Novel PRO1199 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 PRO224, PRO9783, PRO1108, PRO34000, PRO240, PRO943, hu A33, PRO230, PRO178, PRO1199, PRO4333, PRO1336, PRO19598, PRO1083, hu TRPM2 or PRO1801 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 - 25 . (canceled) 
     
     
         26 . A method of identifying an agent that modulates a phenotype associated with a disruption of a gene which encodes for a PRO1199 polypeptide, the method comprising:
 (a) providing a non-human transgenic animal whose genome comprises a disruption of the gene which encodes for the PRO1199 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 said 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 the gene disruption in the non-human transgenic animal.   
     
     
         27 . The method of  claim 26 , wherein the phenotype associated with the gene disruption comprises a cardiovascular disorder; an angiogenic disorder; an immunological disorder; or a lipid metabolic disorder. 
     
     
         28 - 41 . (canceled) 
     
     
         42 . The method of  claim 27 , wherein the cardiovascular or angiogenic disorders are arterial diseases, including diabetes mellitus; papilledema; optic atrophy; atherosclerosis; angina; myocardial infarctions including acute myocardial infarctions, cardiac hypertrophy, and heart failure including congestive heart failure; hypertension; inflammatory vasculitides; Reynaud's disease and Reynaud's phenomenon; aneurysms and arterial restenosis; venous and lymphatic disorders including thrombophlebitis, lymphangitis, and lymphedema; peripheral vascular disease; cancer including vascular tumors, capillary hemangioma and cavernous hemangioma, glomus tumors, telangiectasia, bacillary angiomatosis, hemangioendothelioma, angiosarcoma, haemangiopericytoma, Kaposi's sarcoma, lymphangioma, and lymphangiosarcoma; tumor angiogenesis; trauma including wounds, burns, and other injured tissue, implant fixation, scarring; ischemia reperfusion injury; rheumatoid arthritis; cerebrovascular disease; renal diseases including 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 including scleroderma; idiopathic inflammatory myopathies including dermatomyositis and polymyositis; Sjogren's syndrome; systemic vasculitis; sarcoidosis; autoimmune hemolytic anemia including immune pancytopenia and paroxysmal nocturnal hemoglobinuria; autoimmune thrombocytopenia including idiopathic thrombocytopenic purpura and immune-mediated thrombocytopenia; thyroiditis including Grave's disease, Hashimoto's thyroiditis, juvenile lymphocytic thyroiditis, and atrophic thyroiditis; diabetes mellitus; immune-mediated renal disease including glomerulonephritis and tubulointerstitial nephritis; demyelinating diseases of the central nervous system and of the peripheral nervous system, including multiple sclerosis, idiopathic demyelinating polyneuropathy or Guillain-Barre syndrome, and chronic inflammatory demyelinating polyneuropathy; hepatobiliary diseases including 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 including ulcerative colitis and 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 including eosinophilic pneumonias, idiopathic pulmonary fibrosis and hypersensitivity pneumonitis; or transplantation associated diseases including graft rejection and graft-versus-host disease. 
     
     
         44 . (canceled) 
     
     
         45 . The method of  claim 26 , wherein the non-human transgenic animal exhibits at least one of the following physiological characteristic compared with gender-matched wild-type littermates: an increased mean serum triglyceride level; an increased total tissue mass, or an increased lean body mass. 
     
     
         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 PRO1199 polypeptide, the method comprising:
 (a) providing a non-human transgenic animal whose genome comprises a disruption of the gene which encodes for a PRO1199 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 said gene disruption;   (d) administering a test agent to the non-human transgenic animal of (a); and   (e) determining whether the physiological characteristic associated with the gene disruption is modulated.   
     
     
         51 . The method of  claim 50 , wherein the non-human transgenic animal exhibits the following physiological characteristic compared with gender matched wild-type littermates: an increased mean serum triglyceride level; an increased total tissue mass, or an increased lean body mass. 
     
     
         52 - 55 . (canceled) 
     
     
         56 . A method of identifying an agent which modulates a behavior associated with a disruption of a gene which encodes for a PRO1199 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 PRO1199 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 said 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 the gene disruption.   
     
     
         57 - 66 . (canceled) 
     
     
         67 . A method of identifying an agent that ameliorates or modulates a cardiovascular disorder; an angiogenic disorder; an immunological disorder; or a lipid metabolic disorder associated with a disruption of a gene which encodes for a PRO1199 polypeptide, the method comprising:
 (a) providing a non-human transgenic animal whose genome comprises a disruption of the gene which encodes for a PRO1199 polypeptide;   (b) administering a test agent to said non-human transgenic animal; and   (c) determining whether said test agent ameliorates or modulates a cardiovascular disorder; an angiogenic disorder; an immunological disorder; or a lipid metabolic disorder in the non-human transgenic animal.   
     
     
         68 - 81 . (canceled) 
     
     
         82 . The method of  claim 67 , wherein the cardiovascular or angiogenic disorders are arterial diseases, including diabetes mellitus; papilledema; optic atrophy; atherosclerosis; angina; myocardial infarctions such as acute myocardial infarctions, cardiac hypertrophy, and heart failure including congestive heart failure; hypertension; inflammatory vasculitides; Reynaud's disease and Reynaud's phenomenon; aneurysms and arterial restenosis; venous and lymphatic disorders including thrombophlebitis, lymphangitis, and lymphedema; peripheral vascular disease; cancer including vascular tumors, including capillary hemangioma and cavernous hemangioma, glomus tumors, telangiectasia, bacillary angiomatosis, hemangioendothelioma, angiosarcoma, haemangiopericytoma, Kaposi's sarcoma, lymphangioma, and lymphangiosarcoma; tumor angiogenesis; trauma including wounds, burns, and other injured tissue, implant fixation, and scarring; ischemia reperfusion injury; rheumatoid arthritis; cerebrovascular disease; renal diseases including 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 including scleroderma; idiopathic inflammatory myopathies including dermatomyositis; and polymyositis; Sjogren's syndrome; systemic vasculitis; sarcoidosis; autoimmune hemolytic anemia including immune pancytopenia and paroxysmal nocturnal hemoglobinuria; autoimmune thrombocytopenia including idiopathic thrombocytopenic purpura and immune-mediated thrombocytopenia; thyroiditis including Grave's disease, Hashimoto's thyroiditis, juvenile lymphocytic thyroiditis, and atrophic thyroiditis; diabetes mellitus; immune-mediated renal disease including glomerulonephritis and tubulointerstitial nephritis; demyelinating diseases of the central nervous system and peripheral nervous system including multiple sclerosis, idiopathic demyelinating polyneuropathy or Guillain-Barre syndrome, and chronic inflammatory demyelinating polyneuropathy; hepatobiliary diseases including 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 including ulcerative colitis and 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 including asthma, allergic rhinitis, atopic dermatitis, food hypersensitivity and urticaria; immunologic diseases of the lung including eosinophilic pneumonia, idiopathic pulmonary fibrosis and hypersensitivity pneumonitis; or transplantation associated diseases including graft rejection and graft-versus-host disease. 
     
     
         84 . (canceled) 
     
     
         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: an increased mean serum triglyceride level; an increased total tissue mass, or an increased lean body mass. 
     
     
         86 - 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 PRO1199 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 PRO1199 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 said 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 the gene disruption in the non-human transgenic animal.   
     
     
         97 . The method of  claim 96 , wherein the condition is a cardiovascular disorder; an angiogenic disorder; an immunological disorder; or a lipid metabolic disorder. 
     
     
         98 - 149 . (canceled)