CIB1 regulation of endothelial function

描述（由申请人提供）：这是一份修订后的提案，旨在检查CIB1在内皮功能和病理性血管生成或新血管生长中的作用。CIB1是一种含有22kDa EF- hand的Ca2+结合蛋白，与钙调蛋白同源。多项证据表明，CIB1是内皮细胞功能的关键调节因子。缺乏CIB1的内皮细胞在迁移、形成小管和增殖方面的能力明显受损。此外，Cib1基因敲除小鼠在缺血反应中损伤了病理性和适应性血管生成。新的数据还表明，肿瘤生长在这些小鼠中受到损害，显然是由于不良的血管生成反应。单独的研究表明，CIB1直接结合并激活PAK1， PAK1是一种丝氨酸/苏氨酸激酶，已知可调节内皮细胞迁移。新的生化数据表明，CIB1还直接结合许多整合素1亚基，其中一些在内皮功能中很重要。基于这些数据，我们建议1)验证CIB1直接结合并调节整合素功能的假设，特别是与内皮细胞相关的整合素；2)描述CIB1调节病理和肿瘤血管生成的机制。在这里，我们将确定血管生成的调节是否通过PAK1、整合素和/或其他途径发生。由于病理性血管生成与癌症、动脉粥样硬化、视网膜病变等多种疾病有关，这些研究应使我们能够确定调节内皮细胞功能和血管重塑的基本机制。

DESCRIPTION (provided by applicant): 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.