PATHOLOGY OF ENDOTHELIAL NEOVASCULIZATION

内皮新生血管形成的病理学

• 批准号: 2216259
• 负责人: JOSEPH A MADRI
• 金额: $ 41.9万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-02-01 至 1999-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2216259
• 关键词: atherosclerosis; biological signal transduction; cell adhesion molecules; cell migration; cellular pathology; confocal scanning microscopy; electron microscopy; extracellular matrix; goats; growth factor receptors; human tissue; integrins; laboratory mouse; laboratory rabbit; laboratory rat; nonsurgical revascularization; protein isoforms; receptor binding; transforming growth factors; vascular endothelium; western blottings

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.

动脉粥样硬化性血管疾病仍然是导致 美国的发病率和死亡率， 手术治疗 血管细胞（内皮和平滑肌） 血管成形术和旁路移植术引起的损伤反应是主要的 决定特定环境的最终功能状态的因素 容器。 已知血管细胞对损伤的反应受到调节， 通过复杂的，动态的细胞间相互作用和细胞与 通过整联蛋白与下层和周围的细胞外基质相互作用。 在 此外，多种生长因子（血小板衍化生长因子、转化生长因子-b、碱性成纤维细胞生长因子）的作用， 虽然还没有完全理解，但被认为是至关重要的， 指导血管损伤后的结果。 的长期目标 本研究旨在阐明细胞间相互作用的信号转导 这些机制在选定的细胞参与之后是活跃的， 细胞粘附分子及其配体，整合素与ECM组分 和选择的生长因子及其受体;并了解 血管壁中这些系统之间的相互关系。 具体地说， 大血管内皮细胞剥脱损伤的组织培养模型 修复和微血管内皮细胞血管生成将用于 表征并确定信号转导机制 继细胞粘附分子、整合素和生长因子受体 在内皮细胞对损伤的反应过程中参与。 几 将采用的方法包括组织培养、免疫标记 在光学、共聚焦和电子显微镜水平，北方、南方 以及原位杂交，生物合成标记，免疫沉淀， 免疫印迹，逆转录病毒转导和过表达的基因， 选择实验将围绕使用抗体，cDNA探针 和针对被认为参与的特定激酶的肽， 这些信号级联、选择的生长因子受体及其 配体、基质分子和基质结合蛋白， 这些分子的结构域，特异于这些结构域的cRNA和cDNA探针 分子和特异性嵌合TGF-β分子在体外大血管中的表达 内皮细胞迁移和体外血管生成研究期间， 微血管内皮细胞 更好地理解在细胞分裂过程中发生的信号级联， 血管细胞对损伤的反应过程可能导致这种设计， 改进的合成接枝材料的生产和实施， 在治疗后促进最佳血管细胞行为的药剂 干预，以及可用于调节血管生成的药物。 反应和体细胞基因治疗方法，具有潜在的 进行长期的肠胃外治疗