p68RacGAP signaling in endothelial cell differentiation and angiogenesis

描述(由申请人提供)： 这项建议描述了一个为期五年的培训计划，以发展分子心脏病学的学术生涯，因为它与调控内皮细胞分化、血管生成和RhoGAP蛋白的胚胎发生有关。这位首席研究员除了两年的临床心脏病学培训外，还完成了三年的分子心脏病学博士后培训，目前他具有心脏病学的董事会资格。这项计划提供了一个独特的机会，以首席研究员的临床和分子生物学专业知识为基础，将结构化学习、课程工作和实验室技术结合到多学科方法中，由p68racGAP在国际公认的内皮细胞分化领域的领导者、医学教授Cam Patterson博士的指导下，研究内皮细胞分化的分子、基因组和生理调节。为了加强培训，该计划招募了一个咨询委员会的专业知识，该委员会由具有分子生物学专业知识的资深研究人员组成，以提供科学和职业建议，并得到在细胞生物学、血管生成和基因靶向失活领域具有广泛专业知识和经验的合作者的协助。这项拟议的研究将集中在p68racGAP在调控内皮细胞分化、血管生成和胚胎发育中的作用，该基因通过与内皮细胞特异性转录因子(Vezfl)的体内相互作用而确定。我们已经证明p68racGAP是一种rac1特异性的RhoGAP蛋白，它在体内抑制内皮细胞毛细血管组装。我们假设p68racGAP是一种调控蛋白，对内皮细胞分化和血管生成至关重要，靶向缺失的p68racGAP基因将导致胚胎发育的紊乱。本研究的总体目标是明确p68racGAP依赖的信号调控对内皮细胞分化的生物学作用，确定p68racGAP在血管生成中的作用，并通过免疫组织化学分析和功能分析鉴定p68racGAP基因敲除小鼠的表型，分析血管和心脏缺陷的靶向胚胎。北卡罗来纳大学教堂山分校内科和卡罗莱纳心血管生物学中心凭借其多样化的资源、成熟的研究人员和对年轻研究人员的支持，为内科科学家提供了理想的培训环境。 (摘要结束)

DESCRIPTION (provided by applicant): This proposal describes a five year training program for the development of an academic career in molecular cardiology as it pertains to regulation of endothelial cell differentiation, angiogenesis and embryogenesis by RhoGAP proteins. The principal investigator has completed three years of postdoctoral training in molecular cardiology in addition to a two-year clinical cardiology training, and he is currently board eligible in cardiology. This program provides a unique opportunity to build on the principal investigator's clinical and molecular biology expertise and to combine structured learning, course work and laboratory techniques into a multidisciplinary approach to studying the molecular, genomic and physiologic regulation of endothelial cell differentiation by p68RacGAP under the tutelage of Dr. Cam Patterson, Professor of Medicine who is internationally recognized as a leader in the field of endothelial cell differentiation. To enhance the training, the program has enlisted the expertise of an advisory committee that consists of established investigators with expertise in molecular biology for scientific and career advice, and the assistance of collaborators with extensive expertise and experience in the field of cell biology, angiogenesis, and targeted inactivation of genes. The proposed research will focus on the role of p68RacGAP, identified via its in vivo interaction with an endothelial cell-specific transcription factor (Vezfl), in regulation of endothelial cell differentiation, angiogensis and embryogenesis. We have shown that p68RacGAP is a Rac1-specific RhoGAP protein that inhibits endothelial cell capillary assembly in vivo. We hypothesize that p68RacGAP is a regulatory protein that is critical to endothelial cell differentiation and angiogenesis and that targeted deletion of p68RacGAP gene will lead to perturbation in embryogenesis. The overall objectives of this proposal are to define the biologic effect of p68RacGAP-dependent signal regulation on endothelial cell differentiation, determine the role of p68RacGAP on angiogenesis and to characterize the phenotype of p68RacGAP knockout mice and analyze targeted embryos for vascular and cardiac defects by immunohistochemical analysis and functional assays. The University of North Carolina-Chapel Hill Department of Internal Medicine and the Carolina Cardiovascular Biology Center provides an ideal training environment for physician-scientists by its diverse resources, established investigators, and support for young investigators. (End of Abstract)