Gene disruptions, compositions and methods relating thereto
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 PRO194, PRO220, PRO241, PRO284, PRO331, PRO354, PRO355, PRO533, PRO541, PRO725, PRO937, PRO1014, PRO1120, PRO1182, PRO1325, PRO1382, PRO1410, PRO1555, PRO1556, PRO1760, PRO1787, PRO1868, PRO4326, PRO4332, PRO4346, PRO4400, PRO6003, PRO6094, PRO6244, PRO9820, PRO9828, PRO10274, PRO16090, PRO19644, PRO21340, PRO92165, PRO85143, PRO1124, PRO1026 or PRO23370 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 test agent that modulates a lipid metabolic disorder associated with a disruption of an immunoglobulin superfamily, member 4 (Igsf4), the method comprising:
(a) providing a knockout mouse whose genome comprises a homozygous disruption of a nucleic acid sequence which is an ortholog of a human nucleic acid sequence that encodes for the polypeptide of SEQ ID NO:14, wherein said mouse lacks functional Igsf4 and exhibits as compared to the wild type mouse, at least one of: increased mean serum triglyceride level and increased mean serum tumor necrosis factor-α (TNF-α) response to a lipopolysaccharide (LPS) challenge,
(b) administering a test agent to the knockout mouse of (a),
(c) determining the knockout mouse's susceptibility to at least one of: increased mean serum triglyceride level and increased mean serum TNF-α response to a LPS challenge, and
(d) identifying whether a test agent modulates a lipid metabolic disorder associated with a disruption of an Igsf4, wherein decreasing at least one of: the knockout mouse' mean serum triglyceride level and the knockout mouse' mean serum TNF-α response to a LPS challenge is indicative of an agonist of the Igsf4, and wherein increasing at least one of: the knockout mouse' mean serum triglyceride level and the knockout mouse' mean serum TNF-α response to a LPS challenge is indicative of an antagonist of the Igsf4.
2. The test agent of claim 1 , wherein the agonist is an anti-Igsf4 antibody.
3. The test agent of claim 1 , wherein the antagonist is an anti-Igsf4 antibody.