CIB1 regulation of endothelial function

CIB1对内皮功能的调节

• 批准号: 8265825
• 负责人: Leslie V. Parise
• 金额: $ 36.63万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-15 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8265825
• 关键词: Allografting; Atherosclerosis; Binding; Binding Proteins; Biochemical; Blood Platelets; Blood Vessels; Calcium-Binding Domain; Calmodulin; Cell physiology; Cells; Characteristics; Coronary Arteriosclerosis; Cytoplasmic Tail; Data; Defect; Dependence; Disease; EF Hand Motifs; Endothelial Cells; Endothelium; Exhibits; Growth; Heart Diseases; In Vitro; Inflammatory; Injury; Integrins; Ischemia; Knockout Mice; Lead; Life; MMP2 gene; Malignant Neoplasms; Modeling; Molecular; Mus; Pathologic Neovascularization; Pathway interactions; Peripheral; Physiological; Proliferating; Protein-Serine-Threonine Kinases; Proteins; Psoriasis; Publishing; Regulation; Retinal Diseases; Rheumatoid Arthritis; Role; Signal Transduction; Structure; Tail; Testing; Tumor Angiogenesis; Vascular remodeling; angiogenesis; base; cell motility; cell type; in vivo; insight; migration; novel; p21-activated kinase 1; public health relevance; response; response to injury; therapeutic target; tumor; tumor growth; tumorigenesis

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.

描述(由申请人提供)：这是一项研究CIB1在内皮功能和病理性血管生成或新血管生长中的作用的修订提案。CIB1是一种含22 kDa EF-Hand的钙离子结合蛋白，与钙调蛋白同源。多条证据表明，CIB1是内皮细胞功能的关键调节因子。缺乏CIB1的内皮细胞迁移、形成小管和增殖的能力显著受损。此外，CIB1基因敲除小鼠对缺血的反应损害了病理和适应性血管生成。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较差。单独的研究表明，CIB1直接与PAK1结合并激活PAK1，PAK1是一种已知的调节内皮细胞迁移的丝氨酸/苏氨酸激酶。新的生化数据显示，CIB1还与许多整合素1亚基直接结合，其中几个亚基在内皮功能中起重要作用。基于这些数据，我们建议1)检验CIB1直接与整合素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功能；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控是否通过PAK1、整合素和/或其他途径发生(S)。由于病理性血管生成与多种疾病有关，包括癌症、动脉粥样硬化、视网膜病变等，这些研究应该使我们能够确定调控内皮细胞功能和血管重塑的基本机制。 公共卫生相关性：许多人患有与血管生长异常增加或减少有关的疾病，例如癌症、视网膜疾病、类风湿性关节炎、牛皮癣和心脏病。在这项提议中，我们试图通过研究一种名为CIB1的蛋白质来更好地了解排列在所有血管内的内皮细胞如何控制血管生长，CIB1似乎调节内皮细胞的功能。