagc tgtggaaact gtcgaagcca atgtgcgctg gaaaatgctt 3050taccaagacg agcttttcca atggttagga aaagctctaa gacactaata 3100tatgtatctt ataaacaaac aattcaactc agaagtttat gagaagacac 3150gctttttgtg gaatgaggaa aatgtactac ctagaaaatg gccagatttt 3200cagtgttaac gtgtgggagg aatttttttt tttagttttt attttttggt 3250tttgggggat attttttatt tgtttcattc attctgttct gtttctctac 3300tgggtgttcc tctctaaaga aactcttgca agtgaaacta gccatgattg 3350cttcagctgt acattccttg ctgtacagga ccaaatatga tagtgatgca 3400tgttgatgtt acagtcaatt tggaaaaaca tattcagaat atctgtgcat 3450ggatatattg tcctgcctgt gttccagcat gcttatttca aacgtccagt 3500gttgtgtgtg aatatgtgtt acacctagga tgggcattat gcaaaagcac 3550aaagattata tatgacaatc agtattgcaa tgaaagaaaa actaaaaaca 3600gaaatgatat tctcaatttt gggcaatgtg agaggtaaaa tagcccttga 3650catgatgaac atcacttatt tcagcacttg gattgtctgg caatgattac 3700tgtgttgcta actcattttc tttgagttaa agctgtgtat acattttaaa 3750aggcatatag atagtgtatg catatgtata tgtacatagg gaagccccat 3800atgtatatag tatgttgtac actgcacatg tacaaagaat gtcttcagat 3850caaagaaaat ttatctcttt ttataaactt aaggacagtt gcaaaaggct 3900tcaaggaatt tatctcaaca ttattctttc tatgtcctaa ctaaatttct 3950caactgttat gaatttttca tctacttctt gaacagtggt ctattctgct 4000acatgaagat gaatacaaac aaaatttttg tataaactcc caaaaaaaaa 4050aaaaaaaaaa 40601061024PRTHomo sapiens 106Met Gly Glu Asp Asp Ala Ala Leu Arg Ala Gly Ser Arg Gly Leu1 5 10 15Ser Asp Pro Trp Ala Asp Ser Val Gly Val Arg Pro Arg Thr Thr 20 25 30Glu Arg His Ile Ala Val His Lys Arg Leu Val Leu Ala Phe Ala 35 40 45Val Ser Leu Val Ala Leu Leu Ala Val Thr Met Leu Ala Val Leu 50 55 60Leu Ser Leu Arg Phe Asp Glu Cys Gly Ala Ser Ala Thr Pro Gly 65 70 75Ala Asp Gly Gly Pro Ser Gly Phe Pro Glu Arg Gly Gly Asn Gly 80 85 90Ser Leu Pro Gly Ser Ala Arg Arg Asn His His Ala Gly Gly Asp 95 100 105Ser Trp Gln Pro Glu Ala Gly Gly Val Ala Ser Pro Gly Thr Thr 110 115 120Ser Ala Gln Pro Pro Ser Glu Glu Glu Arg Glu Pro Trp Glu Pro 125 130 135Trp Thr Gln Leu Arg Leu Ser Gly His Leu Lys Pro Leu His Tyr 140 145 150Asn Leu Met Leu Thr Ala Phe Met Glu Asn Phe Thr Phe Ser Gly 155 160 165Glu Val Asn Val Glu Ile Ala Cys Arg Asn Ala Thr Arg Tyr Val 170 175 180Val Leu His Ala Ser Arg Val Ala Val Glu Lys Val Gln Leu Ala 185 190 195Glu Asp Arg Ala Phe Gly Ala Val Pro Val Ala Gly Phe Phe Leu 200 205 210Tyr Pro Gln Thr Gln Val Leu Val Val Val Leu Asn Arg Thr Leu 215 220 225Asp Ala Gln Arg Asn Tyr Asn Leu Lys Ile Ile Tyr Asn Ala Leu 230 235 240Ile Glu Asn Glu Leu Leu Gly Phe Phe Arg Ser Ser Tyr Val Leu 245 250 255His Gly Glu Arg Arg Phe Leu Gly Val Thr Gln Phe Ser Pro Thr 260 265 270His Ala Arg Lys Ala Phe Pro Cys Phe Asp Glu Pro Ile Tyr Lys 275 280 285Ala Thr Phe Lys Ile Ser Ile Lys His Gln Ala Thr Tyr Leu Ser 290 295 300Leu Ser Asn Met Pro Val Glu Thr Ser Val Phe Glu Glu Asp Gly 305 310 315Trp Val Thr Asp His Phe Ser Gln Thr Pro Leu Met Ser Thr Tyr 320 325 330Tyr Leu Ala Trp Ala Ile Cys Asn Phe Thr Tyr Arg Glu Thr Thr 335 340 345Thr Lys Ser Gly Val Val Val Arg Leu Tyr Ala Arg Pro Asp Ala 350 355 360Ile Arg Arg Gly Ser Gly Asp Tyr Ala Leu His Ile Thr Lys Arg 365 370 375Leu Ile Glu Phe Tyr Glu Asp Tyr Phe Lys Val Pro Tyr Ser Leu 380 385 390Pro Lys Leu Asp Leu Leu Ala Val Pro Lys His Pro Tyr Ala Ala 395 400 405Met Glu Asn Trp Gly Leu Ser Ile Phe Val Glu Gln Arg Ile Leu 410 415 420Leu Asp Pro Ser Val Ser Ser Ile Ser Tyr Leu Leu Asp Val Thr 425 430 435Met Val Ile Val His Glu Ile Cys His Gln Trp Phe Gly Asp Leu 440 445 450Val Thr Pro Val Trp Trp Glu Asp Val Trp Leu Lys Glu Gly Phe 455 460 465Ala His Tyr Phe Glu Phe Val Gly Thr Asp Tyr Leu Tyr Pro Gly 470 475 480Trp Asn Met Glu Lys Gln Arg Phe Leu Thr Asp Val Leu His Glu 485 490 495Val Met Leu Leu Asp Gly Leu Ala Ser Ser His Pro Val Ser Gln 500 505 510Glu Val Leu Gln Ala Thr Asp Ile Asp Arg Val Phe Asp Trp Ile 515 520 525Ala Tyr Lys Lys Gly Ala Ala Leu Ile Arg Met Leu Ala Asn Phe 530 535 540Met Gly His Ser Val Phe Gln Arg Gly Leu Gln Asp Tyr Leu Thr 545 550 555Ile His Lys Tyr Gly Asn Ala Ala Arg Asn Asp Leu Trp Asn Thr 560 565 570Leu Ser Glu Ala Leu Lys Arg Asn Gly Lys Tyr Val Asn Ile Gln 575 580 585Glu Val Met Asp Gln Trp Thr Leu Gln Met Gly Tyr Pro Val Ile 590 595 600Thr Ile Leu Gly Asn Thr Thr Ala Glu Asn Arg Ile Ile Ile Thr 605 610 615Gln Gln His Phe Ile Tyr Asp Ile Ser Ala Lys Thr Lys Ala Leu 620 625 630Lys Leu Gln Asn Asn Ser Tyr Leu Trp Gln Ile Pro Leu Thr Ile 635 640 645Val Val Gly Asn Arg Ser His Val Ser Ser Glu Ala Ile Ile Trp 650 655 660Val Ser Asn Lys Ser Glu His His Arg Ile Thr Tyr Leu Asp Lys 665 670 675Gly Ser Trp Leu Leu Gly Asn Ile Asn Gln Thr Gly Tyr Phe Arg 680 685 690Val Asn Tyr Asp Leu Arg Asn Trp Arg Leu Leu Ile Asp Gln Leu 695 700 705Ile

Arg Asn His Glu Val Leu Ser Val Ser Asn Arg Ala Gly Leu 710 715 720Ile Asp Asp Ala Phe Ser Leu Ala Arg Ala Gly Tyr Leu Pro Gln 725 730 735Asn Ile Pro Leu Glu Ile Ile Arg Tyr Leu Ser Glu Glu Lys Asp 740 745 750Phe Leu Pro Trp His Ala Ala Ser Arg Ala Leu Tyr Pro Leu Asp 755 760 765Lys Leu Leu Asp Arg Met Glu Asn Tyr Asn Ile Phe Asn Glu Tyr 770 775 780Ile Leu Lys Gln Val Ala Thr Thr Tyr Ile Lys Leu Gly Trp Pro 785 790 795Lys Asn Asn Phe Asn Gly Ser Leu Val Gln Ala Ser Tyr Gln His 800 805 810Glu Glu Leu Arg Arg Glu Val Ile Met Leu Ala Cys Ser Phe Gly 815 820 825Asn Lys His Cys His Gln Gln Ala Ser Thr Leu Ile Ser Asp Trp 830 835 840Ile Ser Ser Asn Arg Asn Arg Ile Pro Leu Asn Val Arg Asp Ile 845 850 855Val Tyr Cys Thr Gly Val Ser Leu Leu Asp Glu Asp Val Trp Glu 860 865 870Phe Ile Trp Met Lys Phe His Ser Thr Thr Ala Val Ser Glu Lys 875 880 885Lys Ile Leu Leu Glu Ala Leu Thr Cys Ser Asp Asp Arg Asn Leu 890 895 900Leu Asn Arg Leu Leu Asn Leu Ser Leu Asn Ser Glu Val Val Leu 905 910 915Asp Gln Asp Ala Ile Asp Val Ile Ile His Val Ala Arg Asn Pro 920 925 930His Gly Arg Asp Leu Ala Trp Lys Phe Phe Arg Asp Lys Trp Lys 935 940 945Ile Leu Asn Thr Arg Tyr Gly Glu Ala Leu Phe Met Tyr Ser Lys 950 955 960Leu Ile Ser Gly Val Thr Glu Phe Leu Asn Thr Glu Gly Glu Leu 965 970 975Lys Glu Leu Lys Asn Phe Met Lys Asn Tyr Asp Gly Val Ala Ala 980 985 990Ala Ser Phe Ser Arg Ala Val Glu Thr Val Glu Ala Asn Val Arg 995 1000 1005Trp Lys Met Leu Tyr Gln Asp Glu Leu Phe Gln Trp Leu Gly Lys 1010 1015 1020Ala Leu Arg His 1072915DNAHomo sapiens 107ctttccttat ctgtgtgtac tcttatctca ctgttctatt ttttctcctc 50atttatatta actctttctt accttttttt ctgaacttct aggccttctc 100tttccagaac tggtggaaga caaatgaaac ggccaagatg gtaagaaaca 150agccgcattt ctccttgggg agactgataa tttaaaaggt ttgttgtgtc 200agaaacattc ccagcttcat caccaaccct ttccttccac ctctgcccac 250tggagaccac ttacatcccg aagcggacgc ggcagctgaa gtcaggaaac 300catgcatcac attagcagga gccaactgca gactttaaac tccgttcaac 350atgtggatgc ggcagagaaa tgacctgtcc agacaagccg gggcagctca 400taaactggtt catctgctcc ctgtgcgtcc cgcgggtgcg taagctctgg 450agcagccggc gtccaaggac ccggagaaac cttctgctgg gcactgcgtg 500tgccatctac ttgggcttcc tggtgagcca ggtggggagg gcctctctcc 550agcatggaca ggcggctgag aaggggccac atcgcagccg cgacaccgcc 600gagccatcct tccctgagat acccctggat ggtaccctgg cccctccaga 650gtcccagggc aatgggtcca ctctgcagcc caatgtggtg tacattaccc 700tacgctccaa gcgcagcaag ccggccaata tccgtggcac cgtgaagccc 750aagcgcagga aaaagcatgc agtggcatcg gctgccccag ggcaggaggc 800tttggtcgga ccatcccttc agccgcagga agcggcaagg gaagctgatg 850ctgtagcacc tgggtacgct cagggagcaa acctggttaa gattggagag 900cgaccctgga ggttggtgcg gggtccggga gtgcgagccg ggggcccaga 950cttcctgcag cccagctcca gggagagcaa cattaggatc tacagcgaga 1000gcgccccctc ctggctgagc aaagatgaca tccgaagaat gcgactcttg 1050gcggacagcg cagtggcagg gctccggcct gtgtcctcta ggagcggagc 1100ccgtttgctg gtgctggagg ggggcgcacc tggcgctgtg ctccgctgtg 1150gccctagccc ctgtgggctt ctcaagcagc ccttggacat gagtgaggtg 1200tttgccttcc acctagacag gatcctgggg ctcaacagga ccctgccgtc 1250tgtgagcagg aaagcagagt tcatccaaga tggccgccca tgccccatca 1300ttctttggga tgcatcttta tcttcagcaa gtaatgacac ccattcttct 1350gttaagctca cctggggaac ttatcagcag ttgctgaaac agaaatgctg 1400gcagaatggc cgagtaccca agcctgaatc aggttgtact gaaatacatc 1450atcatgagtg gtccaagatg gcactctttg attttttgtt acagatttat 1500aatcgcttag atacaaattg ctgtggattc agacctcgca aggaagatgc 1550ctgtgtacag aatggattga ggccaaaatg tgatgaccaa ggttctgcgg 1600ctctagcaca cattatccag cgaaagcatg acccaaggca tttggttttt 1650atagacaaca agggtttctt tgacaggagt gaagataact taaacttcaa 1700attgttagaa ggcatcaaag agtttccagc ttctgcagtt tctgttttga 1750agagccagca cttacggcag aaacttcttc agtctctgtt tcttgataaa 1800gtgtattggg aaagtcaagg aggtagacaa ggaattgaaa agcttatcga 1850tgtaatagaa cacagagcca aaattcttat cacctatatc aatgcacacg 1900gggtcaaagt attacctatg aatgaatgac aaaagaatct tctggctagg 1950gtgttagata tatttatgca tttttggttt tgtttttaaa tcaagcacat 2000caacctcaag cccgtttagc aatgaggcag tgtagatgaa tacgtaaaat 2050aaatgacttt aaccaagtag ctataaaggg acttagcact gtatgcatac 2100ttaaaaaggt tttgaaaaac aaactacttg agaaatattt gtttatattt 2150ttctctaaca tcatgctatg tgtcagtctg aacatctgac aacagaaatt 2200tcagttatta ttctagctaa gttttgaaaa catttgtcat gctgtttaat 2250agaaaactgc aaaccagaga tactgactcc attaataaac catattttgt 2300gccgttttga ctgttctgac caaatactaa tgggaacaat tcttgacgtt 2350tttctgttgc tgattgttaa catagagcag tctctacact accctgaggc 2400aactctacat tggaacactg aggcttacag cctgcaagag catcagagct 2450gaccatacat ttaaacagaa atgctggttt atttgcaaaa tcaccagtat 2500attttctatt gtgtctataa aaaatcagtc atttaagtac aagaatcata 2550ttttccattc ctttttagaa atttattttg ttgtccctat ggaaatcatt 2600cacatctgac aatttatatg ttaaagagtt ttactctctc tattttggtc 2650caatttgtat ctagtggctg agaaattaaa taattctaaa gtatgaagtt 2700acctatctga aaatgtactt acagagtatc attttaaaat ggatgtctct 2750ttaaaaattt tgttactttt accaacaatg taatataatt tatgtatatt 2800ttattaataa tagtgaattc cttaaaattt gttctatgta cttatattta 2850atttgattta atggttactg cccagatatt gagaaatggt tcaaatattg 2900agtgtgtttc aataa 2915108519PRTHomo sapiens 108Met Thr Cys Pro Asp Lys Pro Gly Gln Leu Ile Asn Trp Phe Ile1 5 10 15Cys Ser Leu Cys Val Pro Arg Val Arg Lys Leu Trp Ser Ser Arg 20 25 30Arg Pro Arg Thr Arg Arg Asn Leu Leu Leu Gly Thr Ala Cys Ala 35 40 45Ile Tyr Leu Gly Phe Leu Val Ser Gln Val Gly Arg Ala Ser Leu 50 55 60Gln His Gly Gln Ala Ala Glu Lys Gly Pro His Arg Ser Arg Asp 65 70 75Thr Ala Glu Pro Ser Phe Pro Glu Ile Pro Leu Asp Gly Thr Leu 80 85 90Ala Pro Pro Glu Ser Gln Gly Asn Gly Ser Thr Leu Gln Pro Asn 95 100 105Val Val Tyr Ile Thr Leu Arg Ser Lys Arg Ser Lys Pro Ala Asn 110 115 120Ile Arg Gly Thr Val Lys Pro Lys Arg Arg Lys Lys His Ala Val 125 130 135Ala Ser Ala Ala Pro Gly Gln Glu Ala Leu Val Gly Pro Ser Leu 140 145 150Gln Pro Gln Glu Ala Ala Arg Glu Ala Asp Ala Val Ala Pro Gly 155 160 165Tyr Ala Gln Gly Ala Asn Leu Val Lys Ile Gly Glu Arg Pro Trp 170 175 180Arg Leu Val Arg Gly Pro Gly Val Arg Ala Gly Gly Pro Asp Phe 185 190 195Leu Gln Pro Ser Ser Arg Glu Ser Asn Ile Arg Ile Tyr Ser Glu 200 205 210Ser Ala Pro Ser Trp Leu Ser Lys Asp Asp Ile Arg Arg Met Arg 215 220 225Leu Leu Ala Asp Ser Ala Val Ala Gly Leu Arg Pro Val Ser Ser 230 235 240Arg Ser Gly Ala Arg Leu Leu Val Leu Glu Gly Gly Ala Pro Gly 245 250 255Ala Val Leu Arg Cys Gly Pro Ser Pro Cys Gly Leu Leu Lys Gln 260 265 270Pro Leu Asp Met Ser Glu Val Phe Ala Phe His Leu Asp Arg Ile 275 280 285Leu Gly Leu Asn Arg Thr Leu Pro Ser Val Ser Arg Lys Ala Glu 290 295 300Phe Ile Gln Asp Gly Arg Pro Cys Pro Ile Ile Leu Trp Asp Ala 305 310 315Ser Leu Ser Ser Ala Ser Asn Asp Thr His Ser Ser Val Lys Leu 320 325 330Thr Trp Gly Thr Tyr Gln Gln Leu Leu Lys Gln Lys Cys Trp Gln 335 340 345Asn Gly Arg Val Pro Lys Pro Glu Ser Gly Cys Thr Glu Ile His 350 355 360His His Glu Trp Ser Lys Met Ala Leu Phe Asp Phe Leu Leu Gln 365 370 375Ile Tyr Asn Arg Leu Asp Thr Asn Cys Cys Gly Phe Arg Pro Arg 380 385 390Lys Glu Asp Ala Cys Val Gln Asn Gly Leu Arg Pro Lys Cys Asp 395 400 405Asp Gln Gly Ser Ala Ala Leu Ala His Ile Ile Gln Arg Lys His 410 415 420Asp Pro Arg His Leu Val Phe Ile Asp Asn Lys Gly Phe Phe Asp 425 430 435Arg Ser Glu Asp Asn Leu Asn Phe Lys Leu Leu Glu Gly Ile Lys 440 445 450Glu Phe Pro Ala Ser Ala Val Ser Val Leu Lys Ser Gln His Leu 455 460 465Arg Gln Lys Leu Leu Gln Ser Leu Phe Leu Asp Lys Val Tyr Trp 470 475 480Glu Ser Gln Gly Gly Arg Gln Gly Ile Glu Lys Leu Ile Asp Val 485 490 495Ile Glu His Arg Ala Lys Ile Leu Ile Thr Tyr Ile Asn Ala His 500 505 510Gly Val Lys Val Leu Pro Met Asn Glu 5151093442DNAHomo sapiens 109ggaaagagtg ctggtactac aaccaggaag tgacagataa tgtgctttaa 50actacattag aaaagcttct catagcaaaa ctgagagatt gaagcagtga 100ttatttttac atagttgtca ttaaatattt ggagctctgc tgtgcataga 150gatggcaaca tacttagaat acacagcttt ctgggccaga aattgatctt 200ctgacttttg agccttatct gattactgct tggttcatct ttattttgtt 250aaactactct gtaggctgaa agggagagac tctccttggt ttgcagagcc 300tgactagaca ggaattctgg caactgctcc agcagaacta tggcactgag 350ctaggtttaa atgctgagga gatggaaaac ttgtcactgt cgattgagga 400tgtgcagcca agaagtccag gaagaagcag cttggatgac tctggggaga 450gagatgaaaa attatccaag tcaatcagtt ttaccagtga atcaattagt 500cgggtttcag aaacagagtc attcgatgga aattcatcaa aaggaggatt 550aggcaaagag gagtcccaaa atgagaaaca gaccaaaaag agtctcttac 600caactttgga aaagaagtta actagagtgc catcaaagtc actggacttg 650aataaaaatg aatatctttc tctggacaaa agcagcactt cagattctgt 700tgatgaagaa aatgttcctg agaaagatct tcatggaaga ctttttatca 750accgtatttt tcatatcagt gctgacagaa tgtttgaatt gctctttacc 800agttcacgct ttatgcagaa atttgccagt tctagaaata taatagatgt 850agtatctacc ccttggactg cagaacttgg aggtgatcag ctgagaacga 900tgacctacac tatagtcctt aatagtccac ttactggaaa atgcactgct 950gccactgaaa agcagacact gtataaagaa agtcgggaag cacgatttta 1000tttggtagat tcagaagtac tgacacatga tgtcccctac catgattact 1050tctataccgt gaacagatac tgtatcatcc gatcttcaaa acagaaatgc 1100aggctaagag tttccacaga tttgaaatac agaaaacagc catggggcct 1150tgtcaaatct ttaattgaaa agaattcctg gagttctttg gaggactatt 1200tcaaacagct tgaatcagat ttgttaattg aagaatctgt attaaatcag 1250gccattgaag accctggaaa acttactggc ctacgaagga gaaggcgaac 1300cttcaaccga acagcagaaa cagttcctaa actttcctct cagcattcct 1350ctggagatgt gggcttaggt gccaaagggg atattacagg aaagaaaaag 1400gaaatggaaa actataacgt cactcttatt gtggtaatga gtatttttgt 1450gttgttatta gttttgttga atgtgacact gtttctgaag ctgtcaaaga 1500tagaacatgc tgctcagtcc ttttaccgtc tccgcctcca agaagagaaa 1550tctttaaatt tagcctctga tatggtgtca agagcagaaa ctattcagaa 1600gaataaagat caggcccatc gtttaaaggg agtgctccga gactccatag 1650tgatgcttga acagctgaag agctcactca ttatgcttca gaaaacgttt 1700gatctactaa ataagaataa gactggcatg gctgttgaaa gctagtgatc 1750tgaaggacta aaaccgcaga gatacttgga acttaaagaa aatacctgga 1800agaaaaccag acgaatgaag gattttggca tagaacattt ctatgttttt 1850tcattattga gatttctaat atgaacattt ctttcagtaa catttatttg 1900ataattagtt tctgctggcc ttaataatcc atcctttcac ttcttataga 1950tatttttaag ctgtgaattt cttcagtgaa ccatgaaata tattatagaa 2000ctgaatttct ctgatacaaa aagaaaatga cacaccctga attgagtggt 2050atggtctcat ttctacagtg aagtctgatg ctttgttagc acagaatccg 2100tacatgtcca ataggtcgct tttgtaactg agataagacc aagaggataa 2150acaggacaat ataagaagaa acctctatgt cattactgat tttaaaggtt 2200ctgttttcag gcatataaca tttccaggtt tgtgtactgt aaagattata 2250atgtcttcat ttatttagca tgcaaattta atagtcaaac tttttgaatc 2300tgcatgttga tgatgattat cagaaagggt cttctgccat gctgtatctt 2350tatgaaagaa atagttgttt tttcttaagg taactatcag aggtgggatt 2400atcttgcctc ctcacttaga ataccaacag tcaaaaggaa gaaccatcct 2450ctgagtttta aaaaccagaa ggttatgtta aaatctgggc atttagtgac 2500agatcaaatg catacttgaa ctaagattgg cttcagctta gcagtctttc 2550atggtggaag tgacacatct ggttgaaaat aatttgtgta ttttcagtaa 2600ccatgtatgg cttccttctt tatgtatgtg tgtgacttgt tttaattggt 2650aagttataag ccagacatag attttagctc tttaataaaa acttcagggg 2700cacgtatgtc ccagtacaag tgtactgact atcaagtttt aactcagatg 2750caagctttgg ctctttcata aaaagttttt atgcatatgt gtctccatac 2800aagtggctca ttaaaataag aactttgtaa actgacttaa aatcagatat 2850tttttcaaga gttagggaaa gttgaagtgt tttactgttt tgtctcttga 2900gccctttctc tggggaaaaa atacatatcc atctatctat ctatatataa 2950actgtgtata cattcttact gtttgaacaa ctattgcctt taattaaatg 3000tttcattttt ctccagagtc cccaaagcca catggcatta ttatagtcat 3050ttttgagatg cctgtagaga atgaaagtat tgactccgtt agagggaaaa 3100tgggtttctc tgggtgaatt ccaacgaagc atacctaggg gtaacagtga 3150acctacctgg gtttgttttg ttttggtaag gatttatgta gtgtctggct 3200gtaagcaaga atgagtggat tataaacttg aagatttctc tgttaaagtc 3250acaaaaatga tcgacaaaca atatttttgt gatgtttatt taaacgttgt 3300attttataac atacttcaag gaagagtatc gaagtaagtt gctttataaa 3350ttaagactaa attcgtatgg atgcagaatt caattaataa aatttgagcc 3400tgttacgtaa attgaatatt aataaaattg aaaatttcaa aa 3442110457PRTHomo sapiens 110Met Glu Asn Leu Ser Leu Ser Ile Glu Asp Val Gln Pro Arg Ser1 5 10 15Pro Gly Arg Ser Ser Leu Asp Asp Ser Gly Glu Arg Asp Glu Lys 20 25 30Leu Ser Lys Ser Ile Ser Phe Thr Ser Glu Ser Ile Ser Arg Val 35 40 45Ser Glu Thr Glu Ser Phe Asp Gly Asn Ser Ser Lys Gly Gly Leu 50 55 60Gly Lys Glu Glu Ser Gln Asn Glu Lys Gln Thr Lys Lys Ser Leu 65 70 75Leu Pro Thr Leu Glu Lys Lys Leu Thr Arg Val Pro Ser Lys Ser 80 85 90Leu Asp Leu Asn Lys Asn Glu Tyr Leu Ser Leu Asp Lys Ser Ser 95 100 105Thr Ser Asp Ser Val Asp Glu Glu Asn Val Pro Glu Lys Asp Leu 110 115 120His Gly Arg Leu Phe Ile Asn Arg Ile Phe His Ile Ser Ala Asp 125 130 135Arg Met Phe Glu Leu Leu Phe Thr Ser Ser Arg Phe Met Gln Lys 140 145 150Phe Ala Ser Ser Arg Asn Ile Ile Asp Val Val Ser Thr Pro Trp 155 160 165Thr Ala Glu Leu Gly Gly Asp Gln Leu Arg Thr Met Thr Tyr Thr 170 175 180Ile Val Leu Asn Ser Pro Leu Thr Gly Lys Cys Thr Ala Ala Thr 185 190 195Glu Lys Gln Thr Leu Tyr Lys Glu Ser Arg Glu Ala Arg Phe Tyr 200 205 210Leu Val Asp Ser Glu Val Leu Thr His Asp Val Pro Tyr His Asp 215 220 225Tyr Phe Tyr Thr Val Asn Arg Tyr Cys Ile Ile Arg Ser Ser Lys 230 235 240Gln Lys Cys Arg Leu Arg Val Ser Thr Asp Leu Lys Tyr Arg Lys 245 250 255Gln Pro Trp Gly Leu Val Lys Ser Leu Ile Glu Lys Asn Ser Trp 260 265 270Ser Ser Leu Glu Asp Tyr Phe Lys Gln Leu Glu Ser Asp Leu Leu 275 280 285Ile Glu Glu Ser Val Leu Asn Gln Ala Ile Glu Asp Pro Gly

Lys 290 295 300Leu Thr Gly Leu Arg Arg Arg Arg Arg Thr Phe Asn Arg Thr Ala 305 310 315Glu Thr Val Pro Lys Leu Ser Ser Gln His Ser Ser Gly Asp Val 320 325 330Gly Leu Gly Ala Lys Gly Asp Ile Thr Gly Lys Lys Lys Glu Met 335 340 345Glu Asn Tyr Asn Val Thr Leu Ile Val Val Met Ser Ile Phe Val 350 355 360Leu Leu Leu Val Leu Leu Asn Val Thr Leu Phe Leu Lys Leu Ser 365 370 375Lys Ile Glu His Ala Ala Gln Ser Phe Tyr Arg Leu Arg Leu Gln 380 385 390Glu Glu Lys Ser Leu Asn Leu Ala Ser Asp Met Val Ser Arg Ala 395 400 405Glu Thr Ile Gln Lys Asn Lys Asp Gln Ala His Arg Leu Lys Gly 410 415 420Val Leu Arg Asp Ser Ile Val Met Leu Glu Gln Leu Lys Ser Ser 425 430 435Leu Ile Met Leu Gln Lys Thr Phe Asp Leu Leu Asn Lys Asn Lys 440 445 450Thr Gly Met Ala Val Glu Ser 4551111606DNAHomo sapiens 111cggacgcgtg gggccgtatg cgcggctctg tggagtgcac ctggggttgg 50gggcactgtg cccccagccc cctgctcctt tggactctac ttctgtttgc 100agccccattt ggcctgctgg gggagaagac ccgccaggtg tctctggagg 150tcatccctaa ctggctgggc cccctgcaga acctgcttca tatacgggca 200gtgggcacca attccacact gcactatgtg tggagcagcc tggggcctct 250ggcagtggta atggtggcca ccaacacccc ccacagcacc ctgagcatca 300actggagcct cctgctatcc cctgagcccg atgggggcct gatggtgctc 350cctaaggaca gcattcagtt ttcttctgcc cttgttttta ccaggctgct 400tgagtttgac agcaccaacg tgtccgatac ggcagcaaag cctttgggaa 450gaccatatcc tccatactcc ttggccgatt tctcttggaa caacatcact 500gattcattgg atcctgccac cctgagtgcc acatttcaag gccaccccat 550gaacgaccct accaggactt ttgccaatgg cagcctggcc ttcagggtcc 600aggccttttc caggtccagc cgaccagccc aaccccctcg cctcctgcac 650acagcagaca cctgtcagct agaggtggcc ctgattggag cctctccccg 700gggaaaccgt tccctgtttg ggctggaggt agccacattg ggccagggcc 750ctgactgccc ctcaatgcag gagcagcact ccatcgacga tgaatatgca 800ccggccgtct tccagttgga ccagctactg tggggctccc tcccatcagg 850ctttgcacag tggcgaccag tggcttactc ccagaagccg gggggccgag 900aatcagccct gccctgccaa gcttcccctc ttcatcctgc cttagcatac 950tctcttcccc agtcacccat tgtccgagcc ttctttgggt cccagaataa 1000cttctgtgcc ttcaatctga cgttcggggc ttccacaggc cctggctatt 1050gggaccaaca ctacctcagc tggtcgatgc tcctgggtgt gggcttccct 1100ccagtggacg gcttgtcccc actagtcctg ggcatcatgg cagtggccct 1150gggtgcccca gggctcatgc tgctaggggg cggcttggtt ctgctgctgc 1200accacaagaa gtactcagag taccagtcca taaattaagg cccgctctct 1250ggagggaagg acattactga acctgtcttg ctgtgcctcg aaactctgga 1300ggttggagca tcaagttcca gccggcccct tcactccccc atcttgcttt 1350tctgtggaac ctcagaggcc agcctcgact tcctggagac ccccaggtgg 1400ggcttccttc atactttgtt gggggacttt ggaggcgggc aggggacagg 1450gctattgata aggtcccctt ggtgttgcct tcttgcatct ccacacattt 1500cccttggatg ggacttgcag gcctaaatga gaggcattct gactggttgg 1550ctgccctgga aggcaagaaa atagatttat tttttttcac agggaaaaaa 1600aaaaaa 1606112406PRTHomo sapiens 112Met Arg Gly Ser Val Glu Cys Thr Trp Gly Trp Gly His Cys Ala1 5 10 15Pro Ser Pro Leu Leu Leu Trp Thr Leu Leu Leu Phe Ala Ala Pro 20 25 30Phe Gly Leu Leu Gly Glu Lys Thr Arg Gln Val Ser Leu Glu Val 35 40 45Ile Pro Asn Trp Leu Gly Pro Leu Gln Asn Leu Leu His Ile Arg 50 55 60Ala Val Gly Thr Asn Ser Thr Leu His Tyr Val Trp Ser Ser Leu 65 70 75Gly Pro Leu Ala Val Val Met Val Ala Thr Asn Thr Pro His Ser 80 85 90Thr Leu Ser Ile Asn Trp Ser Leu Leu Leu Ser Pro Glu Pro Asp 95 100 105Gly Gly Leu Met Val Leu Pro Lys Asp Ser Ile Gln Phe Ser Ser 110 115 120Ala Leu Val Phe Thr Arg Leu Leu Glu Phe Asp Ser Thr Asn Val 125 130 135Ser Asp Thr Ala Ala Lys Pro Leu Gly Arg Pro Tyr Pro Pro Tyr 140 145 150Ser Leu Ala Asp Phe Ser Trp Asn Asn Ile Thr Asp Ser Leu Asp 155 160 165Pro Ala Thr Leu Ser Ala Thr Phe Gln Gly His Pro Met Asn Asp 170 175 180Pro Thr Arg Thr Phe Ala Asn Gly Ser Leu Ala Phe Arg Val Gln 185 190 195Ala Phe Ser Arg Ser Ser Arg Pro Ala Gln Pro Pro Arg Leu Leu 200 205 210His Thr Ala Asp Thr Cys Gln Leu Glu Val Ala Leu Ile Gly Ala 215 220 225Ser Pro Arg Gly Asn Arg Ser Leu Phe Gly Leu Glu Val Ala Thr 230 235 240Leu Gly Gln Gly Pro Asp Cys Pro Ser Met Gln Glu Gln His Ser 245 250 255Ile Asp Asp Glu Tyr Ala Pro Ala Val Phe Gln Leu Asp Gln Leu 260 265 270Leu Trp Gly Ser Leu Pro Ser Gly Phe Ala Gln Trp Arg Pro Val 275 280 285Ala Tyr Ser Gln Lys Pro Gly Gly Arg Glu Ser Ala Leu Pro Cys 290 295 300Gln Ala Ser Pro Leu His Pro Ala Leu Ala Tyr Ser Leu Pro Gln 305 310 315Ser Pro Ile Val Arg Ala Phe Phe Gly Ser Gln Asn Asn Phe Cys 320 325 330Ala Phe Asn Leu Thr Phe Gly Ala Ser Thr Gly Pro Gly Tyr Trp 335 340 345Asp Gln His Tyr Leu Ser Trp Ser Met Leu Leu Gly Val Gly Phe 350 355 360Pro Pro Val Asp Gly Leu Ser Pro Leu Val Leu Gly Ile Met Ala 365 370 375Val Ala Leu Gly Ala Pro Gly Leu Met Leu Leu Gly Gly Gly Leu 380 385 390Val Leu Leu Leu His His Lys Lys Tyr Ser Glu Tyr Gln Ser Ile 395 400 405Asn1132015DNAHomo sapiens 113ggaaaaggta cccgcgagag acagccagca gttctgtgga gcagcggtgg 50ccggctagga tgggctgtct ctggggtctg gctctgcccc ttttcttctt 100ctgctgggag gttggggtct ctgggagctc tgcaggcccc agcacccgca 150gagcagacac tgcgatgaca acggacgaca cagaagtgcc cgctatgact 200ctagcaccgg gccacgccgc tctggaaact caaacgctga gcgctgagac 250ctcttctagg gcctcaaccc cagccggccc cattccagaa gcagagacca 300ggggagccaa gagaatttcc cctgcaagag agaccaggag tttcacaaaa 350acatctccca acttcatggt gctgatcgcc acctccgtgg agacatcagc 400cgccagtggc agccccgagg gagctggaat gaccacagtt cagaccatca 450caggcagtga tcccgaggaa gccatctttg acaccctttg caccgatgac 500agctctgaag aggcaaagac actcacaatg gacatattga cattggctca 550cacctccaca gaagctaagg gcctgtcctc agagagcagt gcctcttccg 600acggccccca tccagtcatc accccgtcac gggcctcaga gagcagcgcc 650tcttccgacg gcccccatcc agtcatcacc ccgtcacggg cctcagagag 700cagcgcctct tccgacggcc cccatccagt catcaccccg tcatggtccc 750cgggatctga tgtcactctc ctcgctgaag ccctggtgac tgtcacaaac 800atcgaggtta ttaattgcag catcacagaa atagaaacaa caacttccag 850catccctggg gcctcagaca tagatctcat ccccacggaa ggggtgaagg 900cctcgtccac ctccgatcca ccagctctgc ctgactccac tgaagcaaaa 950ccacacatca ctgaggtcac agcctctgcc gagaccctgt ccacagccgg 1000caccacagag tcagctgcac ctcatgccac ggttgggacc ccactcccca 1050ctaacagcgc cacagaaaga gaagtgacag cacccggggc cacgaccctc 1100agtggagctc tggtcacagt tagcaggaat cccctggaag aaacctcagc 1150cctctctgtt gagacaccaa gttacgtcaa agtctcagga gcagctccgg 1200tctccataga ggctgggtca gcagtgggca aaacaacttc ctttgctggg 1250agctctgctt cctcctacag cccctcggaa gccgccctca agaacttcac 1300cccttcagag acaccgacca tggacatcgc aaccaagggg cccttcccca 1350ccagcaggga ccctcttcct tctgtccctc cgactacaac caacagcagc 1400cgagggacga acagcacctt agccaagatc acaacctcag cgaagaccac 1450gatgaagccc caacagccac gcccacgact gcccggacga ggccgaccac 1500agacgtgagt gcaggtgaaa atggaggttt cctcctcctg cggctgagtg 1550tggcttcccc ggaagacctc actgacccca gagtggcaga aaggctgatg 1600cagcagctcc accgggaact ccacgcccac gcgcctcact tccaggtctc 1650cttactgcgt gtcaggagag gctaacggac atcagctgca gccaggcatg 1700tcccgtatgc caaaagaggg tgctgcccct agcctgggcc cccaccgaca 1750gactgcagct gcgttactgt gctgagaggt acccagaagg ttcccatgaa 1800gggcagcatg tccaagcccc taaccccaga tgtggcaaca ggaccctcgc 1850tcacatccac cggagtgtat gtatggggag gggcttcacc tgttcccaga 1900ggtgtccttg gactcacctt ggcacatgtt ctgtgtttca gtaaagagag 1950acctgatcac ccatctgtgt gcttccatcc tgcattaaaa ttcactcagt 2000gtggcccaaa aaaaa 2015114482PRTHomo sapiens 114Met Gly Cys Leu Trp Gly Leu Ala Leu Pro Leu Phe Phe Phe Cys1 5 10 15Trp Glu Val Gly Val Ser Gly Ser Ser Ala Gly Pro Ser Thr Arg 20 25 30Arg Ala Asp Thr Ala Met Thr Thr Asp Asp Thr Glu Val Pro Ala 35 40 45Met Thr Leu Ala Pro Gly His Ala Ala Leu Glu Thr Gln Thr Leu 50 55 60Ser Ala Glu Thr Ser Ser Arg Ala Ser Thr Pro Ala Gly Pro Ile 65 70 75Pro Glu Ala Glu Thr Arg Gly Ala Lys Arg Ile Ser Pro Ala Arg 80 85 90Glu Thr Arg Ser Phe Thr Lys Thr Ser Pro Asn Phe Met Val Leu 95 100 105Ile Ala Thr Ser Val Glu Thr Ser Ala Ala Ser Gly Ser Pro Glu 110 115 120Gly Ala Gly Met Thr Thr Val Gln Thr Ile Thr Gly Ser Asp Pro 125 130 135Glu Glu Ala Ile Phe Asp Thr Leu Cys Thr Asp Asp Ser Ser Glu 140 145 150Glu Ala Lys Thr Leu Thr Met Asp Ile Leu Thr Leu Ala His Thr 155 160 165Ser Thr Glu Ala Lys Gly Leu Ser Ser Glu Ser Ser Ala Ser Ser 170 175 180Asp Gly Pro His Pro Val Ile Thr Pro Ser Arg Ala Ser Glu Ser 185 190 195Ser Ala Ser Ser Asp Gly Pro His Pro Val Ile Thr Pro Ser Arg 200 205 210Ala Ser Glu Ser Ser Ala Ser Ser Asp Gly Pro His Pro Val Ile 215 220 225Thr Pro Ser Trp Ser Pro Gly Ser Asp Val Thr Leu Leu Ala Glu 230 235 240Ala Leu Val Thr Val Thr Asn Ile Glu Val Ile Asn Cys Ser Ile 245 250 255Thr Glu Ile Glu Thr Thr Thr Ser Ser Ile Pro Gly Ala Ser Asp 260 265 270Ile Asp Leu Ile Pro Thr Glu Gly Val Lys Ala Ser Ser Thr Ser 275 280 285Asp Pro Pro Ala Leu Pro Asp Ser Thr Glu Ala Lys Pro His Ile 290 295 300Thr Glu Val Thr Ala Ser Ala Glu Thr Leu Ser Thr Ala Gly Thr 305 310 315Thr Glu Ser Ala Ala Pro His Ala Thr Val Gly Thr Pro Leu Pro 320 325 330Thr Asn Ser Ala Thr Glu Arg Glu Val Thr Ala Pro Gly Ala Thr 335 340 345Thr Leu Ser Gly Ala Leu Val Thr Val Ser Arg Asn Pro Leu Glu 350 355 360Glu Thr Ser Ala Leu Ser Val Glu Thr Pro Ser Tyr Val Lys Val 365 370 375Ser Gly Ala Ala Pro Val Ser Ile Glu Ala Gly Ser Ala Val Gly 380 385 390Lys Thr Thr Ser Phe Ala Gly Ser Ser Ala Ser Ser Tyr Ser Pro 395 400 405Ser Glu Ala Ala Leu Lys Asn Phe Thr Pro Ser Glu Thr Pro Thr 410 415 420Met Asp Ile Ala Thr Lys Gly Pro Phe Pro Thr Ser Arg Asp Pro 425 430 435Leu Pro Ser Val Pro Pro Thr Thr Thr Asn Ser Ser Arg Gly Thr 440 445 450Asn Ser Thr Leu Ala Lys Ile Thr Thr Ser Ala Lys Thr Thr Met 455 460 465Lys Pro Gln Gln Pro Arg Pro Arg Leu Pro Gly Arg Gly Arg Pro 470 475 480Gln Thr115526DNAHomo sapiens 115gcgaggcggc cgctgtcttc tgctgcggct tccgcgacca caagtactgc 50tgcgacgacc cgcacagctt cttcccctac gagcacagct acatgtggtg 100gctcagcatt ggcgctctca taggcctgtc cgtagcagca gtggttcttc 150tcgccttcat tgttaccgcc tgtgtgctct gctacctgtt catcagctct 200aagccccaca caaagttgga cctgggcttg agcttacaga cagcaggccc 250tgaggaggtt tctcctgact gccaaggtgt gaacacaggc atggcggcag 300aagtgccaaa agtgagccct ctccagcaga gttactcctg cttgaacccg 350cagctggaga gcaatgaggg gcaggctgtg aactccaaac gcctcctcca 400tcattgcttc atggccacag tgaccaccag tgacattcca ggcagccctg 450aggaagcctc tgtacccaac cctgacctat gtggaccagt cccataaaca 500ttcaataaat gtctccatac catcaa 526116134PRTHomo sapiens 116Met Trp Trp Leu Ser Ile Gly Ala Leu Ile Gly Leu Ser Val Ala1 5 10 15Ala Val Val Leu Leu Ala Phe Ile Val Thr Ala Cys Val Leu Cys 20 25 30Tyr Leu Phe Ile Ser Ser Lys Pro His Thr Lys Leu Asp Leu Gly 35 40 45Leu Ser Leu Gln Thr Ala Gly Pro Glu Glu Val Ser Pro Asp Cys 50 55 60Gln Gly Val Asn Thr Gly Met Ala Ala Glu Val Pro Lys Val Ser 65 70 75Pro Leu Gln Gln Ser Tyr Ser Cys Leu Asn Pro Gln Leu Glu Ser 80 85 90Asn Glu Gly Gln Ala Val Asn Ser Lys Arg Leu Leu His His Cys 95 100 105Phe Met Ala Thr Val Thr Thr Ser Asp Ile Pro Gly Ser Pro Glu 110 115 120Glu Ala Ser Val Pro Asn Pro Asp Leu Cys Gly Pro Val Pro 125 1301171863DNAHomo sapiens 117cctctgtctg tgctcccatc ccagggagta taggtggagc ctccagagcc 50catggacagg gcatgctggg gctgggccag ccccagcggt gtctctaagg 100cacccctggg atccccactg agctggccta cttcagacag ccagggccca 150cccctctggc ccccttagtg tccagctcgt ggccccttgg catttccaca 200agacgccaag atggagattc ccatggggac ccagggctgc ttctcaaaga 250gcctcctgct ctcagcctca atcctggtcc tctggatgct ccaaggctcc 300caggcagctc tctacatcca gaagattcca gagcagcctc aaaagaacca 350ggaccttctc ctgtcagtcc agggtgtccc agacaccttc caggacttca 400actggtacct gggggaggag acgtacggag gcacgaggct atttacctac 450atccctggga tacaacggcc tcagagggat ggcagtgcca tgggacagcg 500agacatcgtg ggcttcccca atggttccat gctgctgcgc cgcgcccagc 550ctacagacag tggcacctac caagtagcca ttaccatcaa ctctgaatgg 600actatgaagg ccaagactga ggtccaggta gctgaaaaga ataaggagct 650gcccagtaca cacctgccca ccaacgctgg gatcctggcg gccaccatca 700ttggatctct tgctgccggg gcccttctca tcagctgcat tgcctatctc 750ctggtgacaa ggaactggag gggccagagc cacagactgc ctgctccgag 800gggccaggga tctctgtcca tcttgtgctc ggctgtatcc ccagtgcctt 850cagtgacgcc cagcacatgg atggcgacca cagagaagcc agaattgggc 900cctgctcatg atgctggtga caacaacatc tatgaagtga tgccctctcc 950agtcctcctg gtgtccccca tcagtgacac aaggtccata aacccagccc 1000ggcccctgcc cacaccccca cacctgcagg cggagccaga gaaccaccag 1050taccagcagg acctgctaaa ccccgaccct gccccctact gccagctggt 1100gccaacttcc tgatgggtcc tgggccaggc cagccaggga gaagacaagg 1150ccccagccct cctctgggag cctcacacct gagaccagca ggacaaggcc 1200attgggggct gtggggccga tgaggtggac tcagccaaag actcagcagc 1250acatggggca ggtgtcctgg cagggggaca ggagactgta acaggcccag 1300gtccttgtgc agcccctgaa tgcacgcccg ccttcggtct gttccttcaa 1350gcaagctggc ctgggccatg tgcctgtgaa aggcaggctc tggccccttt 1400ccatgccaaa gtcccccaag atctggatat ctggggacaa gatggtggcc 1450tcaggcctgc ctcccaggca gttggctggg ctcccaactg tctgtcctca 1500atgccctacc ccaactccac tagtgaccct cagagtcttc tccccttagg 1550acaaggcaga caccccacca tgcgggcctc aggtggcaga gaggcccagc 1600ctcacaggcc tgtggcccca cacaccagtc ccagcaaggt gaccacggct 1650gctggacccc ttccctgttc aggcaggccc agcccctctc agaacctgct 1700gccagctgct ggtcttggcc cccaccctga atcttactga gtccctctgg 1750gcagcagctc ccttctccac cccaccccag cacccgtccc

aaatgtggcc 1800tcagcttgtc ctccccttcc ccaaactatg cattcattca gcaataaatg 1850agcctttgct gca 1863118300PRTHomo sapiens 118Met Glu Ile Pro Met Gly Thr Gln Gly Cys Phe Ser Lys Ser Leu1 5 10 15Leu Leu Ser Ala Ser Ile Leu Val Leu Trp Met Leu Gln Gly Ser 20 25 30Gln Ala Ala Leu Tyr Ile Gln Lys Ile Pro Glu Gln Pro Gln Lys 35 40 45Asn Gln Asp Leu Leu Leu Ser Val Gln Gly Val Pro Asp Thr Phe 50 55 60Gln Asp Phe Asn Trp Tyr Leu Gly Glu Glu Thr Tyr Gly Gly Thr 65 70 75Arg Leu Phe Thr Tyr Ile Pro Gly Ile Gln Arg Pro Gln Arg Asp 80 85 90Gly Ser Ala Met Gly Gln Arg Asp Ile Val Gly Phe Pro Asn Gly 95 100 105Ser Met Leu Leu Arg Arg Ala Gln Pro Thr Asp Ser Gly Thr Tyr 110 115 120Gln Val Ala Ile Thr Ile Asn Ser Glu Trp Thr Met Lys Ala Lys 125 130 135Thr Glu Val Gln Val Ala Glu Lys Asn Lys Glu Leu Pro Ser Thr 140 145 150His Leu Pro Thr Asn Ala Gly Ile Leu Ala Ala Thr Ile Ile Gly 155 160 165Ser Leu Ala Ala Gly Ala Leu Leu Ile Ser Cys Ile Ala Tyr Leu 170 175 180Leu Val Thr Arg Asn Trp Arg Gly Gln Ser His Arg Leu Pro Ala 185 190 195Pro Arg Gly Gln Gly Ser Leu Ser Ile Leu Cys Ser Ala Val Ser 200 205 210Pro Val Pro Ser Val Thr Pro Ser Thr Trp Met Ala Thr Thr Glu 215 220 225Lys Pro Glu Leu Gly Pro Ala His Asp Ala Gly Asp Asn Asn Ile 230 235 240Tyr Glu Val Met Pro Ser Pro Val Leu Leu Val Ser Pro Ile Ser 245 250 255Asp Thr Arg Ser Ile Asn Pro Ala Arg Pro Leu Pro Thr Pro Pro 260 265 270His Leu Gln Ala Glu Pro Glu Asn His Gln Tyr Gln Gln Asp Leu 275 280 285Leu Asn Pro Asp Pro Ala Pro Tyr Cys Gln Leu Val Pro Thr Ser 290 295 3001191830DNAHomo sapiens 119agcatgagag gcctggccgt cctcctcact gtggctctgg ccacgctcct 50ggctcccggg gccggagcac cggtacaaag tcagggctcc cagaacaagc 100tgctcctggt gtccttcgac ggcttccgct ggaactacga ccaggatgtg 150gacaccccca acctggacgc catggcccga gacggggtga aggcacgcta 200catgaccccc gcctttgtca ccatgaccag cccctgccac ttcaccctgg 250tcaccggcaa atatatcgag aaccacgggg tggttcacaa catgtactac 300aacatcacca gcaaggtgaa gctgccctac cacgccacgc tgggcatcca 350gaggtggtgg gacaacggca gcgtgcccat ctggatcaca gcccagaggc 400agggcctgag ggctggctcc ttcttctacc cgggcgggaa cgtcacctac 450caaggggtgg ctgtgacgcg gagccggaaa gaaggcatcg cacacaacta 500caaaaatgag acggagtgga gagcgaacat cgacacagtg atggcgtggt 550tcacagagga ggacctggat ctggtcacac tctacttcgg ggagccggac 600tccacgggcc acaggtacgg ccccgagtcc ccggagagga gggagatggt 650gcggcaggtg gaccggaccg tgggctacct ccgggagagc atcgcgcgca 700accacctcac agaccgcctc aacctgatca tcacatccga ccacggcatg 750acgaccgtgg acaaacgggc tggcgacctg gttgaattcc acaagttccc 800caacttcacc ttccgggaca tcgagtttga gctcctggac tacggaccaa 850acgggatgct gctccctaaa gaagggaggc tggagaaggt gtacgatgcc 900ctcaaggacg cccaccccaa gctccacgtc tacaagaagg aggcgttccc 950cgaggccttc cactacgcca acaaccccag ggtcacaccc ctgctgatgt 1000acagcgacct tggctacgtc atccatggga gaattaacgt ccagttcaac 1050aatggggagc acggctttga caacaaggac atggacatga agaccatctt 1100ccgcgctgtg ggccctagct tcagggcggg cctggaggtg gagccctttg 1150agagcgtcca cgtgtacgag ctcatgtgcc ggctgctggg catcgtgccc 1200gaggccaacg atgggcacct agctactctg ctgcccatgc tgcacacaga 1250atctgctctt ccgcctgatg gaaggcctac tctcctgccc aagggaagat 1300ctgctctccc gcccagcagc aggcccctcc tcgtgatggg actgctgggg 1350accgtgattc ttctgtctga ggtcgcataa cgccccatgg ctcaaggaag 1400ccgccgggag ctgcccgcag gccctgggcc ggctgtctcg ctgcgatgct 1450ctgctggtcg cggacggacc ctgcctcccc agcttatccc aggccagagg 1500ctgcatgcca ctgtccccgg cagcgccaac ccctgcttgg ctgttatggt 1550gctggtaata agcctcgcag cccaggtcca gagcccccgg cgagccggtc 1600ccataaccgg ccccctgccc ctgcccctgc tcctgctcct ccccttcggg 1650ccccctcctc ctgcaaaacc cgctcccgaa gcggcgctgc cgtctgcagc 1700cacgcggggg cgcgcgggag ctctgcgggc gctggaacct gcagacccgg 1750cctcggtcag ctgggagggg cccgccccgg cacaaagcac ccatgggaat 1800aaaggccaag ccgcgacagt caaaaaaaaa 1830120458PRTHomo sapiens 120Met Arg Gly Leu Ala Val Leu Leu Thr Val Ala Leu Ala Thr Leu1 5 10 15Leu Ala Pro Gly Ala Gly Ala Pro Val Gln Ser Gln Gly Ser Gln 20 25 30Asn Lys Leu Leu Leu Val Ser Phe Asp Gly Phe Arg Trp Asn Tyr 35 40 45Asp Gln Asp Val Asp Thr Pro Asn Leu Asp Ala Met Ala Arg Asp 50 55 60Gly Val Lys Ala Arg Tyr Met Thr Pro Ala Phe Val Thr Met Thr 65 70 75Ser Pro Cys His Phe Thr Leu Val Thr Gly Lys Tyr Ile Glu Asn 80 85 90His Gly Val Val His Asn Met Tyr Tyr Asn Ile Thr Ser Lys Val 95 100 105Lys Leu Pro Tyr His Ala Thr Leu Gly Ile Gln Arg Trp Trp Asp 110 115 120Asn Gly Ser Val Pro Ile Trp Ile Thr Ala Gln Arg Gln Gly Leu 125 130 135Arg Ala Gly Ser Phe Phe Tyr Pro Gly Gly Asn Val Thr Tyr Gln 140 145 150Gly Val Ala Val Thr Arg Ser Arg Lys Glu Gly Ile Ala His Asn 155 160 165Tyr Lys Asn Glu Thr Glu Trp Arg Ala Asn Ile Asp Thr Val Met 170 175 180Ala Trp Phe Thr Glu Glu Asp Leu Asp Leu Val Thr Leu Tyr Phe 185 190 195Gly Glu Pro Asp Ser Thr Gly His Arg Tyr Gly Pro Glu Ser Pro 200 205 210Glu Arg Arg Glu Met Val Arg Gln Val Asp Arg Thr Val Gly Tyr 215 220 225Leu Arg Glu Ser Ile Ala Arg Asn His Leu Thr Asp Arg Leu Asn 230 235 240Leu Ile Ile Thr Ser Asp His Gly Met Thr Thr Val Asp Lys Arg 245 250 255Ala Gly Asp Leu Val Glu Phe His Lys Phe Pro Asn Phe Thr Phe 260 265 270Arg Asp Ile Glu Phe Glu Leu Leu Asp Tyr Gly Pro Asn Gly Met 275 280 285Leu Leu Pro Lys Glu Gly Arg Leu Glu Lys Val Tyr Asp Ala Leu 290 295 300Lys Asp Ala His Pro Lys Leu His Val Tyr Lys Lys Glu Ala Phe 305 310 315Pro Glu Ala Phe His Tyr Ala Asn Asn Pro Arg Val Thr Pro Leu 320 325 330Leu Met Tyr Ser Asp Leu Gly Tyr Val Ile His Gly Arg Ile Asn 335 340 345Val Gln Phe Asn Asn Gly Glu His Gly Phe Asp Asn Lys Asp Met 350 355 360Asp Met Lys Thr Ile Phe Arg Ala Val Gly Pro Ser Phe Arg Ala 365 370 375Gly Leu Glu Val Glu Pro Phe Glu Ser Val His Val Tyr Glu Leu 380 385 390Met Cys Arg Leu Leu Gly Ile Val Pro Glu Ala Asn Asp Gly His 395 400 405Leu Ala Thr Leu Leu Pro Met Leu His Thr Glu Ser Ala Leu Pro 410 415 420Pro Asp Gly Arg Pro Thr Leu Leu Pro Lys Gly Arg Ser Ala Leu 425 430 435Pro Pro Ser Ser Arg Pro Leu Leu Val Met Gly Leu Leu Gly Thr 440 445 450Val Ile Leu Leu Ser Glu Val Ala 4551211524DNAHomo sapiens 121gcggcagcag cgcgggcccc agcagcctcg gcagccacag ccgctgcagc 50cggggcagcc tccgctgctg tcgcctcctc tgatgcgctt gccctctccc 100ggccccggga ctccgggaga atgtgggtcc taggcatcgc ggcaactttt 150tgcggattgt tcttgcttcc aggctttgcg ctgcaaatcc agtgctacca 200gtgtgaagaa ttccagctga acaacgactg ctcctccccc gagttcattg 250tgaattgcac ggtgaacgtt caagacatgt gtcagaaaga agtgatggag 300caaagtgccg ggatcatgta ccgcaagtcc tgtgcatcat cagcggcctg 350tctcatcgcc tctgccgggt accagtcctt ctgctcccca gggaaactga 400actcagtttg catcagctgc tgcaacaccc ctctttgtaa cgggccaagg 450cccaagaaaa ggggaagttc tgcctcggcc ctcaggccag ggctccgcac 500caccatcctg ttcctcaaat tagccctctt ctcggcacac tgctgaagct 550gaaggagatg ccaccccctc ctgcattgtt cttccagccc tcgcccccaa 600ccccccacct ccctgagtga gtttcttctg ggtgtccttt tattctgggt 650agggagcggg agtccgtgtt ctcttttgtt cctgtgcaaa taatgaaaga 700gctcggtaaa gcattctgaa taaattcagc ctgactgaat tttcagtatg 750tacttgaagg aaggaggtgg agtgaaagtt cacccccatg tctgtgtaac 800cggagtcaag gccaggctgg cagagtcagt ccttagaagt cactgaggtg 850ggcatctgcc ttttgtaaag cctccagtgt ccattccatc cctgatgggg 900gcatagtttg agactgcaga gtgagagtga cgttttctta gggctggagg 950gccagttccc actcaaggct ccctcgcttg acattcaaac ttcatgctcc 1000tgaaaaccat tctctgcagc agaattggct ggtttcgcgc ctgagttggg 1050ctctagtgac tcgagactca atgactggga cttagactgg ggctcggcct 1100cgctctgaaa agtgcttaag aaaatcttct cagttctcct tgcagaggac 1150tggcgccggg acgcgaagag caacgggcgc tgcacaaagc gggcgctgtc 1200ggtggtggag tgcgcatgta cgcgcaggcg cttctcgtgg ttggcgtgct 1250gcagcgacag gcggcagcac agcacctgca cgaacacccg ccgaaactgc 1300tgcgaggaca ccgtgtacag gagcgggttg atgaccgagc tgaggtagaa 1350aaacgtctcc gagaagggga ggaggatcat gtacgcccgg aagtaggacc 1400tcgtccagtc gtgcttgggt ttggccgcag ccatgatcct ccgaatctgg 1450ttgggcatcc agcatacggc caatgtcaca acaatcagcc ctgggcagac 1500acgagcagga gggagagaca gaga 1524122141PRTHomo sapiens 122Met Trp Val Leu Gly Ile Ala Ala Thr Phe Cys Gly Leu Phe Leu1 5 10 15Leu Pro Gly Phe Ala Leu Gln Ile Gln Cys Tyr Gln Cys Glu Glu 20 25 30Phe Gln Leu Asn Asn Asp Cys Ser Ser Pro Glu Phe Ile Val Asn 35 40 45Cys Thr Val Asn Val Gln Asp Met Cys Gln Lys Glu Val Met Glu 50 55 60Gln Ser Ala Gly Ile Met Tyr Arg Lys Ser Cys Ala Ser Ser Ala 65 70 75Ala Cys Leu Ile Ala Ser Ala Gly Tyr Gln Ser Phe Cys Ser Pro 80 85 90Gly Lys Leu Asn Ser Val Cys Ile Ser Cys Cys Asn Thr Pro Leu 95 100 105Cys Asn Gly Pro Arg Pro Lys Lys Arg Gly Ser Ser Ala Ser Ala 110 115 120Leu Arg Pro Gly Leu Arg Thr Thr Ile Leu Phe Leu Lys Leu Ala 125 130 135Leu Phe Ser Ala His Cys 1401232786DNAHomo sapiens 123agcactctcc agcctctcac cgcaaaatta cacaccccag tacaccagca 50gaggaaactt ataacctcgg gaggcgggtc cttcccctca gtgcggtcac 100atacttccag aagagcggac cagggctgct gccagcacct gccactcaga 150gcgcctctgt cgctgggacc cttcagaact ctctttgctc acaagttacc 200aaaaaaaaaa gagccaacat gttggtattg ctggctggta tctttgtggt 250ccacatcgct actgttatta tgctatttgt tagcaccatt gccaatgtct 300ggttggtttc caatacggta gatgcatcag taggtctttg gaaaaactgt 350accaacatta gctgcagtga cagcctgtca tatgccagtg aagatgccct 400caagacagtg caggccttca tgattctctc tatcatcttc tgtgtcattg 450ccctcctggt cttcgtgttc cagctcttca ccatggagaa gggaaaccgg 500ttcttcctct caggggccac cacactggtg tgctggctgt gcattcttgt 550gggggtgtcc atctacacta gtcattatgc gaatcgtgat ggaacgcagt 600atcaccacgg ctattcctac atcctgggct ggatctgctt ctgcttcagc 650ttcatcatcg gcgttctcta tctggtcctg agaaagaaat aaggccggac 700gagttcatgg ggatctgggg ggtggggagg aggaagccgt tgaatctggg 750agggaagtgg aggttgctgt acaggaaaaa ccgagatagg ggagggggga 800gggggaagca aaggggggag gtcaaatccc aaaccattac tgaggggatt 850ctctactgcc aagcccctgc cctggggaga aagtagttgg ctagtacttt 900gatgctccct tgatggggtc cagagagcct ccctgcagcc accagacttg 950gcctccagct gttcttagtg acacacactg tctggggccc catcagctgc 1000cacaacacca gccccacttc tgggtcatgc actgaggtcc acagacctac 1050tgcactgagt taaaatagcg gtacaagttc tggcaagagc agatactgtc 1100tttgtgctga atacgctaag cctggaagcc atcctgccct tctgacccaa 1150agcaaaacat cacattccag tctgaagtgc ctactggggg gctttggcct 1200gtgagccatt gtccctcttt ggaacagata tttagctctg tggaattcag 1250tgacaaaatg ggaggaggaa agagagtttg taaggtcatg ctggtgggtt 1300agctaaacca agaaggagac cttttcacaa tggaaaacct gggggatggt 1350cagagcccag tcgagacctc acacacggct gtccctcatg gagacctcat 1400gccatggtct ttgctaggcc tcttgctgaa agccaaggca gctcttctgg 1450agtttctcta aagtcactag tgaacaattc ggtggtaaaa gtaccacaca 1500aactatggga tccaaggggc agtcttgcaa cagtgccatg ttagggttat 1550gtttttagga ttcccctcaa tgcagtcagt gtttctttta agtatacaac 1600aggagagaga tggacatggc tcattgtagc acaatcctat tactcttcct 1650ctaacatttt tgaggaagtt ttgtctaatt atcaatattg aggatcaggg 1700ctcctaggct cagtggtagc tctggcttag acaccacctg gagtgatcac 1750ctcttgggga ccctgcctat cccacttcac aggtgaggca tggcaattct 1800ggaagctgat taaaacacac ataaaccaaa accaaacaac aggcccttgg 1850gtgaaaggtg ctatataatt gtgaagtatt aagcctaccg tatttcagcc 1900atgataagaa cagagtgcct gcattcccag gaaaatacga aaatcccatg 1950agataaataa aaatataggt gatgggcaga tcttttcttt aaaataaaaa 2000agcaaaaact cttgtggtac ctagtcagat ggtagacgag ctgtctgctg 2050ccgcaggagc acctctatac aggacttaga agtagtatgt tattcctggt 2100taagcaggca ttgctttgcc ctggagcagc tattttaagc catctcagat 2150tctgtctaaa ggggtttttt gggaagacgt tttctttatc gccctgagaa 2200gatctacccc agggagaatc tgagacatct tgcctacttt tctttattag 2250ctttctcctc atccatttct tttatacctt tcctttttgg ggagttgtta 2300tgccatgatt tttggtattt atgtaaaagg attattacta attctatttc 2350tctatgttta ttctagttaa ggaaatgttg agggcaagcc accaaattac 2400ctaggctgag gttagagaga ttggccagca aaaactgtgg gaagatgaac 2450tttgtcatta tgatttcatt atcacatgat tatagaaggc tgtcttagtg 2500caaaaaacat acttacattt cagacatatc caaagggaat actcacattt 2550tgttaagaag ttgaactatg actggagtaa accatgtatt cccttatctt 2600ttactttttt tctgtgacat ttatgtctca tgtaatttgc attactctgg 2650tggattgttc tagtactgta ttgggcttct tcgttaatag attatttcat 2700atactataat tgtaaatatt ttgatacaaa tgtttataac tctagggata 2750taaaaacaga ttctgattcc cttcaaaaaa aaaaaa 2786124157PRTHomo sapiens 124Met Leu Val Leu Leu Ala Gly Ile Phe Val Val His Ile Ala Thr1 5 10 15Val Ile Met Leu Phe Val Ser Thr Ile Ala Asn Val Trp Leu Val 20 25 30Ser Asn Thr Val Asp Ala Ser Val Gly Leu Trp Lys Asn Cys Thr 35 40 45Asn Ile Ser Cys Ser Asp Ser Leu Ser Tyr Ala Ser Glu Asp Ala 50 55 60Leu Lys Thr Val Gln Ala Phe Met Ile Leu Ser Ile Ile Phe Cys 65 70 75Val Ile Ala Leu Leu Val Phe Val Phe Gln Leu Phe Thr Met Glu 80 85 90Lys Gly Asn Arg Phe Phe Leu Ser Gly Ala Thr Thr Leu Val Cys 95 100 105Trp Leu Cys Ile Leu Val Gly Val Ser Ile Tyr Thr Ser His Tyr 110 115 120Ala Asn Arg Asp Gly Thr Gln Tyr His His Gly Tyr Ser Tyr Ile 125 130 135Leu Gly Trp Ile Cys Phe Cys Phe Ser Phe Ile Ile Gly Val Leu 140 145 150Tyr Leu Val Leu Arg Lys Lys 1551251056DNAHomo sapiens 125gtctgcgcgg agtctgagcg gcgctcgtcc cgtcccaagg ccgacgccag 50cacgccgtca tggcccccgc agcggcgacg gggggcagca ccctgcccag 100tggcttctcg gtcttcacca ccttgcccga cttgctcttc atctttgagt 150ttatcttcgg gggcctggtg tggatcctgg tggcctcctc cctggtgccc 200tggcccctgg tccagggctg ggtgatgttc gtgtctgtgt tctgcttcgt 250ggccaccacc accttgatca tcctgtacat aattggagcc cacggtggag 300agacttcctg ggtcaccttg gacgcagcct accactgcac cgctgccctc 350ttttacctca gcgcctcagt cctggaggcc ctggccacca tcacgatgca 400agacggcttc acctacaggc actaccatga

aaacattgct gccgtggtgt 450tctcctacat agccactctg ctctacgtgg tccatgcggt gttctcttta 500atcagatgga agtcttcata aagccgcagt agaacttgag ctgaaaaccc 550agatggtgtt aactggccgc cccactttcc ggcataactt tttagaaaac 600agaaatgccc ttgatggtgg aaaaaagaaa acaaccaccc ccccactgcc 650caaaaaaaaa agccctgccc tgttgctcgt gggtgctgtg tttactctcc 700cgtgtgcctt cgcgtccggg ttgggagctt gctgtgtcta acctccaact 750gctgtgctgt ctgctagggt cacctcctgt ttgtgaaagg ggaccttctt 800gttcgggggt gggaagtggc gaccgtgacc tgagaaggaa agaaagatcc 850tctgctgacc cctggagcag ctctcgagaa ctacctgttg gtattgtcca 900caagctctcc cgagcgcccc atcttgtgcc atgttttaag tcttcatgga 950tgttctgcat gtcatgggga ctaaaactca cccaacagat ctttccagag 1000gtccatggtg gaagacgata accctgtgaa atactttata aaatgtctta 1050atgttc 1056126153PRTHomo sapiens 126Met Ala Pro Ala Ala Ala Thr Gly Gly Ser Thr Leu Pro Ser Gly1 5 10 15Phe Ser Val Phe Thr Thr Leu Pro Asp Leu Leu Phe Ile Phe Glu 20 25 30Phe Ile Phe Gly Gly Leu Val Trp Ile Leu Val Ala Ser Ser Leu 35 40 45Val Pro Trp Pro Leu Val Gln Gly Trp Val Met Phe Val Ser Val 50 55 60Phe Cys Phe Val Ala Thr Thr Thr Leu Ile Ile Leu Tyr Ile Ile 65 70 75Gly Ala His Gly Gly Glu Thr Ser Trp Val Thr Leu Asp Ala Ala 80 85 90Tyr His Cys Thr Ala Ala Leu Phe Tyr Leu Ser Ala Ser Val Leu 95 100 105Glu Ala Leu Ala Thr Ile Thr Met Gln Asp Gly Phe Thr Tyr Arg 110 115 120His Tyr His Glu Asn Ile Ala Ala Val Val Phe Ser Tyr Ile Ala 125 130 135Thr Leu Leu Tyr Val Val His Ala Val Phe Ser Leu Ile Arg Trp 140 145 150Lys Ser Ser1272973DNAHomo sapiens 127ccgcggaact ggcaggcgtt tcagagcgtc agaggctgcg gatgagcaga 50cttggaggac tccaggccag agactaggct gggcgaagag tcgagcgtga 100agggggctcc gggccagggt gacaggaggc gtgcttgaga ggaagaagtt 150gacgggaagg ccagtgcgac ggcaaatctc gtgaaccttg ggggacgaat 200gctcaggatg cgggtccccg ccctcctcgt cctcctcttc tgcttcagag 250ggagagcagg cccgtcgccc catttcctgc aacagccaga ggacctggtg 300gtgctgctgg gggaggaagc ccggctgccg tgtgctctgg gcgcctactg 350ggggctagtt cagtggacta agagtgggct ggccctaggg ggccaaaggg 400acctaccagg gtggtcccgg tactggatat cagggaatgc agccaatggc 450cagcatgacc tccacattag gcccgtggag ctagaggatg aagcatcata 500tgaatgtcag gctacacaag caggcctccg ctccagacca gcccaactgc 550acgtgctggt ccccccagaa gccccccagg tgctgggcgg cccctctgtg 600tctctggttg ctggagttcc tgcgaacctg acatgtcgga gccgtgggga 650tgcccgccct acccctgaat tgctgtggtt ccgagatggg gtcctgttgg 700atggagccac ctttcatcag accctgctga aggaagggac ccctgggtca 750gtggagagca ccttaaccct gacccctttc agccatgatg atggagccac 800ctttgtctgc cgggcccgga gccaggccct gcccacagga agagacacag 850ctatcacact gagcctgcag taccccccag aggtgactct gtctgcttcg 900ccacacactg tgcaggaggg agagaaggtc attttcctgt gccaggccac 950agcccagcct cctgtcacag gctacaggtg ggcaaaaggg ggctctccgg 1000tgctcggggc ccgcgggcca aggttagagg tcgtggcaga cgcctcgttc 1050ctgactgagc ccgtgtcctg cgaggtcagc aacgccgtgg gtagcgccaa 1100ccgcagtact gcgctggatg tgctgtttgg gccgattctg caggcaaagc 1150cggagcccgt gtccgtggac gtgggggaag acgcttcctt cagctgcgcc 1200tggcgcggga acccgcttcc acgggtaacc tggacccgcc gcggtggcgc 1250gcaggtgctg ggctctggag ccacactgcg tcttccgtcg gtggggcccg 1300aggacgcagg cgactatgtg tgcagagctg aggctgggct atcgggcctg 1350cggggcggcg ccgcggaggc tcggctgact gtgaacgctc ccccagtagt 1400gaccgccctg cactctgcgc ctgccttcct gaggggccct gctcgcctcc 1450agtgtctggt tttcgcctct cccgccccag atgccgtggt ctggtcttgg 1500gatgagggct tcctggaggc ggggtcgcag ggccggttcc tggtggagac 1550attccctgcc ccagagagcc gcgggggact gggtccgggc ctgatctctg 1600tgctacacat ttcggggacc caggagtctg actttagcag gagctttaac 1650tgcagtgccc ggaaccggct gggcgaggga ggtgcccagg ccagcctggg 1700ccgtagagac ttgctgccca ctgtgcggat agtggccgga gtggccgctg 1750ccaccacaac tctccttatg gtcatcactg gggtggccct ctgctgctgg 1800cgccacagca aggcctcagc ctctttctcc gagcaaaaga acctgatgcg 1850aatccctggc agcagcgacg gctccagttc acgaggtcct gaagaagagg 1900agacaggcag ccgcgaggac cggggcccca ttgtgcacac tgaccacagt 1950gatctggttc tggaggagga agggactctg gagaccaagg acccaaccaa 2000cggttactac aaggtccgag gagtcagtgt gagcctgagc cttggcgaag 2050cccctggagg aggtctcttc ctgccaccac cctcccccct tgggccccca 2100gggaccccta ccttctatga cttcaaccca cacctgggca tggtcccccc 2150ctgcagactt tacagagcca gggcaggcta tctcaccaca ccccaccctc 2200gagctttcac cagctacatc aaacccacat cctttgggcc cccagatctg 2250gcccccggga ctcccccctt cccatatgct gccttcccca cacctagcca 2300cccgcgtctc cagactcacg tgtgacatct ttccaatgga agagtcctgg 2350gatctccaac ttgccataat ggattgttct gatttctgag gagccaggac 2400aagttggcga ccttactcct ccaaaactga acacaagggg agggaaagat 2450cattacattt gtcaggagca tttgtataca gtcagctcag ccaaaggaga 2500tgccccaagt gggagcaaca tggccaccca atatgcccac ctattccccg 2550gtgtaaaaga gattcaagat ggcaggtagg ccctttgagg agagatgggg 2600acagggcagt gggtgttggg agtttggggc cgggatggaa gttgtttcta 2650gccactgaaa gaagatattt caagatgacc atctgcattg agaggaaagg 2700tagcatagga tagatgaaga tgaagagcat accaggcccc accctggctc 2750tccctgaggg gaactttgct cggccaatgg aaatgcagcc aagatggcca 2800tatactccct aggaacccaa aatggccacc atcttgattt tactttcctt 2850aaagactcag aaagacttgg acccaaggag tggggataca gtgagaatta 2900ccactgttgg ggcaaaatat tgggataaaa atatttatgt ttaataataa 2950aaaaaagtca aagagaaaaa aaa 2973128708PRTHomo sapiens 128Met Leu Arg Met Arg Val Pro Ala Leu Leu Val Leu Leu Phe Cys1 5 10 15Phe Arg Gly Arg Ala Gly Pro Ser Pro His Phe Leu Gln Gln Pro 20 25 30Glu Asp Leu Val Val Leu Leu Gly Glu Glu Ala Arg Leu Pro Cys 35 40 45Ala Leu Gly Ala Tyr Trp Gly Leu Val Gln Trp Thr Lys Ser Gly 50 55 60Leu Ala Leu Gly Gly Gln Arg Asp Leu Pro Gly Trp Ser Arg Tyr 65 70 75Trp Ile Ser Gly Asn Ala Ala Asn Gly Gln His Asp Leu His Ile 80 85 90Arg Pro Val Glu Leu Glu Asp Glu Ala Ser Tyr Glu Cys Gln Ala 95 100 105Thr Gln Ala Gly Leu Arg Ser Arg Pro Ala Gln Leu His Val Leu 110 115 120Val Pro Pro Glu Ala Pro Gln Val Leu Gly Gly Pro Ser Val Ser 125 130 135Leu Val Ala Gly Val Pro Ala Asn Leu Thr Cys Arg Ser Arg Gly 140 145 150Asp Ala Arg Pro Thr Pro Glu Leu Leu Trp Phe Arg Asp Gly Val 155 160 165Leu Leu Asp Gly Ala Thr Phe His Gln Thr Leu Leu Lys Glu Gly 170 175 180Thr Pro Gly Ser Val Glu Ser Thr Leu Thr Leu Thr Pro Phe Ser 185 190 195His Asp Asp Gly Ala Thr Phe Val Cys Arg Ala Arg Ser Gln Ala 200 205 210Leu Pro Thr Gly Arg Asp Thr Ala Ile Thr Leu Ser Leu Gln Tyr 215 220 225Pro Pro Glu Val Thr Leu Ser Ala Ser Pro His Thr Val Gln Glu 230 235 240Gly Glu Lys Val Ile Phe Leu Cys Gln Ala Thr Ala Gln Pro Pro 245 250 255Val Thr Gly Tyr Arg Trp Ala Lys Gly Gly Ser Pro Val Leu Gly 260 265 270Ala Arg Gly Pro Arg Leu Glu Val Val Ala Asp Ala Ser Phe Leu 275 280 285Thr Glu Pro Val Ser Cys Glu Val Ser Asn Ala Val Gly Ser Ala 290 295 300Asn Arg Ser Thr Ala Leu Asp Val Leu Phe Gly Pro Ile Leu Gln 305 310 315Ala Lys Pro Glu Pro Val Ser Val Asp Val Gly Glu Asp Ala Ser 320 325 330Phe Ser Cys Ala Trp Arg Gly Asn Pro Leu Pro Arg Val Thr Trp 335 340 345Thr Arg Arg Gly Gly Ala Gln Val Leu Gly Ser Gly Ala Thr Leu 350 355 360Arg Leu Pro Ser Val Gly Pro Glu Asp Ala Gly Asp Tyr Val Cys 365 370 375Arg Ala Glu Ala Gly Leu Ser Gly Leu Arg Gly Gly Ala Ala Glu 380 385 390Ala Arg Leu Thr Val Asn Ala Pro Pro Val Val Thr Ala Leu His 395 400 405Ser Ala Pro Ala Phe Leu Arg Gly Pro Ala Arg Leu Gln Cys Leu 410 415 420Val Phe Ala Ser Pro Ala Pro Asp Ala Val Val Trp Ser Trp Asp 425 430 435Glu Gly Phe Leu Glu Ala Gly Ser Gln Gly Arg Phe Leu Val Glu 440 445 450Thr Phe Pro Ala Pro Glu Ser Arg Gly Gly Leu Gly Pro Gly Leu 455 460 465Ile Ser Val Leu His Ile Ser Gly Thr Gln Glu Ser Asp Phe Ser 470 475 480Arg Ser Phe Asn Cys Ser Ala Arg Asn Arg Leu Gly Glu Gly Gly 485 490 495Ala Gln Ala Ser Leu Gly Arg Arg Asp Leu Leu Pro Thr Val Arg 500 505 510Ile Val Ala Gly Val Ala Ala Ala Thr Thr Thr Leu Leu Met Val 515 520 525Ile Thr Gly Val Ala Leu Cys Cys Trp Arg His Ser Lys Ala Ser 530 535 540Ala Ser Phe Ser Glu Gln Lys Asn Leu Met Arg Ile Pro Gly Ser 545 550 555Ser Asp Gly Ser Ser Ser Arg Gly Pro Glu Glu Glu Glu Thr Gly 560 565 570Ser Arg Glu Asp Arg Gly Pro Ile Val His Thr Asp His Ser Asp 575 580 585Leu Val Leu Glu Glu Glu Gly Thr Leu Glu Thr Lys Asp Pro Thr 590 595 600Asn Gly Tyr Tyr Lys Val Arg Gly Val Ser Val Ser Leu Ser Leu 605 610 615Gly Glu Ala Pro Gly Gly Gly Leu Phe Leu Pro Pro Pro Ser Pro 620 625 630Leu Gly Pro Pro Gly Thr Pro Thr Phe Tyr Asp Phe Asn Pro His 635 640 645Leu Gly Met Val Pro Pro Cys Arg Leu Tyr Arg Ala Arg Ala Gly 650 655 660Tyr Leu Thr Thr Pro His Pro Arg Ala Phe Thr Ser Tyr Ile Lys 665 670 675Pro Thr Ser Phe Gly Pro Pro Asp Leu Ala Pro Gly Thr Pro Pro 680 685 690Phe Pro Tyr Ala Ala Phe Pro Thr Pro Ser His Pro Arg Leu Gln 695 700 705Thr His Val1293197DNAHomo sapiens 129ggaccacagc tcctcccgtg catccactcg gcctgggagg ttctggattt 50tggctgtcga gggagtttgc ctgcctctcc agagaaagat ggtcatgagg 100cccctgtgga gtctgcttct ctgggaagcc ctacttccca ttacagttac 150tggtgcccaa gtgctgagca aagtcggggg ctcggtgctg ctggtggcag 200cgcgtccccc tggcttccaa gtccgtgagg ctatctggcg atctctctgg 250ccttcagaag agctcctggc cacgtttttc cgaggctccc tggagactct 300gtaccattcc cgcttcctgg gccgagccca gctacacagc aacctcagcc 350tggagctcgg gccgctggag tctggagaca gcggcaactt ctccgtgttg 400atggtggaca caaggggcca gccctggacc cagaccctcc agctcaaggt 450gtacgatgca gtgcccaggc ccgtggtaca agtgttcatt gctgtagaaa 500gggatgctca gccctccaag acctgccagg ttttcttgtc ctgttgggcc 550cccaacatca gcgaaataac ctatagctgg cgacgggaga caaccatgga 600ctttggtatg gaaccacaca gcctcttcac agacggacag gtgctgagca 650tttccctggg accaggagac agagatgtgg cctattcctg cattgtctcc 700aaccctgtca gctgggactt ggccacagtc acgccctggg atagctgtca 750tcatgaggca gcaccaggga aggcctccta caaagatgtg ctgctggtgg 800tggtgcctgt ctcgctgctc ctgatgctgg ttactctctt ctctgcctgg 850cactggtgcc cctgctcagg gaaaaagaaa aaggatgtcc atgctgacag 900agtgggtcca gagacagaga acccccttgt gcaggatctg ccataaagga 950caatatgaac tgatgcctgg actatcagta accccactgc acaggcacac 1000gatgctctgg gacataactg gtgcctggaa atcaccatgg tcctcatatc 1050tcccatggga atcctgtcct gcctcgaagg agcagcctgg gcagccatca 1100caccacgagg acaggaagca ccagcacgtt tcacacctcc cccttccctc 1150tcccatcttc tcatatcctg gctcttctct gggcaagatg agccaagcag 1200aacattccat ccaggacact ggaagttctc caggatccag atccatgggg 1250acattaatag tccaaggcat tccctccccc accactattc ataaagtatt 1300aaccaactgg caccaaggaa ttgcctccag cctgagtcct aggctctaaa 1350agatattaca tatttgaact aatagaggaa ctctgagtca cccatgccag 1400catcagcttc agccccagac cctgcagttt gagatctgat gcttcctgag 1450ggccaaggca ttgctgtaag aaaaggtcta gaaataggtg aaagtgagag 1500gtgggggaca ggggtttctc tttctggcct aaggactttc aggtaatcag 1550agttcatggg ccctcaaagg taaattgcag ttgtagacac cgaggatggt 1600tgacaaccca tggttgagat gggcaccgtt ttgcaggaaa caccatatta 1650atagacatcc tcaccatctc catccgctct cacgcctcct gcaggatctg 1700ggagtgaggg tggagagtct ttcctcacgc tccagcacag tggccaggaa 1750aagaaatact gaatttgccc cagccaacag gacgttcttg cacaacttca 1800agaaaagcag ctcagctcag gatgagtctt cctgcctgaa actgagagag 1850tgaagaacca taaaacgcta tgcagaagga acattatgga gagaaagggt 1900actgaggcac tctagaatct gccacattca ttttcaaatg caaatgcaga 1950agacttacct tagttcaagg ggaggggaca aagaccccac agcccaacag 2000caggactgta gaggtcactc tgactccatc aaacttttta ttgtggccat 2050cttaggaaaa tacattctgc ccctgaatga ttctgtctag aaaagctctg 2100gagtattgat cactactgga aaaacactta aggagctaaa cttaccttcg 2150gggattatta gctgataagg ttcacagttt ctctcaccca ggtgtaactg 2200gattttttct ggggcctcaa tccagtcttg ataacagcga ggaaagaggt 2250attgaagaaa caggggtggg tttgaagtac tattttcccc agggtggctt 2300caatctcccc acctaggatg tcagccctgt ccaaggacct tccctcttct 2350cccccagttc cctgggcaat cacttcacct tggacaaagg atcagcacag 2400ctggcctcca gatccacatc accactcttc cactcgattg ttcccagatc 2450ctccctgcct ggcctgctca gaggttccct gttggtaacc tggctttatc 2500aaattctcat ccctttccca cacccacttc tctcctatca ccttccccca 2550agattacctg aacagggtcc atggccactc aacctgtcag cttgcaccat 2600ccccacctgc cacctacagt caggccacat gcctggtcac tgaatcatgc 2650aaaactggcc tcagtcccta aaaatgatgt ggaaaggaaa gcccaggatc 2700tgacaatgag ccctggtgga tttgtgggga aaaaatacac agcactcccc 2750acctttcttt cgttcatctc cagggcccca cctcagatca aagcagctct 2800ggatgagatg ggacctgcag ctctccctcc acaaggtgac tcttagcaac 2850ctcatttcga cagtggtttg tagcgtggtg caccagggcc ttgttgaaca 2900gatccacact gctctaataa agttcccatc cttaatgact cacttgtcaa 2950ctagtggact aattaaccct ccaccaaaaa aacacaaagt gcttctgtga 3000gaccaatttt gtgctaatga gcattgagac tgatgctttg taagtcacac 3050cacaacaaat attgattgag ggcgctgcat gtgctgggta catttcttgg 3100cacttgggaa tcagtagtca agcgaaaccc ttgcctttga gagtttatgg 3150tctggataat ataaataaac aagtaagcat aaaaaaaaaa aaaaaaa 3197130285PRTHomo sapiens 130Met Val Met Arg Pro Leu Trp Ser Leu Leu Leu Trp Glu Ala Leu1 5 10 15Leu Pro Ile Thr Val Thr Gly Ala Gln Val Leu Ser Lys Val Gly 20 25 30Gly Ser Val Leu Leu Val Ala Ala Arg Pro Pro Gly Phe Gln Val 35 40 45Arg Glu Ala Ile Trp Arg Ser Leu Trp Pro Ser Glu Glu Leu Leu 50 55 60Ala Thr Phe Phe Arg Gly Ser Leu Glu Thr Leu Tyr His Ser Arg 65 70 75Phe Leu Gly Arg Ala Gln Leu His Ser Asn Leu Ser Leu Glu Leu 80 85 90Gly Pro Leu Glu Ser Gly Asp Ser Gly Asn Phe Ser Val Leu Met 95 100 105Val Asp Thr Arg Gly Gln Pro Trp Thr Gln Thr Leu Gln Leu Lys 110 115 120Val Tyr Asp Ala Val Pro Arg Pro Val Val Gln Val Phe Ile Ala 125 130 135Val Glu Arg Asp Ala Gln Pro Ser Lys Thr Cys Gln Val Phe Leu 140 145 150Ser Cys Trp Ala Pro Asn Ile Ser Glu Ile Thr Tyr Ser Trp Arg 155 160 165Arg Glu Thr Thr Met Asp Phe Gly Met Glu Pro His Ser Leu Phe 170 175

180Thr Asp Gly Gln Val Leu Ser Ile Ser Leu Gly Pro Gly Asp Arg 185 190 195Asp Val Ala Tyr Ser Cys Ile Val Ser Asn Pro Val Ser Trp Asp 200 205 210Leu Ala Thr Val Thr Pro Trp Asp Ser Cys His His Glu Ala Ala 215 220 225Pro Gly Lys Ala Ser Tyr Lys Asp Val Leu Leu Val Val Val Pro 230 235 240Val Ser Leu Leu Leu Met Leu Val Thr Leu Phe Ser Ala Trp His 245 250 255Trp Cys Pro Cys Ser Gly Lys Lys Lys Lys Asp Val His Ala Asp 260 265 270Arg Val Gly Pro Glu Thr Glu Asn Pro Leu Val Gln Asp Leu Pro 275 280 2851311288DNAHomo sapiens 131gggaagccat ggagccgcgg gcgctcgtca cggcgctcag cctcggcctc 50agcctgtgct ccctggggct gctcgtcacg gccatcttca ccgaccactg 100gtacgagacc gacccccggc gccacaagga gagctgcgag cgcagccgcg 150cgggcgccga ccccccggac cagaagaacc gcctgatgcc gctgtcgcac 200ctactcgggc ctctggagga agtgctactt cctgggcatc gaccgggaca 250tcgacaccct catcctgaaa ggtattgcgc agcgatgcac ggccatcaag 300taccactttt ctcagcccat ccgcttgcga aacattcctt ttaatttaac 350caagaccata cagcaagatg agtggcacct gcttcggata ttttgcacca 400tttccctctg tacttatgcc gccagtatct cgtatgattt gaaccggctc 450ccaaagctaa tttatagcct gcctgctgat gtggaacatg gttacagctg 500gtccatcttt tgcgcctggt gcagtttagg ctttattgtg gcagctggag 550gtctctgcat cgcttatccg tttattagcc ggaccaagat tgcacagcta 600aagtctggca gagactccac ggtatgactg tcctcactgg gcctgtccaa 650gcacaaagcg gtcttttaca ttccaacctg ttgcctgcca gccctttctg 700gattactgat agaaaatcat gcaaaacctc ccaacctttc taaggacaag 750actactgtgg attcaagtgc tttaatgact atttatgcgt tgactgtgag 800aatagggagc agtgccatgg gacatttcta ggtgtagaga aagaagaaac 850tgcaatggaa aaatttgtat gatttccatt tatttcagaa agtttgtatg 900taacaattac ccgagagtca tttctacttg caaaaggatt cgtaacaaag 950cgagtataat tttcttgtca ttgtatcatg cttgttaaat tttaatgcag 1000catcttcaga acttgtcctg atggtgtctt attgtgtcag caccaaatat 1050ttgtgcatta tttgtggacg ttccttgtca caggaagatt cttcttctgt 1100tgccttattg tttttttttt ttttttaagt ctcttctctg tctttgtact 1150ggaatcgaaa tcataagata aacagatcaa acgtgcttaa gagctaactc 1200gtgacactat gcagtattgt ttgaagacct gttgttcaac ctctgtctct 1250ttatgttaat ggatttctgc attaaatgac tgcccccc 1288132111PRTHomo sapiens 132Met Glu Pro Arg Ala Leu Val Thr Ala Leu Ser Leu Gly Leu Ser1 5 10 15Leu Cys Ser Leu Gly Leu Leu Val Thr Ala Ile Phe Thr Asp His 20 25 30Trp Tyr Glu Thr Asp Pro Arg Arg His Lys Glu Ser Cys Glu Arg 35 40 45Ser Arg Ala Gly Ala Asp Pro Pro Asp Gln Lys Asn Arg Leu Met 50 55 60Pro Leu Ser His Leu Leu Gly Pro Leu Glu Glu Val Leu Leu Pro 65 70 75Gly His Arg Pro Gly His Arg His Pro His Pro Glu Arg Tyr Cys 80 85 90Ala Ala Met His Gly His Gln Val Pro Leu Phe Ser Ala His Pro 95 100 105Leu Ala Lys His Ser Phe 1101331285DNAHomo sapiens 133caaagcggcg gctgtccgcg gtgccggctg ggggcggaga ggcggcggtg 50ggctccctgg ggtgtgtgag cccggtgatg gagccgggcc cgacagccgc 100gcagcggagg tgttcgttgc cgccgtggct gccgctgggg ctgctgctgt 150ggtcggggct ggccctgggc gcgctcccct tcggcagcag tccgcacagg 200gtcttccacg acctcctgtc ggagcagcag ttgctggagg tggaggactt 250gtccctgtcc ctcctgcagg gtggagggct ggggcctctg tcgctgcccc 300cggacctgcc ggatctggat cctgagtgcc gggagctcct gctggacttc 350gccaacagca gcgcagagct gacagggtgt ctggtgcgca gcgcccggcc 400cgtgcgcctc tgtcagacct gctaccccct cttccaacag gtcgtcagca 450agatggacaa catcagccga gccgcgggga atacttcaga gagtcagagt 500tgtgccagaa gtctcttaat ggcagataga atgcaaatag ttgtgattct 550ctcagaattt tttaatacca catggcagga ggcaaattgt gcaaattgtt 600taacaaacaa cagtgaagaa ttatcaaaca gcacagtata tttccttaat 650ctatttaatc acaccctgac ctgctttgaa cataaccttc aggggaatgc 700acatagtctt ttacagacaa aaaattattc agaagtatgc aaaaactgcc 750gtgaagcata caaaactctg agtagtctgt acagtgaaat gcaaaaaatg 800aatgaacttg agaataaggc tgaacctgga acacatttat gcattgatgt 850ggaagatgca atgaacatca ctcgaaaact atggagtcga actttcaact 900gttcagtccc ttgcagtgac acagtgcctg taattgctgt ttctgtgttc 950attctctttc tacctgttgt cttctacctt agtagctttc ttcactcaga 1000gcaaaagaaa cgcaaactca ttctgcccaa acgtctcaag tccagtacca 1050gttttgcaaa tattcaggaa aattcaaact gagacctaca aaatggagaa 1100ttgacatatc acgtgaatga atggtggaag acacaacttg gtttcagaaa 1150gaagataaac tgtgatttga caagtcaagc tcttaagaaa tacaaggact 1200tcagatccat ttttaaataa gaattttcga tttttctttc cttttccact 1250tctttctaac agatttggat atttttaatt tccag 1285134334PRTHomo sapiens 134Met Glu Pro Gly Pro Thr Ala Ala Gln Arg Arg Cys Ser Leu Pro1 5 10 15Pro Trp Leu Pro Leu Gly Leu Leu Leu Trp Ser Gly Leu Ala Leu 20 25 30Gly Ala Leu Pro Phe Gly Ser Ser Pro His Arg Val Phe His Asp 35 40 45Leu Leu Ser Glu Gln Gln Leu Leu Glu Val Glu Asp Leu Ser Leu 50 55 60Ser Leu Leu Gln Gly Gly Gly Leu Gly Pro Leu Ser Leu Pro Pro 65 70 75Asp Leu Pro Asp Leu Asp Pro Glu Cys Arg Glu Leu Leu Leu Asp 80 85 90Phe Ala Asn Ser Ser Ala Glu Leu Thr Gly Cys Leu Val Arg Ser 95 100 105Ala Arg Pro Val Arg Leu Cys Gln Thr Cys Tyr Pro Leu Phe Gln 110 115 120Gln Val Val Ser Lys Met Asp Asn Ile Ser Arg Ala Ala Gly Asn 125 130 135Thr Ser Glu Ser Gln Ser Cys Ala Arg Ser Leu Leu Met Ala Asp 140 145 150Arg Met Gln Ile Val Val Ile Leu Ser Glu Phe Phe Asn Thr Thr 155 160 165Trp Gln Glu Ala Asn Cys Ala Asn Cys Leu Thr Asn Asn Ser Glu 170 175 180Glu Leu Ser Asn Ser Thr Val Tyr Phe Leu Asn Leu Phe Asn His 185 190 195Thr Leu Thr Cys Phe Glu His Asn Leu Gln Gly Asn Ala His Ser 200 205 210Leu Leu Gln Thr Lys Asn Tyr Ser Glu Val Cys Lys Asn Cys Arg 215 220 225Glu Ala Tyr Lys Thr Leu Ser Ser Leu Tyr Ser Glu Met Gln Lys 230 235 240Met Asn Glu Leu Glu Asn Lys Ala Glu Pro Gly Thr His Leu Cys 245 250 255Ile Asp Val Glu Asp Ala Met Asn Ile Thr Arg Lys Leu Trp Ser 260 265 270Arg Thr Phe Asn Cys Ser Val Pro Cys Ser Asp Thr Val Pro Val 275 280 285Ile Ala Val Ser Val Phe Ile Leu Phe Leu Pro Val Val Phe Tyr 290 295 300Leu Ser Ser Phe Leu His Ser Glu Gln Lys Lys Arg Lys Leu Ile 305 310 315Leu Pro Lys Arg Leu Lys Ser Ser Thr Ser Phe Ala Asn Ile Gln 320 325 330Glu Asn Ser Asn1352319DNAHomo sapiens 135gccaggccct atctccctgc caggaggccg gagtggggga ggtcagacgg 50ggcggttgga gggggaggga tgccacgcgc ttctgcctca ggtgttcctg 100cgttgtttgt cagtggagag cagggagtgg ggccagccag cagaaacagt 150gggctgtaca acatcacctt caaatatgac aattgtacca cctacttgaa 200tccagtgggg aagcatgtga ttgctgacgc ccagaatatc accatcagcc 250agtatgcttg ccatgaccaa gtggcagtca ccattctttg gtccccaggg 300gccctcggca tcgaattcct gaaaggattt cgggtaatac tggaggagct 350gaagtcggag ggaagacagt gccaacaact gattctaaag gatccgaagc 400agctcaacag tagcttcaaa agaactggaa tggaatctca acctttcctg 450aatatgaaat ttgaaacgga ttatttcgta aaggttgtcc cttttccttc 500cattaaaaac gaaagcaatt accacccttt cttctttaga acccgagcct 550gtgacctgtt gttacagccg gacaatctag cttgtaaacc cttctggaag 600cctcggaacc tgaacatcag ccagcatggc tcggacatgc aggtgtcctt 650cgaccacgca ccgcatggct cggacatgca ggtgtccttc gaccacgcac 700cgcacaactt cggcttccgt ttcttctatc ttcactacaa gctcaagcac 750gaaggacctt tcaagcgaaa gacctgtaag caggagcaaa ctacagagat 800gaccagctgc ctccttcaaa atgtttctcc aggggattat ataattgagc 850tggtggatga cactaacaca acaagaaaag tgatgcatta tgccttaaag 900ccagtgcact ccccgtgggc cgggcccatc agagccgtgg ccatcacagt 950gccactggta gtcatatcgg cattcgcgac gctcttcact gtgatgtgcc 1000gcaagaagca acaagaaaat atatattcac atttagatga agagagctct 1050gagtcttcca catacactgc agcactccca agagagaggc tccggccgcg 1100gccgaaggtc tttctctgct attccagtaa agatggccag aatcacatga 1150atgtcgtcca gtgtttcgcc tacttcctcc aggacttctg tggctgtgag 1200gtggctctgg acctgtggga agacttcagc ctctgtagag aagggcagag 1250agaatgggtc atccagaaga tccacgagtc ccagttcatc attgtggttt 1300gttccaaagg tatgaagtac tttgtggaca agaagaacta caaacacaaa 1350ggaggtggcc gaggctcggg gaaaggagag ctcttcctgg tggcggtgtc 1400agccattgcc gaaaagctcc gccaggccaa gcagagttcg tccgcggcgc 1450tcagcaagtt tatcgccgtc tactttgatt attcctgcga gggagacgtc 1500cccggtatcc tagacctgag taccaagtac agactcatgg acaatcttcc 1550tcagctctgt tcccacctgc actcccgaga ccacggcctc caggagccgg 1600ggcagcacac gcgacagggc agcagaagga actacttccg gagcaagtca 1650ggccggtccc tatacgtcgc catttgcaac atgcaccagt ttattgacga 1700ggagcccgac tggttcgaaa agcagttcgt tcccttccat cctcctccac 1750tgcgctaccg ggagccagtc ttggagaaat ttgattcggg cttggtttta 1800aatgatgtca tgtgcaaacc agggcctgag agtgacttct gcctaaaggt 1850agaggcggct gttcttgggg caaccggacc agccgactcc cagcacgaga 1900gtcagcatgg gggcctggac caagacgggg aggcccggcc tgcccttgac 1950ggtagcgccg ccctgcaacc cctgctgcac acggtgaaag ccggcagccc 2000ctcggacatg ccgcgggact caggcatcta tgactcgtct gtgccctcat 2050ccgagctgtc tctgccactg atggaaggac tctcgacgga ccagacagaa 2100acgtcttccc tgacggagag cgtgtcctcc tcttcaggcc tgggtgagga 2150ggaacctcct gcccttcctt ccaagctcct ctcttctggg tcatgcaaag 2200cagatcttgg ttgccgcagc tacactgatg aactccacgc ggtcgcccct 2250ttgtaacaaa acgaaagagt ctaagcattg ccactttaaa aaaaaaaaaa 2300aaaaaaaaaa aaaaaaaaa 2319136728PRTHomo sapiens 136Met Pro Arg Ala Ser Ala Ser Gly Val Pro Ala Leu Phe Val Ser1 5 10 15Gly Glu Gln Gly Val Gly Pro Ala Ser Arg Asn Ser Gly Leu Tyr 20 25 30Asn Ile Thr Phe Lys Tyr Asp Asn Cys Thr Thr Tyr Leu Asn Pro 35 40 45Val Gly Lys His Val Ile Ala Asp Ala Gln Asn Ile Thr Ile Ser 50 55 60Gln Tyr Ala Cys His Asp Gln Val Ala Val Thr Ile Leu Trp Ser 65 70 75Pro Gly Ala Leu Gly Ile Glu Phe Leu Lys Gly Phe Arg Val Ile 80 85 90Leu Glu Glu Leu Lys Ser Glu Gly Arg Gln Cys Gln Gln Leu Ile 95 100 105Leu Lys Asp Pro Lys Gln Leu Asn Ser Ser Phe Lys Arg Thr Gly 110 115 120Met Glu Ser Gln Pro Phe Leu Asn Met Lys Phe Glu Thr Asp Tyr 125 130 135Phe Val Lys Val Val Pro Phe Pro Ser Ile Lys Asn Glu Ser Asn 140 145 150Tyr His Pro Phe Phe Phe Arg Thr Arg Ala Cys Asp Leu Leu Leu 155 160 165Gln Pro Asp Asn Leu Ala Cys Lys Pro Phe Trp Lys Pro Arg Asn 170 175 180Leu Asn Ile Ser Gln His Gly Ser Asp Met Gln Val Ser Phe Asp 185 190 195His Ala Pro His Gly Ser Asp Met Gln Val Ser Phe Asp His Ala 200 205 210Pro His Asn Phe Gly Phe Arg Phe Phe Tyr Leu His Tyr Lys Leu 215 220 225Lys His Glu Gly Pro Phe Lys Arg Lys Thr Cys Lys Gln Glu Gln 230 235 240Thr Thr Glu Met Thr Ser Cys Leu Leu Gln Asn Val Ser Pro Gly 245 250 255Asp Tyr Ile Ile Glu Leu Val Asp Asp Thr Asn Thr Thr Arg Lys 260 265 270Val Met His Tyr Ala Leu Lys Pro Val His Ser Pro Trp Ala Gly 275 280 285Pro Ile Arg Ala Val Ala Ile Thr Val Pro Leu Val Val Ile Ser 290 295 300Ala Phe Ala Thr Leu Phe Thr Val Met Cys Arg Lys Lys Gln Gln 305 310 315Glu Asn Ile Tyr Ser His Leu Asp Glu Glu Ser Ser Glu Ser Ser 320 325 330Thr Tyr Thr Ala Ala Leu Pro Arg Glu Arg Leu Arg Pro Arg Pro 335 340 345Lys Val Phe Leu Cys Tyr Ser Ser Lys Asp Gly Gln Asn His Met 350 355 360Asn Val Val Gln Cys Phe Ala Tyr Phe Leu Gln Asp Phe Cys Gly 365 370 375Cys Glu Val Ala Leu Asp Leu Trp Glu Asp Phe Ser Leu Cys Arg 380 385 390Glu Gly Gln Arg Glu Trp Val Ile Gln Lys Ile His Glu Ser Gln 395 400 405Phe Ile Ile Val Val Cys Ser Lys Gly Met Lys Tyr Phe Val Asp 410 415 420Lys Lys Asn Tyr Lys His Lys Gly Gly Gly Arg Gly Ser Gly Lys 425 430 435Gly Glu Leu Phe Leu Val Ala Val Ser Ala Ile Ala Glu Lys Leu 440 445 450Arg Gln Ala Lys Gln Ser Ser Ser Ala Ala Leu Ser Lys Phe Ile 455 460 465Ala Val Tyr Phe Asp Tyr Ser Cys Glu Gly Asp Val Pro Gly Ile 470 475 480Leu Asp Leu Ser Thr Lys Tyr Arg Leu Met Asp Asn Leu Pro Gln 485 490 495Leu Cys Ser His Leu His Ser Arg Asp His Gly Leu Gln Glu Pro 500 505 510Gly Gln His Thr Arg Gln Gly Ser Arg Arg Asn Tyr Phe Arg Ser 515 520 525Lys Ser Gly Arg Ser Leu Tyr Val Ala Ile Cys Asn Met His Gln 530 535 540Phe Ile Asp Glu Glu Pro Asp Trp Phe Glu Lys Gln Phe Val Pro 545 550 555Phe His Pro Pro Pro Leu Arg Tyr Arg Glu Pro Val Leu Glu Lys 560 565 570Phe Asp Ser Gly Leu Val Leu Asn Asp Val Met Cys Lys Pro Gly 575 580 585Pro Glu Ser Asp Phe Cys Leu Lys Val Glu Ala Ala Val Leu Gly 590 595 600Ala Thr Gly Pro Ala Asp Ser Gln His Glu Ser Gln His Gly Gly 605 610 615Leu Asp Gln Asp Gly Glu Ala Arg Pro Ala Leu Asp Gly Ser Ala 620 625 630Ala Leu Gln Pro Leu Leu His Thr Val Lys Ala Gly Ser Pro Ser 635 640 645Asp Met Pro Arg Asp Ser Gly Ile Tyr Asp Ser Ser Val Pro Ser 650 655 660Ser Glu Leu Ser Leu Pro Leu Met Glu Gly Leu Ser Thr Asp Gln 665 670 675Thr Glu Thr Ser Ser Leu Thr Glu Ser Val Ser Ser Ser Ser Gly 680 685 690Leu Gly Glu Glu Glu Pro Pro Ala Leu Pro Ser Lys Leu Leu Ser 695 700 705Ser Gly Ser Cys Lys Ala Asp Leu Gly Cys Arg Ser Tyr Thr Asp 710 715 720Glu Leu His Ala Val Ala Pro Leu 725137559DNAHomo sapiens 137caactgcacc tcggttctat cgatagccac cagcgcaaca tgacagtgaa 50gaccctgcat ggcccagcca tggtcaagta cttgctgctg tcgatattgg 100ggcttgcctt tctgagtgag gcggcagctc ggaaaatccc caaagtagga 150catacttttt tccaaaagcc tgagagttgc ccgcctgtgc caggaggtag 200tatgaagctt gacattggca tcatcaatga aaaccagcgc gtttccatgt 250cacgtaacat cgagagccgc tccacctccc cctggaatta cactgtcact 300tgggacccca accggtaccc ctcggaagtt gtacaggccc agtgtaggaa 350cttgggctgc atcaatgctc aaggaaagga agacatctcc atgaattccg 400ttcccatcca gcaagagacc ctggtcgtcc ggaggaagca ccaaggctgc 450tctgtttctt tccagttgga gaaggtgctg gtgactgttg gctgcacctg 500cgtcacccct gtcatccacc atgtgcagta agaggtgcat atccactcag 550ctgaagaag

559138163PRTHomo sapiens 138Met Thr Val Lys Thr Leu His Gly Pro Ala Met Val Lys Tyr Leu1 5 10 15Leu Leu Ser Ile Leu Gly Leu Ala Phe Leu Ser Glu Ala Ala Ala 20 25 30Arg Lys Ile Pro Lys Val Gly His Thr Phe Phe Gln Lys Pro Glu 35 40 45Ser Cys Pro Pro Val Pro Gly Gly Ser Met Lys Leu Asp Ile Gly 50 55 60Ile Ile Asn Glu Asn Gln Arg Val Ser Met Ser Arg Asn Ile Glu 65 70 75Ser Arg Ser Thr Ser Pro Trp Asn Tyr Thr Val Thr Trp Asp Pro 80 85 90Asn Arg Tyr Pro Ser Glu Val Val Gln Ala Gln Cys Arg Asn Leu 95 100 105Gly Cys Ile Asn Ala Gln Gly Lys Glu Asp Ile Ser Met Asn Ser 110 115 120Val Pro Ile Gln Gln Glu Thr Leu Val Val Arg Arg Lys His Gln 125 130 135Gly Cys Ser Val Ser Phe Gln Leu Glu Lys Val Leu Val Thr Val 140 145 150Gly Cys Thr Cys Val Thr Pro Val Ile His His Val Gln 155 1601392283DNAHomo sapiens 139ttctgctata gagatggaac agtatatgga aagctcccaa gaaagtgaag 50agaggaaatt ggaaaattgt gagtggacct tctgatactg ctcctccttg 100cgtggaaaag gggaaagaac tgcatgcata ttattcagcg tcctatattc 150aaaggatatt cttggtgatc ttggaagtgt ccgtatcatg gaatcaatct 200ctatgatggg aagccctaag agccttagtg aaacttgttt acctaatggc 250ataaatggta tcaaagatgc aaggaaggtc actgtaggtg tgattggaag 300tggagatttt gccaaatcct tgaccattcg acttattaga tgcggctatc 350atgtggtcat aggaagtaga aatcctaagt ttgcttctga attttttcct 400catgtggtag atgtcactca tcatgaagat gctctcacaa aaacaaatat 450aatatttgtt gctatacaca gagaacatta tacctccctg tgggacctga 500gacatctgct tgtgggtaaa atcctgattg atgtgagcaa taacatgagg 550ataaaccagt acccagaatc caatgctgaa tatttggctt cattattccc 600agattctttg attgtcaaag gatttaatgt tgtctcagct tgggcacttc 650agttaggacc taaggatgcc agccggcagg tttatatatg cagcaacaat 700attcaagcgc gacaacaggt tattgaactt gcccgccagt tgaatttcat 750tcccattgac ttgggatcct tatcatcagc cagagagatt gaaaatttac 800ccctacgact ctttactctc tggagagggc cagtggtggt agctataagc 850ttggccacat tttttttcct ttattccttt gtcagagatg tgattcatcc 900atatgctaga aaccaacaga gtgactttta caaaattcct atagagattg 950tgaataaaac cttacctata gttgccatta ctttgctctc cctagtatac 1000cttgcaggtc ttctggcagc tgcttatcaa ctttattacg gcaccaagta 1050taggagattt ccaccttggt tggaaacctg gttacagtgt agaaaacagc 1100ttggattact aagttttttc ttcgctatgg tccatgttgc ctacagcctc 1150tgcttaccga tgagaaggtc agagagatat ttgtttctca acatggctta 1200tcagcaggtt catgcaaata ttgaaaactc ttggaatgag gaagaagttt 1250ggagaattga aatgtatatc tcctttggca taatgagcct tggcttactt 1300tccctcctgg cagtcacttc tatcccttca gtgagcaatg ctttaaactg 1350gagagaattc agttttattc agtctacact tggatatgtc gctctgctca 1400taagtacttt ccatgtttta atttatggat ggaaacgagc ttttgaggaa 1450gagtactaca gattttatac accaccaaac tttgttcttg ctcttgtttt 1500gccctcaatt gtaattctgg atcttttgca gctttgcaga tacccagact 1550gagctggaac tggaatttgt cttcctattg actctacttc tttaaaagcg 1600gctgcccatt acattcctca gctgtccttg cagttaggtg tacatgtgac 1650tgagtgttgg ccagtgagat gaagtctcct caaaggaagg cagcatgtgt 1700cctttttcat cccttcatct tgctgctggg attgtggata taacaggagc 1750cctggcagct gtctccagag gatcaaagcc acacccaaag agtaaggcag 1800attagagacc agaaagacct tgactacttc cctacttcca ctgctttttc 1850ctgcatttaa gccattgtaa atctgggtgt gttacatgaa gtgaaaatta 1900attctttctg cccttcagtt ctttatcctg ataccattta acactgtctg 1950aattaactag actgcaataa ttctttcttt tgaaagcttt taaaggataa 2000tgtgcaattc acattaaaat tgattttcca ttgtcaatta gttatactca 2050ttttcctgcc ttgatctttc attagatatt ttgtatctgc ttggaatata 2100ttatcttctt tttaactgtg taattggtaa ttactaaaac tctgtaatct 2150ccaaaatatt gctatcaaat tacacaccat gttttctatc attctcatag 2200atctgcctta taaacattta aataaaaagt actatttaat gatttaactt 2250ctgttttgaa aaaaaaaaaa aaaaaaaaaa aaa 2283140454PRTHomo sapiens 140Met Glu Ser Ile Ser Met Met Gly Ser Pro Lys Ser Leu Ser Glu1 5 10 15Thr Cys Leu Pro Asn Gly Ile Asn Gly Ile Lys Asp Ala Arg Lys 20 25 30Val Thr Val Gly Val Ile Gly Ser Gly Asp Phe Ala Lys Ser Leu 35 40 45Thr Ile Arg Leu Ile Arg Cys Gly Tyr His Val Val Ile Gly Ser 50 55 60Arg Asn Pro Lys Phe Ala Ser Glu Phe Phe Pro His Val Val Asp 65 70 75Val Thr His His Glu Asp Ala Leu Thr Lys Thr Asn Ile Ile Phe 80 85 90Val Ala Ile His Arg Glu His Tyr Thr Ser Leu Trp Asp Leu Arg 95 100 105His Leu Leu Val Gly Lys Ile Leu Ile Asp Val Ser Asn Asn Met 110 115 120Arg Ile Asn Gln Tyr Pro Glu Ser Asn Ala Glu Tyr Leu Ala Ser 125 130 135Leu Phe Pro Asp Ser Leu Ile Val Lys Gly Phe Asn Val Val Ser 140 145 150Ala Trp Ala Leu Gln Leu Gly Pro Lys Asp Ala Ser Arg Gln Val 155 160 165Tyr Ile Cys Ser Asn Asn Ile Gln Ala Arg Gln Gln Val Ile Glu 170 175 180Leu Ala Arg Gln Leu Asn Phe Ile Pro Ile Asp Leu Gly Ser Leu 185 190 195Ser Ser Ala Arg Glu Ile Glu Asn Leu Pro Leu Arg Leu Phe Thr 200 205 210Leu Trp Arg Gly Pro Val Val Val Ala Ile Ser Leu Ala Thr Phe 215 220 225Phe Phe Leu Tyr Ser Phe Val Arg Asp Val Ile His Pro Tyr Ala 230 235 240Arg Asn Gln Gln Ser Asp Phe Tyr Lys Ile Pro Ile Glu Ile Val 245 250 255Asn Lys Thr Leu Pro Ile Val Ala Ile Thr Leu Leu Ser Leu Val 260 265 270Tyr Leu Ala Gly Leu Leu Ala Ala Ala Tyr Gln Leu Tyr Tyr Gly 275 280 285Thr Lys Tyr Arg Arg Phe Pro Pro Trp Leu Glu Thr Trp Leu Gln 290 295 300Cys Arg Lys Gln Leu Gly Leu Leu Ser Phe Phe Phe Ala Met Val 305 310 315His Val Ala Tyr Ser Leu Cys Leu Pro Met Arg Arg Ser Glu Arg 320 325 330Tyr Leu Phe Leu Asn Met Ala Tyr Gln Gln Val His Ala Asn Ile 335 340 345Glu Asn Ser Trp Asn Glu Glu Glu Val Trp Arg Ile Glu Met Tyr 350 355 360Ile Ser Phe Gly Ile Met Ser Leu Gly Leu Leu Ser Leu Leu Ala 365 370 375Val Thr Ser Ile Pro Ser Val Ser Asn Ala Leu Asn Trp Arg Glu 380 385 390Phe Ser Phe Ile Gln Ser Thr Leu Gly Tyr Val Ala Leu Leu Ile 395 400 405Ser Thr Phe His Val Leu Ile Tyr Gly Trp Lys Arg Ala Phe Glu 410 415 420Glu Glu Tyr Tyr Arg Phe Tyr Thr Pro Pro Asn Phe Val Leu Ala 425 430 435Leu Val Leu Pro Ser Ile Val Ile Leu Asp Leu Leu Gln Leu Cys 440 445 450Arg Tyr Pro Asp1412301DNAHomo sapiens 141cagagccctg cgggaggact cagagtcagg gacacagcag cgtccggcga 50gatgaaggcg cttggggctg tcctgcttgc cctcttgctg tgcgggcggc 100cagggagagg gcagacacag caggaggaag aggaagagga cgaggaccac 150gggccagatg actacgacga ggaagatgag gatgaggtgg aagaggagga 200gaccaacagg ctccctggtg gcaggagcag agtgctgctg cggtgctaca 250cctgcaagtc cctgcccagg gacgagcgct gcaacctgac gcagaactgc 300tcacatggcc agacctgcac aaccctcatt gcccacggga acaccgagtc 350aggcctcctg accacccact ccacgtggtg cacagacagc tgccagccca 400tcaccaagac ggtggagggg acccaggtga ccatgacctg ctgccagtcc 450agcctgtgca atgtcccacc ctggcaaagc tcccgagtcc aggacccaac 500aggcaagggg gcaggcggcc cccggggcag ctccgaaact gtgggcgcag 550ccctcctgct caacctcctt gccggccttg gagcaatggg ggccaggaga 600ccctgaccca cggcccctcc ccacccccac ccggctcacc cccggccctg 650ccagcactct gtctggtacc ttcccctcct gcccctgcac cagctttgga 700gaatggattt ggagtgtctt gggcgatcca gccagcgcag gccccccggc 750ccggttgctt cctcagttcc cggctgtgtc cttggtgtcc tttctccacc 800acctgtgagc agcaagactg ccgcacgtgg gcgctgggtc cagacctcgg 850ctgccacgtc ccaggacctg cagccctcac gggggctggg gatccccatc 900agcacagcca ggcagagatg atacccacca cacacctggg ggcccccaca 950cccagtcctc acccttaact tctgccatgg gaatttctcc atctgcagca 1000gtcacacggg cccaccctgc ccttccccag gtcggcctct ccgctgtctg 1050gagggaaggg gatttggagg gaggctgtcg tcgcccccag gaaagacggg 1100cctgggggag gcgggacagt gggagaggcg cgctgaggat gagagggcac 1150agggaggtgg gttggggtga ggccacatgc ggaggggcgg ggcggggcgg 1200ggctgggggg acaggcacca agtatgaaga ggatggggcc agcggggcct 1250gtctggctgt ggcgtgagca ccgctatggg agaccctgct tggaaagtga 1300acttgcagcc ttggatgggg aagggccaga tgctgggtgg gtgcctgtca 1350ccttgaggtg accatctagg gtcagtacct gctgggctta ggacagcgcc 1400tgaggctggg aatacctgtc tctgctctag cagaggctaa agcaggctag 1450agcagtggag gggtggagtt gatgaaagga gaggagtaga tgagatggaa 1500tttttccagc ctcatcctgg cctgccctct agactccagt ccccaagccc 1550tcagcctagt gggtgtcatg gatggatctg ggggtgtcag acaggctacc 1600ctgtgccagg gagggggcag aatgggcctg cagcttcctg cagaggaagc 1650aggactgggt agcagagccg ggaaggtggg tggcccatta caggggggtc 1700cccagggtgt cctctggcag ggctgtgact gctgcaagct ctgccttcac 1750cagtagctgg tgccaggaca gagctctggg acagcaggca gaggccgagc 1800ctgggccaca gctcagccac tgacttgggt atcagtttcc ccttctgaga 1850agtacagagt gagacttaaa gaacccctag atccccacca gttcaacact 1900ccattaactg ggaagcccag agtcctgtcc ggcctgccaa gttcatcctg 1950gtggacagcg ggaggcctcc gctaactgtt ctcttctttt ccttattaat 2000aaaacacaca atgcctagct ggggggtcgg aaggcaaatg ccctagatgg 2050tggggtcacg tctttctcct tctccttcct ccttctgctg gctgaagtga 2100tgactggagc tcagcaacca ctttgcacca tgaggcagca ctgagcacgg 2150tagggcagcc tggtgagagg ggcctagctc gctgccgaca gaagtcactg 2200cctacctcag ggtcccctta cctgggtggg aaataaattt ctgctgtgtt 2250gaagctaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 2300a 2301142184PRTHomo sapiens 142Met Lys Ala Leu Gly Ala Val Leu Leu Ala Leu Leu Leu Cys Gly1 5 10 15Arg Pro Gly Arg Gly Gln Thr Gln Gln Glu Glu Glu Glu Glu Asp 20 25 30Glu Asp His Gly Pro Asp Asp Tyr Asp Glu Glu Asp Glu Asp Glu 35 40 45Val Glu Glu Glu Glu Thr Asn Arg Leu Pro Gly Gly Arg Ser Arg 50 55 60Val Leu Leu Arg Cys Tyr Thr Cys Lys Ser Leu Pro Arg Asp Glu 65 70 75Arg Cys Asn Leu Thr Gln Asn Cys Ser His Gly Gln Thr Cys Thr 80 85 90Thr Leu Ile Ala His Gly Asn Thr Glu Ser Gly Leu Leu Thr Thr 95 100 105His Ser Thr Trp Cys Thr Asp Ser Cys Gln Pro Ile Thr Lys Thr 110 115 120Val Glu Gly Thr Gln Val Thr Met Thr Cys Cys Gln Ser Ser Leu 125 130 135Cys Asn Val Pro Pro Trp Gln Ser Ser Arg Val Gln Asp Pro Thr 140 145 150Gly Lys Gly Ala Gly Gly Pro Arg Gly Ser Ser Glu Thr Val Gly 155 160 165Ala Ala Leu Leu Leu Asn Leu Leu Ala Gly Leu Gly Ala Met Gly 170 175 180Ala Arg Arg Pro14343DNAArtificial sequenceOligonucleotide Probe 143tgtaaaacga cggccagtta aatagacctg caattattaa tct 4314441DNAArtificial sequenceOligonucleotide Probe 144caggaaacag ctatgaccac ctgcacacct gcaaatccat t 4114542DNAArtificial sequenceOligonucleotide Probe 145ggcatgcagc agctggacat ttgcgagggc ttttgctggc tg 4214621DNAArtificial sequenceOligonucleotide Probe 146ctgctgcaga gttgcacgaa c 2114723DNAArtificial sequenceOligonucleotide Probe 147cagttgttgt tgtcacagag aag 2314822DNAArtificial sequenceOligonucleotide Probe 148agttcgtgca actctgcagc ag 2214950DNAArtificial sequenceOligonucleotide Probe 149cctggctatc agcaggtggg ctccaagtgt ctcgatgtgg atgagtgtga 5015022DNAArtificial sequenceOligonucleotide Probe 150attctgcgtg aacactgagg gc 2215122DNAArtificial sequenceOligonucleotide Probe 151atctgcttgt agccctcggc ac 2215223DNAArtificial sequenceOligonucleotide Probe 152atctcctatc gctgctttcc cgg 2315323DNAArtificial sequenceOligonucleotide Probe 153agccaggatc gcagtaaaac tcc 2315450DNAArtificial sequenceOligonucleotide Probe 154atttaaactt gatgggtctg cgtatcttga gtgcttacaa aaccttatct 5015550DNAArtificial sequenceOligonucleotide Probe 155gttcattgaa aacctcttgc catctgatgg tgacttctgg attgggctca 5015624DNAArtificial sequenceOligonucleotide Probe 156aagccaaaga agcctgcagg aggg 2415724DNAArtificial sequenceOligonucleotide Probe 157cagtccaagc ataaaggtcc tggc 2415821DNAArtificial sequenceOligonucleotide Probe 158cggtctacct gtatggcaac c 2115922DNAArtificial sequenceOligonucleotide Probe 159gcaggacaac cagataaacc ac 2216022DNAArtificial sequenceOligonucleotide Probe 160acgcagattt gagaaggctg tc 2216146DNAArtificial sequenceOligonucleotide Probe 161ttcacgggct gctcttgccc agctcttgaa gcttgaagag ctgcac 4616230DNAArtificial sequenceOligonucleotide Probe 162actgaggcct gttgaaagtg cagagctcag 3016318DNAArtificial sequenceOligonucleotide Probe 163gctgaagaag agcttcag 1816450DNAArtificial sequenceOligonucleotide Probe 164ggccagcatg atggacatgg tgtggaacct ttccagcagg tctaggcgta 5016518DNAArtificial sequenceOligonucleotide Probe 165ggtgcagccc aggatgtc 1816622DNAArtificial sequenceOligonucleotide Probe 166gcattggccg cgagactttg cc 2216722DNAArtificial sequenceOligonucleotide Probe 167gcggccacgg tccttggaaa tg 2216845DNAArtificial sequenceOligonucleotide Probe 168tggaggagct caacctcagc tacaaccgca tcaccagccc acagg 4516931DNAArtificial sequenceOligonucleotide Probe 169ttcagcacca aggacaagga caatgacaac t 3117032DNAArtificial sequenceOligonucleotide Probe 170tgtgcacact tgtccaagca gttgtcattg tc 3217123DNAArtificial sequenceOligonucleotide Probe 171gtagtacact ccattgaggt tgg 2317223DNAArtificial sequenceOligonucleotide Probe 172ctggggctac acacggggtg agg 2317324DNAArtificial sequenceOligonucleotide Probe 173ggtgccgctg cagaaagtag agcg 2417445DNAArtificial sequenceOligonucleotide Probe 174gccccaaatg aaaacgggcc ctacttcctg gccctccgcg agatg 4517524DNAArtificial sequenceOligonucleotide Probe 175taacagctgc ccactgcttc cagg 2417622DNAArtificial sequenceOligonucleotide Probe 176taatccagca gtgcaggccg gg 2217750DNAArtificial sequenceOligonucleotide Probe 177atggcctcca cggtgctgtg gaccgtgttc ctgggcaagg tgtggcagaa

5017825DNAArtificial sequenceOligonucleotide Probe 178tgcctatgca ctgaggaggc agaag 2517925DNAArtificial sequenceOligonucleotide Probe 179aggcagggac acagagtcca ttcac 2518050DNAArtificial sequenceOligonucleotide Probe 180agtatgattt gccgtgcacc cagggccagt ggacgatcca gaacaggagg 5018121DNAArtificial sequenceOligonucleotide Probe 181cgagcgagtc atggccaacg c 2118226DNAArtificial sequenceOligonucleotide Probe 182gtgtcacacg tagtctttcc cgctgg 2618343DNAArtificial sequenceOligonucleotide Probe 183ctgcagctgt tgggcttcat tctcgccttc ctgggatgga tcg 4318424DNAArtificial sequenceOligonucleotide Probe 184atccacagaa gctggccttc gccg 2418524DNAArtificial sequenceOligonucleotide Probe 185gggacgtgga tgaactcggt gtgg 2418640DNAArtificial sequenceOligonucleotide Probe 186tatccacaga agctggcctt cgccgagtgc ctgtgcagag 4018725DNAArtificial sequenceOligonucleotide Probe 187gggaaacaca gcagtcattg cctgc 2518824DNAArtificial sequenceOligonucleotide Probe 188gcacacgtag cctgtcgctg gagc 2418942DNAArtificial sequenceOligonucleotide Probe 189caccccaaag cccaggtccg gtacagcgtc aaacaagagt gg 4219046DNAArtificial sequenceOligonucleotide Probe 190tccgtgcagg gggacgcctt tcagaaactg cgccgagtta aggaac 4619126DNAArtificial sequenceOligonucleotide Probe 191catttcctta ccctggaccc agctcc 2619225DNAArtificial sequenceOligonucleotide Prob 192gaaaggccca cagcacatct ggcag 2519346DNAArtificial sequenceOligonucleotide Probe 193ccacgacccg agcaacttcc tcaagaccga cttgtttctc tacagc 4619424DNAArtificial sequenceOligonucleotide Probe 194tgcagcccct gtgacacaaa ctgg 2419526DNAArtificial sequenceOligonucleotide Probe 195ctgagataac cgagccatcc tcccac 2619646DNAArtificial sequenceOligonucleotide Probe 196ggagatagct gctatgggtt cttcaggcac aacttaacat gggaag 4619724DNAArtificial sequenceOligonucleotide Probe 197gaggtgtcgc tgtgaagcca acgg 2419824DNAArtificial sequenceOligonucleotide Probe 198cgctcgattc tccatgtgcc ttcc 2419945DNAArtificial sequenceOligonucleotide Probe 199gacggagtgt gtggaccctg tgtacgagcc tgatcagtgc tgtcc 4520025DNAArtificial sequenceOligonucleotide Probe 200gatggcaaaa cgtgtgtttg acacg 2520122DNAArtificial sequenceOligonucleotide Probe 201cctcaaccag gccacgggcc ac 2220224DNAArtificial sequenceOligonucleotide Probe 202cccaggcaga gatgcagtac aggc 2420326DNAArtificial sequenceOligonucleotide Probe 203cctccagtag gtggatggat tggctc 2620447DNAArtificial sequenceOligonucleotide Probe 204ctcacctcat gaggatgagg ccatggtgct attcctcaac atggtag 4720524DNAArtificial sequenceOligonucleotide Probe 205gacgtctgca acagctcctg gaag 2420623DNAArtificial sequenceOligonucleotide Probe 206cgagaaggaa acgaggccgt gag 2320744DNAArtificial sequenceOligonucleotide Probe 207tgacacttac catgctctgc acccgcagtg gggacagcca caga 4420824DNAArtificial sequenceOligonucleotide Probe 208ctgggatctg aacagtttcg gggc 2420924DNAArtificial sequenceOligonucleotide Probe 209ggtccccagg acatggtctg tccc 2421048DNAArtificial sequenceOligonucleotide Probe 210gctgagttta catttacggt ctaactccct gagaaccatc cctgtgcg 4821124DNAArtificial sequenceOligonucleotide Probe 211ctgttacact gacgtggccc tccc 2421224DNAArtificial sequenceOligonucleotide Probe 212cattctgacc cacgggccat tgtc 2421344DNAArtificial sequenceOligonucleotide Probe 213gtggagcagc cggtgaactt gagcagcctt gcccagaagt atgc 4421423DNAArtificial sequenceOligonucleotide Probe 214ccctgccagc cgagagcttc acc 2321523DNAArtificial sequenceOligonucleotide Probe 215ggttggtgcc cgaaaggtcc agc 2321644DNAArtificial sequenceOligonucleotide Probe 216caaccccaag cttaactggg caggagctga ggtgttttca ggcc 4421724DNAArtificial sequenceOligonucleotide Probe 217ctcctccagg atgaaccacc tgcc 2421818DNAArtificial sequenceOligonucleotide Probe 218caggatgctt cagagagg 1821924DNAArtificial sequenceOligonucleotide Probe 219cctgccttcg gattccagga gggg 2422042DNAArtificial sequenceOligonucleotide Probe 220ccatcaaccc cacacaactc atggccagga ttgagtccta tg 4222128DNAArtificial sequenceOligonucleotide Probe 221ggagacatgt ttcgaatgga caactgtc 2822224DNAArtificial sequenceOligonucleotide Probe 222ctggatcttc acacactggg cagc 2422346DNAArtificial sequenceOligonucleotide Probe 223cccagtgtgg tgagataaac tgcgagaggt actacgtgcc cgaagg 4622424DNAArtificial sequenceOligonucleotide Probe 224atgccaataa ctttgcctcg gagc 2422523DNAArtificial sequenceOligonucleotide Probe 225ccagaaggcc agggctttct ctg 2322640DNAArtificial sequenceOligonucleotide Probe 226gagtgcatga gcagctgcca gggatctctc catgggcccc 4022723DNAArtificial sequenceOligonucleotide Probe 227caaccgtatg ggaccgatac tcg 2322821DNAArtificial sequenceOligonucleotide Probe 228cacgctcaac gagtcttcat g 2122941DNAArtificial sequenceOligonucleotide Probe 229gtggccctcg cagtgcaggc cttctacgtc caatacaagt g 4123025DNAArtificial sequenceOligonucleotide Probe 230actccatatt ttcctacttg tggca 2523119DNAArtificial sequenceOligonucleotide Probe 231cccaaagtga cctaagaac 1923227DNAArtificial sequenceOligonucleotide Probe 232tcactgaatt tcttcaaaac cattgca 2723350DNAArtificial sequenceOligonucleotide Probe 233tgtggcagcg actgcatccg acataaagga acagttgtgc tctgcccaca 5023428DNAArtificial sequenceOligonucleotide Probe 234ggatctcttg ttcaagcatc ctaccaac 2823527DNAArtificial sequenceOligonucleotide Probe 235tgtcatcact gcaagttaag gcttccc 2723647DNAArtificial sequenceOligonucleotide Probe 236cgtagagaag ttataatgct ggcctgcagt tttggcaaca agcactg 4723722DNAArtificial sequenceOligonucleotide Probe 237gtcgccccat ttcctgcaac ag 2223822DNAArtificial sequenceOligonucleotide Probe 238gggcctgctc tccctctgaa gc 2223935DNAArtificial sequenceOligonucleotide Probe 239gtgctgggct ctggagccac actgcgtctt ccgtc 3524020DNAArtificial sequenceOligonucleotide Probe 240agccccaggg agcacaggct 2024122DNAArtificial sequenceOligonucleotide Probe 241gctcgtcacg gccatcttca cc 2224227DNAArtificial sequenceOligonucleotide Probe 242tgcgacagcg gcatcaggcg gttcttc 2724321DNAArtificial sequenceOligonucleotide Probe 243tccacgacct cctgtcggag c 2124421DNAArtificial sequenceOligonucleotide Probe 244agaccctgtg cggactgctg c 2124524DNAArtificial sequenceOligonucleotide Probe 245agccccgacc acagcagcag cccc 2424625DNAArtificial sequenceOligonucleotide Probe 246cgttgtttgt cagtggagag caggg 2524723DNAArtificial sequenceOligonucleotide Probe 247caggaacacc tgaggcagaa gcg 2324840DNAArtificial sequenceOligonucleotide Probe 248ctatctccct gccaggaggc cggagtgggg gaggtcagac 4024933DNAArtificial sequenceOligonucleotide Probe 249gatatttgtt tctcaacatg gcttatcagc agg 3325029DNAArtificial sequenceOligonucleotide Probe 250tctctgacct tctcatcggt aagcagagg 2925143DNAArtificial sequenceOligonucleotide Probe 251tcttttgcag ctttgcagat acccagactg agctggaact gga 43

Claims

1-174. (canceled)

175. A method of identifying an agent that modulates a phenotype associated with a disruption of a gene which encodes for a PRO1079 polypeptide, the method comprising: (a) providing a non-human transgenic animal whose genome comprises a disruption of a gene which is an ortholog of a human gene that encodes for the PRO1079 polypeptide; (b) measuring a physiological characteristic of the non-human transgenic animal of (a); (c) comparing the measured physiological characteristic of (b) with that of a gender matched wild-type animal, wherein the physiological characteristic of the non-human transgenic animal that differs from the physiological characteristic of the wild-type animal is identified as a phenotype resulting from the gene disruption in the non-human transgenic animal; (d) administering a test agent to the non-human transgenic animal of (a); and (e) determining whether the test agent modulates the identified phenotype associated with gene disruption in the non-human transgenic animal.

176. The method of claim 175, wherein the phenotype associated with the gene disruption comprises a neurological disorder; a cardiovascular, endothelial or angiogenic disorder; an eye abnormality; an immunological disorder; an oncological disorder; a bone metabolic abnormality or disorder; a lipid metabolic disorder; or a developmental abnormality.

177. The method of claim 176, wherein the neurological disorder is an increased anxiety-like response during open field activity testing.

178. The method of claim 176, wherein the neurological disorder is a decreased anxiety-like response during open field activity testing.

179. The method of claim 176, wherein the neurological disorder is an abnormal circadian rhythm during home-cage activity testing.

180. The method of claim 176, wherein the neurological disorder is an enhanced motor coordination during inverted screen testing.

181. The method of claim 176, wherein the neurological disorder is an impaired motor coordination during inverted screen testing.

182. The method of claim 176, wherein the neurological disorder is depression, generalized anxiety disorders, attention deficit disorder, sleep disorder, hyperactivity disorder, obsessive compulsive disorder, schizophrenia, cognitive disorders, hyperalgesia or sensory disorders.

183. The method of claim 176, wherein the eye abnormality is a retinal abnormality.

184. The method of claim 176, wherein the eye abnormality is consistent with vision problems or blindness.

185. The method of claim 183, wherein the retinal abnormality is consistent with retinitis pigmentosa.

186. The method of claim 183, wherein the retinal abnormality is characterized by retinal degeneration or retinal dysplasia.

187. The method of claim 183, wherein the retinal abnormality is consistent with retinal dysplasia, various retinopathies, including retinopathy of prematurity, retrolental fibroplasia, neovascular glaucoma, age-related macular degeneration, diabetic macular edema, corneal neovascularization, corneal graft neovascularization, corneal graft rejection, retinal/choroidal neovascularization, neovascularization of the angle (rubeosis), ocular neovascular disease, vascular restenosis, arteriovenous malformations (AVM), meningioma, hemangioma, angiofibroma, thyroid hyperplasias (including Grave's disease), corneal and other tissue transplantation, retinal artery obstruction or occlusion; retinal degeneration causing secondary atrophy of the retinal vasculature, retinitis pigmentosa, macular dystrophies, Stargardt's disease, congenital stationary night blindness, choroideremia, gyrate atrophy, Leber's congenital amaurosis, retinoschisis disorders, Wagner's syndrome, Usher syndromes, Zellweger syndrome, Saldino-Mainzer syndrome, Senior-Loken syndrome, Bardet-Biedl syndrome, Alport's syndrome, Alstrom's syndrome, Cockayne's syndrome, dysplaisa spondyloepiphysaria congentia, Flynn-Aird syndrome, Friedreich ataxia, Hallgren syndrome, Marshall syndrome, Albers-Schnoberg disease, Refsum's disease, Kearns-Sayre syndrome, Waardenburg's syndrome, Alagile syndrome, myotonic dystrophy, olivopontocerebellar atrophy, Pierre-Marie dunsdrome, Stickler syndrome, carotinemeia, cystinosis, Wolfram syndrome, Bassen-Kornzweig syndrome, abetalipoproteinemia, incontinentia pigmenti, Batten's disease, mucopolysaccharidoses, homocystinuria, or mannosidosis.

188. The method of claim 176, wherein the eye abnormality is a cataract.

189. The method of claim 188, wherein the cataract is consistent with systemic diseases such as human Down's syndrome, Hallerman-Streiff syndrome, Lowe syndrome, galactosemia, Marfan syndrome, Trismoy 13-15, Alport syndrome, myotonic dystrophy, Fabry disease, hypoparathroidism or Conradi syndrome.

190. The method of claim 176, wherein the developmental abnormality comprises embryonic lethality or reduced viability.

191. The method of claim 176, wherein the cardiovascular, endothelial or angiogenic disorders are arterial diseases, such as diabetes mellitus; papilledema; optic atrophy; atherosclerosis; angina; myocardial infarctions such as acute myocardial infarctions, cardiac hypertrophy, and heart failure such as congestive heart failure; hypertension; inflammatory vasculitides; Reynaud's disease and Reynaud's phenomenon; aneurysms and arterial restenosis; venous and lymphatic disorders such as thrombophlebitis, lymphangitis, and lymphedema; peripheral vascular disease; cancer such as vascular tumors, e.g., hemangioma (capillary and cavernous), glomus tumors, telangiectasia, bacillary angiomatosis, hemangioendothelioma, angiosarcoma, haemangiopericytoma, Kaposi's sarcoma, lymphangioma, and lymphangiosarcoma; tumor angiogenesis; trauma such as wounds, burns, and other injured tissue, implant fixation, scarring; ischemia reperfusion injury; rheumatoid arthritis; cerebrovascular disease; renal diseases such as acute renal failure, or osteoporosis.

192. The method of claim 176, wherein the immunological disorders are systemic lupus erythematosis; rheumatoid arthritis; juvenile chronic arthritis spondyloarthropathies; systemic sclerosis (scleroderma); idiopathic inflammatory myopathies (dermatomyositis, polymyositis); Sjogren's syndrome; systemic vasculitis; sarcoidosis; autoimmune hemolytic anemia (immune pancytopenia, paroxysmal nocturnal hemoglobinuria); autoimmune thrombocytopenia (idiopathic thrombocytopenic purpura, immune-mediated thrombocytopenia); thyroiditis (Grave's disease, Hashimoto's thyroiditis, juvenile lymphocytic thyroiditis, atrophic thyroiditis); diabetes mellitus; immune-mediated renal disease (glomerulonephritis, tubulointerstitial nephritis); demyelinating diseases of the central and peripheral nervous systems such as multiple sclerosis, idiopathic demyelinating polyneuropathy or Guillain-Barre syndrome, and chronic inflammatory demyelinating polyneuropathy; hepatobiliary diseases such as infectious hepatitis (hepatitis A, B, C, D, E and other non-hepatotropic viruses), autoimmune chronic active hepatitis, primary biliary cirrhosis, granulomatous hepatitis, and sclerosing cholangitis; inflammatory bowel disease (ulcerative colitis: Crohn's disease); gluten-sensitive enteropathy, and Whipple's disease; autoimmune or immune-mediated skin diseases including bullous skin diseases, erythema multiforme and contact dermatitis, psoriasis; allergic diseases such as asthma, allergic rhinitis, atopic dermatitis, food hypersensitivity and urticaria; immunologic diseases of the lung such as eosinophilic pneumonia, idiopathic pulmonary fibrosis and hypersensitivity pneumonitis; or transplantation-associated diseases including graft rejection and graft-versus-host disease.

193. The method of claim 176, wherein said bone metabolic abnormality or disorder is arthritis, osteoporosis or osteopetrosis.

194. The method of claim 175, wherein the non-human transgenic animal exhibits at least one of the following physiological characteristics compared with gender matched wild-type littermates: increased anxiety-like response during open field testing; decreased anxiety during open field testing; hypoactivity with no circadian rhythm; increased total distance traveled during open field testing (hyperactivity); decreased locomotor activity during open field testing; abnormal circadiian rhythm during home-cage activity testing (low activity during the light phase); abnormal circadian rhythm during home-cage activity testing including decreased ambulatory counts; abnormal circadian rhythm during home-cage activity testing including increased ambulatory counts; whiskers absent due to anxiety phenotype; enhanced circadian rhythm; increased stress induced hyperthermia with increased stress response (increased anxiety); increased resistance to stress induced hyperthermia; decreased resistance to stress induced hyperthermia; enhanced motor coordination during inverted screen testing; impaired motor coordination during inverted screen testing; increased immobility in tail suspension (increased depressive-like response); increased depressive-like response during tail suspension testing; decreased depressive-like response during tail suspension testing; clutched hind limbs during tail suspension testing; decreased startle response during prepulse inhibition testing; no startle response indicating deafness; increased prepulse inhibition with enhanced sensorimotor gating/attention; increased latency on hotplate indicative of decreased sensitivity to heat-induced pain; opthamological abnormalities; corneal epidermidalization of the corneal stroma with scarring and blocked vision; metaplasia of the cornea and sclera; attenuated retinal arteries; retinal hemorrhage; optic nerve abnormalities; dilated optic disc; increased intraocular pressure; corneal epithelialization with underdeveloped eyelids; retinal degeneration; agenesis of the Harderian gland; retinal vessel disorganization, microaneurysms and retinal capillary leakage; impaired vision; decreased heart rate; decreased mean systolic blood pressure; increased mean systolic blood pressure; increased insulin sensitivity; increased mean fasting serum glucose levels; decreased mean serum glucose levels; increased mean serum cholesterol levels; decreased mean serum cholesterol levels; increased mean serum triglyceride levels; enhanced glucose tolerance; impaired glucose tolerance; decreased mean serum insulin levels; ketonemia; decreased mean serum calcium; blood urobilinogen, nitrites, protein and ketones; decreased sodium and chloride; increased bilirubin; notable lipemia; increased uric acid and potassium levels; increased mean serum alkaline phosphatase levels; decreased mean serum alkaline phosphatase levels; blood in the urine; glucosuria; increased nitrituria; ketonuria; increased mean percentage of natural killer cells; decreased mean percentage of natural killer cells; abnormal leukocyte count; leukopenia due to lymphopenia and granulocytopenia; increased mean percentage of CD4 cells; decreased mean percentage of CD4 cells; decreased mean percentage of CD8 cells; reduced percentage of naive CD4 and CD8 T cells in lymph nodes; increased mean percentage of B cells in peripheral blood; decrease total white blood cells and lymphocyte counts; decreased absolute lymphocyte counts; increased mean absolute monocyte count; increased mean absolute neutrophil count; decreased in mean serum IgA levels; increase in mean serum IgA levels; increase in IgG1 levels; decreased mean serum IgG1 levels; decreased mean serum IgG1, IgG3, IgG2b and IgG2a levels; decreased mean serum IgG2a levels; decreased mean serum IgG2b levels; decreased mean serum IgG3 and IgM levels; increase in mean serum IgG2a levels; increase in mean serum IgG1, IgG2a and IgG3 levels; increase in mean serum IgG3 levels; anemia; decreased red blood cell count, decreased hemoglobin and decreased hematocrit with increased mean red blood cell count; increased mean corpuscular volume; decreased mean corpuscular volume; decreased mean corpuscular hemoglobin; increased red blood cell distribution width; defect in erythropoiesis; increased IgM+ IgD+ and B220hi/CD43- cells in bone marrow; decreased percentage of B220hi/CD43- IgM+ IgD+ cells in bone marrow; increased percentage of TCRB+ cells in Peyer's patches; reduction in naive T cells (especially CD4) in lymph nodes; increased percentage of CD11b+CD11c- cells (monocytes) in spleen; increased percentage of IgM+, CD117+ cells in bone marrow, higher percentage of dead B cells, decreased B cells, increased CD4 and CD8 T cells in lymph; B cells increased in bone marrow and significantly decreased in lymph node; notably decreased CD21hiCD23med B cells in spleen; decrease in Peyer's patch B220+ cells; decreased mean percentages of CD8 and natural killer cells with increased mean percentage of B cells; reduced number of TCRB+CD38+ activated T cells in Peyer's patches; decreased mean percentage of CD4 cells with increased mean percentage of B cells; decreased B220+ CD38low and IgM in Payer's patches; increased mean platelet count; decreased mean platelet count; widespread apoptosis and loss of T lymphocytes in the thymic cortex and depletion of T cells in spleen; increased mean serum IgG2a response to an ovalbumin challenge; decreased to no serum IgG1 and IgG2a response to ovalbumin challenge; increased mean serum IgG1 response to an ovalbumin challenge; decreased mean serum TNF-alpha, MCP-1 and IL-6 responses to LPS challenge; increased mean serum MCP-1 response to a LPS challenge; increased mean serum TNF-alpha response to a LPS challenge; increased mean serum IL-6 response to a LPS challenge; increased skin fibroblast proliferation; decreased skin fibroblast proliferation; increased mean percent of total body fat and total fat mass; increased mean body weight; increased mean body length; increased total tissue mass (TTM); increased lean body mass (LBM); increased femoral bone mineral density (BMD); increased vertebral bone mineral density (BMD); increased bone mineral density (BMD); increased total body volumetric bone mineral density (vBMD); increased bone mineral content (BMC); increased mean femoral midshaft cortical thickness and cross-sectional area; increased mean vertebral trabecular bone volume, number and connectivity density; decreased mean percent of total body fat and total fat mass; decreased mean body weight; decreased mean body length; decreased total tissue mass (TTM); decreased lean body mass (LBM); decreased femoral bone mineral density (BMD); decreased vertebral bone mineral density (BMD); decreased bone mineral density (BMD); decreased bone mineral content (BMC); decreased bone mineral density index; decreased volumetric bone mineral density (vBMD); decreased mean femoral midshaft cortical thickness and cross-sectional area; decreased mean vertebral trabecular bone volume, number and connectivity density; marked osteopetrosis with increased bone mineralization; chronic inflammation in various tissues; thymic atrophy; systemic histiocytic storage disease affecting macrophages in liver, spleen and mesenteric lymph nodes; reduced liver size; chronic active hepatitis with focal hepatocyte necrosis; fatty changes in the liver; increased intracytoplasmic vacuolization of glycogen in hepatocytes; pancreatic dyserythropoietic anemia (type 1); multifocal neuronal necrosis; diffuse abiotrophy of the cerebellum granule cell layer; multifocal developmental malformation of the brain; hydronephosis; diffuse alopecia; epidermal hyperkeratosis; hypochromasia and anisocytosis characterized by abnormal erythrocytes (abnormally low hemoglobin and decreased erythropoiesis); growth retardation; development abnormalities; granulocytic hypoplasia of bone marrow; decreased numbers of myeloid granulocytic cell precursors; decreased granulocytopoiesis; no teeth; stunted growth with general reduction in all organ size; myocardial defects with defective structure and arrangement of the cardiac myocytes; cardiomyopathy with condensed eosinophilic sarcoplasm; congestive heart failure; pancreatic islets of Langerhans smaller and distribution of alpha (glycogen) and beta (insulin) cells altered; notable histopathologic alteration in cytoplasm of all cells in the zona fasciculata of the adrenal gland consistent with altered lipid/cholesterol uptake or metabolism (elevated cholesterol and triglycerides); infertility; testicular degeneration; vacuolar degeneration of seminiferous tubules; hypospermia; atrophic testes; ovarian and uterine hypoplasia; mammary gland was represented with just a few ducts; growth retardation with reduced viability; and embryonic lethality.

195-198. (canceled)

199. A method of identifying an agent that modulates a physiological characteristic associated with a disruption of a gene which encodes for a PRO1079 polypeptide, the method comprising: (a) providing a non-human transgenic animal whose genome comprises a disruption of a gene which is an ortholog of a human gene that encodes for a PRO1079 polypeptide; (b) measuring a physiological characteristic exhibited by the non-human transgenic animal of (a); (c) comparing the measured physiological characteristic of (b) with that of a gender matched wild-type animal, wherein the physiological characteristic exhibited by the non-human transgenic animal that differs from the physiological characteristic exhibited by the wild-type animal is identified as a physiological characteristic associated with gene disruption; (d) administering a test agent to the non-human transgenic animal of (a); and (e) determining whether the physiological characteristic associated with gene disruption is modulated.

200. The method of claim 199, wherein the non-human transgenic animal exhibits at least one of the following physiological characteristics during open field testing; decreased anxiety during open field testing; hypoactivity with no circadian rhythm; increased total distance traveled during open field testing (hyperactivity); decreased locomotor activity during open field testing; abnormal circadian rhythm during home-cage activity testing (low activity during the light phase); abnormal circadian rhythm during home-cage activity testing including decreased ambulatory counts; abnormal circadian rhythm during home-cage activity testing including increased ambulatory counts; whiskers absent due to anxiety phenotype; enhanced circadian rhythm; increased stress induced hyperthermia with increased stress response (increased anxiety); increased resistance to stress induced hyperthermia; decreased resistance to stress induced hyperthermia; enhanced motor coordination during inverted screen testing; impaired motor coordination during inverted screen testing; increased immobility in tail suspension (increased depressive-like response); increased depressive-like response during tail suspension testing; decreased depressive-like response during tail suspension testing; clutched hind limbs during tail suspension testing; decreased startle response during prepulse inhibition testing; no startle response indicating deafness; increased prepulse inhibition with enhanced sensorimotor gating/attention; increased latency on hotplate indicative of decreased sensitivity to heat-induced pain; opthamological abnormalities; corneal epidermidalization of the corneal stroma with scarring and blocked vision; metaplasia of the cornea and sclera; attenuated retinal arteries; retinal hemorrhage; optic nerve abnormalities; dilated optic disc; increased intraocular pressure; corneal epithelialization with underdeveloped eyelids; retinal degeneration; agenesis of the Harderian gland; retinal vessel disorganization, microaneurysms and retinal capillary leakage; impaired vision; decreased heart rate; decreased mean systolic blood pressure; increased mean systolic blood pressure; increased insulin sensitivity; increased mean fasting serum glucose levels; decreased mean serum glucose levels; increased mean serum cholesterol levels; decreased mean serum cholesterol levels; increased mean serum triglyceride levels; enhanced glucose tolerance; impaired glucose tolerance; decreased mean serum insulin levels; ketonemia; decreased mean serum calcium; blood urobilinogen, nitrites, protein and ketones; decreased sodium and chloride; increased bilirubin; notable lipemia; increased uric acid and potassium levels; increased mean serum alkaline phosphatase levels; decreased mean serum alkaline phosphatase levels; blood in the urine; glucosuria; increased nitrituria; ketonuria; increased mean percentage of natural killer cells; decreased mean percentage of natural killer cells; abnormal leukocyte count; leukopenia due to lymphopenia and granulocytopenia; increased mean percentage of CD4 cells; decreased mean percentage of CD4 cells; decreased mean percentage of CD8 cells; reduced percentage of naive CD4 and CD8 T cells in lymph nodes; increased mean percentage of B cells in peripheral blood; decrease total white blood cells and lymphocyte counts; decreased absolute lymphocyte counts; increased mean absolute monocyte count; increased mean absolute neutrophil count; decreased in mean serum IgA levels; increase in mean serum IgA levels; increase in IgG1 levels; decreased mean serum IgG1 levels; decreased mean serum IgG1, IgG3, IgG2b and IgG2a levels; decreased mean serum IgG2a levels; decreased mean serum IgG2b levels; decreased mean serum IgG3 and IgM levels; increase in mean serum IgG2a levels; increase in mean serum IgG1, IgG2a and IgG3 levels; increase in mean serum IgG3 levels; anemia; decreased red blood cell count, decreased hemoglobin and decreased hematocrit with increased mean red blood cell count; increased mean corpuscular volume; decreased mean corpuscular volume; decreased mean corpuscular hemoglobin; increased red blood cell distribution width; defect in erythropoiesis; increased IgM+ IgD+ and B220hi/CD43- cells in bone marrow; decreased percentage of B220hi/CD43- IgM+ IgD+ cells in bone marrow; increased percentage of TCRB+ cells in Peyer's patches; reduction in naive T cells (especially CD4) in lymph nodes; increased percentage of CD11b+CD11c- cells (monocytes) in spleen; increased percentage of IgM+, CD117+ cells in bone marrow, higher percentage of dead B cells, decreased B cells, increased CD4 and CD8 T cells in lymph; B cells increased in bone marrow and significantly decreased in lymph node; notably decreased CD21hiCD23med B cells in spleen; decrease in Peyer's patch B220+ cells; decreased mean percentages of CD8 and natural killer cells with increased mean percentage of B cells; reduced number of TCRB+ CD38+ activated T cells in Peyer's patches; decreased mean percentage of CD4 cells with increased mean percentage of B cells; decreased B220+ CD38low and IgM in Payer's patches; increased mean platelet count; decreased mean platelet count; widespread apoptosis and loss of T lymphocytes in the thymic cortex and depletion of T cells in spleen; increased mean serum IgG2a response to an ovalbumin challenge; decreased to no serum IgG1 and IgG2a response to ovalbumin challenge; increased mean serum IgG1 response to an ovalbumin challenge; decreased mean serum TNF-alpha, MCP-1 and IL-6 responses to LPS challenge; increased mean serum MCP-1 response to a LPS challenge; increased mean serum TNF-alpha response to a LPS challenge; increased mean serum IL-6 response to a LPS challenge; increased skin fibroblast proliferation; decreased skin fibroblast proliferation; increased mean percent of total body fat and total fat mass; increased mean body weight; increased mean body length; increased total tissue mass (TTM); increased lean body mass (LBM); increased femoral bone mineral density (BMD); increased vertebral bone mineral density (BMD); increased bone mineral density (BMD); increased total body volumetric bone mineral density (vBMD); increased bone mineral content (BMC); increased mean femoral midshaft cortical thickness and cross-sectional area; increased mean vertebral trabecular bone volume, number and connectivity density; decreased mean percent of total body fat and total fat mass; decreased mean body weight; decreased mean body length; decreased total tissue mass (TTM); decreased lean body mass (LBM); decreased femoral bone mineral density (BMD); decreased vertebral bone mineral density (BMD); decreased bone mineral density (BMD); decreased bone mineral content (BMC); decreased bone mineral density index; decreased volumetric bone mineral density (vBMD); decreased mean femoral midshaft cortical thickness and cross-sectional area; decreased mean vertebral trabecular bone volume, number and connectivity density; marked osteopetrosis with increased bone mineralization; chronic inflammation in various tissues; thymic atrophy; systemic histiocytic storage disease affecting macrophages in liver, spleen and mesenteric lymph nodes; reduced liver size; chronic active hepatitis with focal hepatocyte necrosis; fatty changes in the liver; increased intracytoplasmic vacuolization of glycogen in hepatocytes; pancreatic dyserythropoietic anemia (type 1); multifocal neuronal necrosis; diffuse abiotrophy of the cerebellum granule cell layer; multifocal developmental malformation of the brain; hydronephosis; diffuse alopecia; epidermal hyperkeratosis; hypochromasia and anisocytosis characterized by abnormal erythrocytes (abnormally low hemoglobin and decreased erythropoiesis); growth retardation; development abnormalities; granulocytic hypoplasia of bone marrow; decreased numbers of myeloid granulocytic cell precursors; decreased granulocytopoiesis; no teeth; stunted growth with general reduction in all organ size; myocardial defects with defective structure and arrangement of the cardiac myocytes; cardiomyopathy with condensed eosinophilic sarcoplasm; congestive heart failure; pancreatic islets of Langerhans smaller and distribution of alpha (glycogen) and beta (insulin) cells altered; notable histopathologic alteration in cytoplasm of all cells in the zona fasciculata of the adrenal gland consistent with altered lipid/cholesterol uptake or metabolism (elevated cholesterol and triglycerides); infertility; testicular degeneration; vacuolar degeneration of seminiferous tubules; hypospermia; atrophic testes; ovarian and uterine hypoplasia; mammary gland was represented with just a few ducts; growth retardation with reduced viability; and embryonic lethality.

201-204. (canceled)

205. A method of identifying an agent which modulates a behavior associated with a disruption of a gene which encodes for a PRO1079 polypeptide, the method comprising: (a) providing a non-human transgenic animal whose genome comprises a disruption of a gene which is an ortholog of a human gene that encodes for a PRO1079 polypeptide; (b) observing the behavior exhibited by the non-human transgenic animal of (a); (c) comparing the observed behavior of (b) with that of a gender matched wild-type animal, wherein the observed behavior exhibited by the non-human transgenic animal that differs from the observed behavior exhibited by the wild-type animal is identified as a behavior associated with gene disruption; (d) administering a test agent to the non-human transgenic animal of (a); and (e) determining whether the agent modulates the behavior associated with gene disruption.

206. The method of claim 205, wherein the behavior is an increased anxiety-like response during open field activity testing.

207. The method of claim 205, wherein the behavior is a decreased anxiety-like response during open field activity testing.

208. The method of claim 205, wherein the behavior is an abnormal circadian rhythm during home-cage activity testing.

209. The method of claim 205, wherein the behavior is an enhanced motor coordination during inverted screen testing.

210. The method of claim 205, wherein the behavior is an impaired motor coordination during inverted screen testing.

211. The method of claim 205, wherein the behavior is depression, generalized anxiety disorders, attention deficit disorder, sleep disorder, hyperactivity disorder, obsessive compulsive disorder, schizophrenia, cognitive disorders, hyperalgesia or sensory disorders.

212-289. (canceled)