ENDOTHELIUM IN RELATION TO ATHEROGENESIS

内皮与动脉粥样硬化的关系

• 批准号: 3350598
• 负责人: Peter Francis Davies
• 金额: $ 15.1万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-08-01 至 1992-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3350598
• 关键词: atherosclerosis; autoradiography; binding proteins; blood lipoprotein metabolism; cell cell interaction; cell morphology; cell population study; cell type; cow; electron microscopy; gap junctions; growth factor; human tissue; laboratory mouse; laboratory rabbit; low density lipoprotein; macrophage; membrane activity; membrane channels; pinocytosis; platelet derived growth factor; radiotracer; receptor mediated endocytosis; scanning electron microscopy; simian virus 40; tissue /cell culture; transforming virus; vascular endothelium; vascular smooth muscle

Atherosclerosis, the underlying cause of most human heart disease, results from a focal imbalance of the normal equilibria of the arterial wall. While metabolic cooperation between vascular cells is essential for the maintenance of normal vascular homeostasis, little is known about the nature of these interactions or whether disturbance of their equilibria will precipitate irreversible pathological changes in arterial tissue. We propose to investigate mechanisms of cellular interactions between vascular endothelium, smooth muscle cells (SMC) and monocyte-derived macrophages in vitro and in intact vascular tissue. Two separate general mechanisms of cell cooperativity will be studied: a) cell contact-mediated communication via gap junctional channels connecting the cytoplasm of adjacent cells, and b) humoral communication in which diffusible substances secreted by one cell type pass via the interstitial fluid to specific receptors on the surface of the other cell population. The effects of cell biological pertubations associated with hypercholesterolemia (cellular cholesterol, lipoprotein metabolism), a major risk factor for atherogenesis, will be investigated. New techniques to probe cellular communication in intact normal and atherosclerotic (fibrofatty lesion) vascular tissue will be tested and developed to integrate the in vitro findings with vessel wall biology and pathology. Gap junctional-mediated cell interactions will be investigated biochemically in vitro (transfer of 3H-nucleotides, fluorescent dyes and putative second messengers such as cyclic nucleotides and Ca++ and electrophysiological measurements) using cocultures of endothelial cells, SMC and macrophages. The effects of various mediators of gap junctional transfer, particularly cellular cholesterol composition, will be evaluated. The effects of heterocellular communication upon receptor-mediated lipoprotein metabolism in endothelial cells will be measured. Gap junctional communication will also be investigated in normal and atherosclerotic intact arterial tissues both at the ultrastructural level and functionally using new methods to deliver tracers to the vascular tissue. The regulation of platelet-derived growth factor-like mitogens (c-sis related) synthesized and secreted by endothelial cells will be investigated in the context of the interactions of these cells with SMC and macrophages using molecular biology techniques.

动脉粥样硬化是大多数人类心脏病的根本原因， 动脉壁正常平衡的局部失衡 虽然血管细胞之间的代谢合作是必不可少的， 维持正常的血管稳态，很少有人知道， 这些相互作用的性质，或者是否干扰了它们的平衡， 会导致动脉组织发生不可逆的病理变化 我们建议研究细胞间相互作用的机制， 血管内皮细胞、平滑肌细胞（SMC）和单核细胞源性 巨噬细胞在体外和完整的血管组织。 两个单独的将军 将研究细胞协同性的机制：a）细胞接触介导的 通过连接细胞质的间隙连接通道进行通信 相邻细胞，和B）体液通讯，其中可扩散物质 由一种细胞类型分泌，通过间质液到达特定的 另一个细胞群体表面的受体。 细胞的影响 与高胆固醇血症（细胞 胆固醇，脂蛋白代谢），一个主要的危险因素， 动脉粥样硬化，将进行研究。 探测细胞的新技术 完整正常和动脉粥样硬化（纤维脂肪病变）中的交通 将测试和开发血管组织，以整合体外 血管壁生物学和病理学的发现。 将研究间隙连接介导的细胞相互作用 生物化学体外（转移3 H-核苷酸，荧光染料和 假定的第二信使，如环核苷酸和Ca++， 电生理学测量）使用内皮细胞的共培养物， SMC和巨噬细胞。 缝隙连接蛋白的各种介质的作用 转移，特别是细胞胆固醇组合物，将是 评估。 异细胞通讯对 内皮细胞中受体介导的脂蛋白代谢将是 测定了 缝隙连接通讯也将在正常的 和动脉粥样硬化完整动脉组织的超微结构 水平和功能上使用新方法将示踪剂递送到血管 组织. 血小板衍生生长因子样有丝分裂原的调控 由内皮细胞合成和分泌的（c-sis相关）将被 在这些细胞与SMC的相互作用的背景下研究， 使用分子生物学技术研究巨噬细胞。