THE PATHOLOGY OF ENDOTHELIAL NEOVASCULIZATION

内皮新生血管形成的病理学

• 批准号: 3339748
• 负责人: JOSEPH A MADRI
• 金额: $ 33.67万
• 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 1995-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3339748
• 关键词: DNA; RNA; aorta; atherosclerosis; capillary; cell cycle; cell differentiation; cell migration; collagen; cow; disease /disorder model; electrophoresis; extracellular matrix; fibronectins; histopathology; laboratory rabbit; monoclonal antibody; nonsurgical revascularization; nucleic acid hybridization; nucleic acid probes; radiotracer; receptor binding; synthetic peptide; tissue /cell culture; vascular endothelium; western blottings

Atherosclerotic vascular disease is a major cause of morbidity and mortality in the U.S. Endothelial cell injury/dysfunction is responsible for the initiation of at least some of the disease and the endothelial cell (EC) response to injury is a major factor in determining and modulating the resultant migratory, proliferative, synthetic and contractile responses of the medial smooth muscle cells and the angiogenic response of the adventitial microvasculature. The EC response to injury, modulated by the composition and organization of the underlying extracellular matrix and endothelial cell-extracellular matrix interactions, although incompletely understood, is thought to be a dynamic, complex one involving several classes of matrix binding proteins. The long-term goal of this proposal is to elucidate the roles of integrin and non-integrin cell surface matrix binding proteins in modulating large vessel endothelial cell migration and proliferation and microvascular endothelial cell angiogenesis following injury and in response to soluble factors. Specifically, tissue culture and animal 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 action of integrin and non- integrin matrix binding proteins during tissue culture, immunolabeling at light, confocal and electron microscopic levels, Northern, Southern and in situ hybridization and differential library screening, biosynthetic labeling, immunoprecipitation and immunoblotting. Experiments will center around the use of synthetic peptides of various binding domains of matrix molecules, antibodies raised against matrix molecules and matrix binding proteins and cRNA and cDNA probes specific for matrix molecules and matrix binding proteins in vitro large vessel endothelial cell migrations and during in vitro angiogenesis studies with microvascular endothelial cells. A better understanding of cell-matrix interactions during these processes may lead to the design, production and implementation of improved synthetic grafting materials, agents that promote optimal endothelial cell migration following therapeutic intervention and agents that can be used to modulate the angiogenic response following injury and during the metastatic spread of cancer.

动脉粥样硬化性血管疾病是发病率和死亡率的主要原因 美国的死亡率是内皮细胞损伤/功能障碍造成的 至少部分疾病和内皮细胞的起始 (EC) 对损伤的反应是决定和调节损伤的主要因素 由此产生的迁移、增殖、合成和收缩反应 内侧平滑肌细胞和血管生成反应 外膜微血管。 EC 对损伤的反应，由 底层细胞外基质的组成和组织以及 内皮细胞-细胞外基质相互作用，尽管不完全 理解，被认为是一个动态的、复杂的涉及多个 基质结合蛋白的类别。 该提案的长期目标是 阐明整合素和非整合素细胞表面基质的作用 结合蛋白调节大血管内皮细胞迁移和 增殖和微血管内皮细胞血管生成 损伤和对可溶性因素的反应。 具体来说，组织培养 大血管内皮细胞剥脱损伤修复动物模型 微血管内皮细胞血管生成将被用于 表征并确定整合素和非整合素的作用机制 组织培养期间的整合素基质结合蛋白，免疫标记 光、共焦和电子显微镜水平，北方、南方和中 原位杂交和差异文库筛选、生物合成 标记、免疫沉淀和免疫印迹。 实验将集中 围绕基质的各种结合域的合成肽的使用 分子、针对基质分子和基质结合产生的抗体 基质分子和基质特异的蛋白质和 cRNA 和 cDNA 探针 结合蛋白体外大血管内皮细胞迁移和 在微血管内皮细胞的体外血管生成研究中。 更好地了解这些过程中的细胞-基质相互作用 可能会导致改进合成的设计、生产和实施 移植材料、促进内皮细胞最佳迁移的试剂 治疗干预和可用于调节的药物之后 损伤后和转移扩散期间的血管生成反应 癌症。