CIB1 regulation of endothelial function

描述（由申请人提供）：这是一项修订提案，旨在检查CIB 1在内皮功能和病理性血管生成或新血管生长中的作用。CIB 1是一个22 kDa的EF-手，含有Ca ~（2+）结合蛋白，与钙调蛋白同源。几条证据表明，CIB 1是内皮细胞功能的关键调节因子。缺乏CIB 1的内皮细胞迁移、形成小管和增殖的能力显著受损。此外，Cib 1基因敲除小鼠在响应缺血时具有受损的病理性和适应性血管生成。新的数据还表明，这些小鼠的肿瘤生长受到影响，显然是由于血管生成反应不良。单独的研究表明，CIB 1直接结合并激活PAK 1，PAK 1是一种已知调节内皮细胞迁移的丝氨酸/苏氨酸激酶。新的生物化学数据表明，CIB 1也直接结合到许多整合素1-亚基，其中几个是重要的内皮功能。基于这些数据，我们提出1）检验CIB 1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，和2）描绘CIB 1调节病理和肿瘤血管生成的机制。在这里，我们将确定是否通过PAK 1，整合素和/或其他途径调节血管生成。由于病理性血管生成导致广泛的疾病，包括癌症、动脉粥样硬化、视网膜病变等，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。 公共卫生相关性：许多人患有与异常增加或减少的血管生长相关的疾病，例如癌症、视网膜病、类风湿性关节炎、牛皮癣和心脏病。在这项提案中，我们试图通过研究一种名为CIB 1的蛋白质来更好地了解所有血管中的内皮细胞如何控制血管生长，CIB 1似乎可以调节内皮细胞的功能。

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. PUBLIC HEALTH RELEVANCE: 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.