PATHOLOGY OF ENDOTHELIAL NEOVASCULIZATION

动脉粥样硬化性血管疾病仍然是 美国的发病率和死亡率，尽管有激进的医疗和 外科治疗。血管细胞(内皮和平滑肌) 血管成形术和搭桥术对损伤的反应是主要的 决定特定的最终功能状态的因素 船只。已知血管细胞对损伤的反应是调节的。 通过复杂、动态的细胞-细胞相互作用和细胞与 通过整合素的底层和周围的细胞外基质。在……里面 此外，多种生长因子(PDGF、转化生长因子-β、碱性成纤维细胞生长因子)、 尽管仍不完全了解，但被认为在 指导血管损伤后的转归。的长期目标是 这项建议是为了阐明交互信号转导 在选定细胞接合后处于活动状态的机构- 细胞黏附分子及其配体，整合素与细胞外基质成分 和选定的生长因子及其受体；并理解 血管壁中这些系统之间的相互关系。具体来说， 大血管内皮细胞剥脱损伤组织培养模型的建立 修复和微血管内皮细胞血管生成将用于 表征和确定信号转导的机制(S) 继细胞黏附分子、整合素和生长因子受体之后 内皮细胞对损伤的反应过程中的参与。几个 将采用组织培养、免疫标记等方法学 在光、共焦和电子显微镜水平上，北方、南方 以及原位杂交，生物合成标记，免疫沉淀， 免疫印迹、逆转录病毒转导和基因过表达 选择。实验将围绕抗体、cdna探针的使用展开。 以及针对被认为参与其中的特定激酶的多肽 这些信号级联、选定的生长因子受体和它们的 配体、基质分子和基质结合蛋白 这些分子的结构域、cRNA和cdna探针 体外大血管中的分子和特异性嵌合转化生长因子-β分子 血管内皮细胞迁移和血管生成的体外研究 微血管内皮细胞。 更好地理解发生在 血管细胞对损伤的反应过程可能会导致设计， 改进的合成接枝材料的生产和实施， 促进治疗后血管细胞最佳行为的药物 干预措施，以及可用于调节血管生成的药物 应答和有潜力的体细胞基因治疗方法 来提供长期的非肠道治疗。

Atherosclerotic vascular disease continues to be a major cause of morbidity and mortality in the U.S despite aggressive medical and surgical therapy. Vascular cell (endothelial and smooth muscle) responses to injury elicited by angioplasty and bypass grafting are major factors in determining the ultimate functional state of the particular vessel. The vascular cell responses to injury are known to be modulated by complex, dynamic cell-cell interactions and cellular interactions with the underlying and surrounding extracellular martix via integrins. In addition, the roles of a variety of growth factors (PDGF, TGF-b, bFGF), although still incompletely understood, are thought to be critical in directing the outcome following vessel injury. The long-term goal of this proposal is to elucidate the interactive signal transduction mechanisms which are active following the engagement of selected cell- cell adhesion molecules with their ligands, integrins with ECM components and selected growth factors with their receptors; and to understand the interrelationships among these systems in the vessel wall. Specifically, tissue culture models of large vessel endothelial cell denudation injury- repair and microvascular endothelial cell angiogenesis will be used to characterize and determine the mechanism(s) of signal transduction following cell adhesion molecule, integrin and growth factor receptor engagement during endothelial cell responses to injury. Several methodologies will be employed including tissue culture, immunolabeling at light, confocal and electron microscopic levels, Northern, Southern and in situ hybridizations, biosynthetic labeling, immunoprecipitation, immunoblotting, retroviral transduction and over-expression of genes of choice. Experiments will center around the use of antibodies, cDNA probes and peptides directed against specific kinases thought to be involved in these signalling cascades, selected growth factor receptors and their ligands, matrix molecules and matrix binding proteins and selected domains of these molecules, cRNA and cDNA probes specific for these molecules and specific chimeric TGF-b molecules in in vitro large vessel endothelial cell migrations and during in vitro angiogenesis studies with microvascular endothelial cells. A better understanding of the signalling cascades that occur during the processes of vascular cell response to injury may lead to the design, production and implementation of improved synthetic grafting materials, agents that promote optimal vascular cell behavior following therapeutic intervention, and agents that can be used to modulate the angiogenic response and a somatic cell gene therapy approach which has the potential to deliver long-term parenteral therapy.