Novel pro258 gene disruptions, 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 PRO196, PRO217, PRO231, PRO236, PRO245, PRO246, PRO258, PRO287, PRO328, PRO344, PRO357, PRO526, PRO724, PRO731, PRO732, PRO1003, PRO1104, PRO1151, PRO1244, PRO1298, PRO1313, PRO1570, PRO1886, PRO1891, PRO4409, PRO5725, PRO5994, PRO6097, PRO7425, PRO10102, PRO10282, PRO61709 or PRO779 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.

1 . A method of identifying a phenotype associated with a disruption of a gene which encodes for a PRO258 polypeptide, the method comprising:
 (a) providing a non-human transgenic animal whose genome comprises a disruption of the gene which encodes for a PRO258 polypeptide;   (b) measuring a physiological characteristic of the non-human transgenic animal; and   (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 PRO258 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 immunological disorder; a bone metabolic abnormality or disorder; or a lipid metabolic disorder. 
     
     
         4 - 5 . (canceled) 
     
     
         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 - 17 . (canceled) 
     
     
         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); Sjögren'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-Barré 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: abnormal circadian rhythm during home-cage activity testing including decreased ambulatory counts; enhanced motor coordination during inverted screen testing; increased mean fasting serum glucose levels; decreased heart rate; increased mean serum cholesterol levels; increased mean percentage of CD4 cells and decreased mean percentage of B cells; decreased mean serum IgG2a response to an ovalbumin challenge; decreased mean total white blood cell (WBC) counts; decreased absolute lymphocyte counts; decreased absolute monocyte counts; decreased total femoral midshaft cross-sectional area; decreased mean vertebral trabecular bone volume, number and connectivity density. 
     
     
         22 . An isolated cell derived from a non-human transgenic animal whose genome comprises a disruption of the gene which encodes for a PRO258 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 immunological disorder; a bone metabolic abnormality or disorder; or a lipid metabolic disorder. 
     
     
         26 . A method of identifying an agent that modulates a phenotype associated with a disruption of a gene which encodes for a PRO258 polypeptide, the method comprising:
 (a) providing a non-human transgenic animal whose genome comprises a disruption of the gene which encodes for the PRO258 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.   
     
     
         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 - 29 . (canceled) 
     
     
         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 - 41 . (canceled) 
     
     
         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); Sjögren'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-Barré 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: abnormal circadian rhythm during home-cage activity testing including decreased ambulatory counts; enhanced motor coordination during inverted screen testing; increased mean fasting serum glucose levels; decreased heart rate; increased mean serum cholesterol levels; increased mean percentage of CD4 cells and decreased mean percentage of B cells; decreased mean serum IgG2a response to an ovalbumin challenge; decreased mean total white blood cell (WBC) counts; decreased absolute lymphocyte counts; decreased absolute monocyte counts; decreased total femoral midshaft cross-sectional area; decreased mean vertebral trabecular bone volume, number and connectivity density. 
     
     
         46 - 49 . (canceled) 
     
     
         50 . A method of identifying an agent that modulates a physiological characteristic associated with a disruption of the gene which encodes for a PRO258 polypeptide, the method comprising:
 (a) providing a non-human transgenic animal whose genome comprises a disruption of the gene which encodes for a PRO258 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.   
     
     
         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: abnormal circadian rhythm during home-cage activity testing including decreased ambulatory counts; enhanced motor coordination during inverted screen testing; increased mean fasting serum glucose levels; decreased heart rate; increased mean serum cholesterol levels; increased mean percentage of CD4 cells and decreased mean percentage of B cells; decreased mean serum IgG2a response to an ovalbumin challenge; decreased mean total white blood cell (WBC) counts; decreased absolute lymphocyte counts; decreased absolute monocyte counts; decreased total femoral midshaft cross-sectional area; decreased mean vertebral trabecular bone volume, number and connectivity density. 
     
     
         52 - 55 . (canceled) 
     
     
         56 . A method of identifying an agent which modulates a behavior associated with a disruption of the gene which encodes for a PRO258 polypeptide, the method comprising:
 (a) providing a non-human transgenic animal whose genome comprises a disruption of the gene which encodes for a PRO258 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.   
     
     
         57 - 58 . (canceled) 
     
     
         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 - 66 . (canceled) 
     
     
         67 . A method of identifying an agent that ameliorates or modulates a neurological disorder; a cardiovascular, endothelial or angiogenic disorder; an immunological disorder; a bone metabolic abnormality or disorder; or a lipid metabolic disorder associated with a disruption in the gene which encodes for a PRO258 polypeptide, the method comprising:
 (a) providing a non-human transgenic animal whose genome comprises a disruption of the gene which encodes for a PRO258 polypeptide;   (b) administering a test agent to said non-human transgenic animal; and   (c) determining whether said test agent ameliorates or modulates the neurological disorder; cardiovascular, endothelial or angiogenic disorder; immunological disorder; bone metabolic abnormality or disorder; or lipid metabolic disorder; in the non-human transgenic animal.   
     
     
         68 - 69 . (canceled) 
     
     
         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 - 81 . (canceled) 
     
     
         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); Sjögren'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-Barré 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: abnormal circadian rhythm during home-cage activity testing including decreased ambulatory counts; enhanced motor coordination during inverted screen testing; increased mean fasting serum glucose levels; decreased heart rate; increased mean serum cholesterol levels; increased mean percentage of CD4 cells and decreased mean percentage of B cells; decreased mean serum IgG2a response to an ovalbumin challenge; decreased mean total white blood cell (WBC) counts; decreased absolute lymphocyte counts; decreased absolute monocyte counts; decreased total femoral midshaft cross-sectional area; decreased mean vertebral trabecular bone volume, number and connectivity density. 
     
     
         86 - 90 . (canceled) 
     
     
         91 . A method of identifying an agent that modulates the expression of a PRO258 polypeptide, the method comprising:
 (a) contacting a test agent with a host cell expressing a PRO258 polypeptide; and   (b) determining whether the test agent modulates the expression of the PRO258 polypeptide by the host cell.   
     
     
         92 - 95 . (canceled) 
     
     
         96 . A method of evaluating a therapeutic agent capable of affecting a condition associated with a disruption of a gene which encodes for a PRO258 polypeptide, the method comprising:
 (a) providing a non-human transgenic animal whose genome comprises a disruption of the gene which encodes for the PRO258 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 condition 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) 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 immunological disorder; a bone metabolic abnormality or disorder; or a lipid metabolic disorder. 
     
     
         98 - 102 . (canceled) 
     
     
         103 . A method of treating or preventing or ameliorating a neurological disorder; cardiovascular, endothelial or angiogenic disorder; immunological disorder; bone metabolic abnormality or disorder; or lipid metabolic disorder associated with the disruption of a gene which encodes for a PRO258 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 therapeutic agent identified by the method of  claim 91 , or agonists or antagonists thereof, thereby effectively treating or preventing or ameliorating said disorder. 
     
     
         104 - 105 . (canceled) 
     
     
         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 - 117 . (canceled) 
     
     
         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); Sjögren'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-Barré 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 immunological disorder; a bone metabolic abnormality or disorder; or a lipid metabolic disorder associated with a disruption in the gene which encodes for a PRO258 polypeptide, the method comprising:
 (a) providing a non-human transgenic animal cell culture, each cell of said culture comprising a disruption of the gene which encodes for a PRO258 polypeptide;   (b) administering a test agent to said cell culture; and   (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 - 123 . (canceled) 
     
     
         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 . (canceled) 
     
     
         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 - 135 . (canceled) 
     
     
         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); Sjögren'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-Barré 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 - 143 . (canceled) 
     
     
         144 . A method of modulating a phenotype associated with a disruption of a gene which encodes for a PRO258 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 by the method of  claim 26 , 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 PRO258 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 by the method of  claim 50 , 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 PRO258 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 by the method of  claim 56 , or agonists or antagonists thereof, thereby effectively modulating the behavior. 
     
     
         147 . A method of modulating the expression of a PRO258 polypeptide, the method comprising administering to a host cell expressing said PRO258 polypeptide, an effective amount of an agent identified by the method of  claim 91 , 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 PRO258 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 by the method of  claim 96 , 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; bone metabolic abnormality or disorder, or lipid metabloc disorder associated with the disruption of a gene which encodes for a PRO258 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 PRO258 polypeptide, a therapeutically effective amount of an agent identified by the method of  claim 121 , or agonists or antagonists thereof, thereby effectively treating or preventing or ameliorating said disorder.