This is a revised proposal to examine the role of CIB1, in endothelial function and pathological angiogenesis, or new blood vessel growth. CIB1 is a 22kDa EF- hand containing, Ca2+binding protein, homologous to calmodulin. Several lines of evidence indicate that CIB1 is a key regulator of endothelial cell function. Endothelial cells lacking CIB1 are significantly impaired in their ability to migrate, form tubules and proliferate. In addition, Cib1 knockout mice have impaired pathological and adaptive angiogenesis in response to ischemia. New data also indicate that tumor growth is compromised in these mice, apparently due to a poor angiogenic response. Separate studies have shown that CIB1 binds directly to, and activates, PAK1, a serine/threonine kinase known to regulate endothelial cell migration. New biochemical data show that CIB1 also binds directly to many integrin 1-subunits, several of which are important in endothelial function. Based on these data, we propose to 1) test the hypothesis that CIB1 directly binds to and regulates the function of integrins, especially those relevant to endothelial cells and 2) delineate the mechanisms by which CIB1 regulates pathological and tumor angiogenesis. Here we will determine whether regulation of angiogenesis occurs via a PAK1, integrin and/or another pathway(s). Since pathological angiogenesis contributes to a wide range of diseases involving cancer, atherosclerosis, retinopathies, etc, these studies should allow us to identify fundamental mechanisms regulating endothelial cell function and vascular remodeling.
Many people suffer from illnesses related to abnormally increased or decreased blood vessel growth, e.g. in cancers, retinopathies, rheumatoid arthritis, psoriasis and heart disease. In this proposal we seek to better understand how endothelial cells, which line all blood vessels, control blood vessel growth, by studying a protein called CIB1, which appears to regulate endothelial cell function.
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