SMOOTH MUSCLE CELL PROLIFERATION AND ATHEROSCLEROSIS

平滑肌细胞增殖和动脉粥样硬化

• 批准号: 3364913
• 负责人: WILLIAM D WAGNER
• 金额: $ 15.27万
• 依托单位: WAKE FOREST UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-08-16 至 1994-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3364913
• 关键词: aorta; atherosclerosis; atherosclerotic plaque; cell differentiation; cell type; chromatography; disease /disorder proneness /risk; genetic disorder; genetic strain; glycoprotein structure; heparan sulfate; membrane activity; pigeons; proteoglycan; tissue /cell culture; vascular smooth muscle; western blottings

Atherosclerosis is a complex pathological process that results from an interplay of genetic and environmental components. Although several risk factors for disease development (e.g., plasma cholesterol, blood pressure) have been described, many human beings develop accelerated atherosclerosis in the absence of known risk factors. It has been proposed that some individuals may be genetically predisposed to develop atherosclerosis as a result of mechanisms operating at the level of the arterial wall. Proliferation of smooth muscle cells in the arterial intima is of key importance in the development and growth of atherosclerotic lesions. In the proposed study the hypothesis to be tested is that genetic susceptibility to atherosclerosis at the artery wall level includes a differential proliferative response of smooth muscle cells manifested through a regulatory molecule heparan sulfate proteoglycan (HS-PG). The studies are possible because of the availability of a genetically selected atherosclerosis-susceptible White Carneau (WC) and -resistant Show Racer (SR) pigeon. Through an unknown mechanism(s) the smooth muscle cells of the atherosclerosis-susceptible WC pigeon demonstrate a greater proliferation capacity in culture. Preliminary examination of cell surface proteoglycans has demonstrated a reduction in HS-PG in WC compared to SR cells, and structural variations in the HS-PG isolated from the two cell types. Through a series of studies outlined in this proposal, the structure, amount and metabolic properties of the cell surface HS-PG will be characterized and compared in cultured aortic smooth muscle cells of WC and SR pigeons. Radioactive precursors and the new technique of oligosaccharide mapping will be used to determine whether structural diversities result in altered functional properties of the HS-PG molecule in these cells. The detailed structure of the HS chain will be examined. Pulse chase and kinetic modeling techniques will be sued to describe the metabolic and cellular pathways characteristic for the cell surface HS-PG and to define the role of HS-PG in regulation of the WC and SR smooth muscle cell proliferative state and potential. The ultimate goal of the proposal is to determine the role of HS-PG in relation to cell proliferation in the atherosclerosis-susceptible pigeon as a model for human atherosclerosis.

动脉粥样硬化是一种复杂的病理过程， 遗传和环境因素的相互作用。 虽然有几个风险 疾病发展的因素（例如，血浆胆固醇、血压） 已经描述，许多人发展加速的动脉粥样硬化 在没有已知危险因素的情况下。 有人建议， 个体可能在遗传上倾向于发展动脉粥样硬化， 这是在动脉壁水平运作的机制的结果。 动脉内膜中平滑肌细胞的增殖是关键 在动脉粥样硬化病变的发展和生长中的重要性。 在 这项研究提出的假设是， 动脉壁水平的动脉粥样硬化易感性包括 平滑肌细胞的不同增殖反应 通过调节分子硫酸乙酰肝素蛋白聚糖（HS-PG）。 的 研究是可能的，因为可用的遗传选择， 动脉粥样硬化易感的白色白纹伊蚊（WC）和抗动脉粥样硬化的白纹伊蚊 (SR)的过错信息 通过一种未知的机制， 动脉粥样硬化易感WC鸽子表现出更大的 培养增殖能力。 细胞表面的初步检查 与SR相比，蛋白聚糖已证明WC中HS-PG减少 细胞，以及从两种细胞分离的HS-PG的结构变异 类型 通过本提案中概述的一系列研究， 细胞表面HS-PG的结构、数量和代谢特性将 在培养的WC主动脉平滑肌细胞中进行表征和比较 和鸽子。 放射性前体与放射性核素检测新技术 将使用寡糖图谱来确定结构是否 DIFFERENTIATION导致HS-PG分子的功能特性改变 在这些细胞中。 将研究HS链的详细结构。 脉冲追踪和动力学建模技术将被用来描述 细胞表面HS-PG特有的代谢和细胞途径 并明确HS-PG在WC和SR平滑调节中的作用 肌细胞增殖状态和潜能。 的最终目标 建议是确定HS-PG在细胞中的作用， 在动脉粥样硬化易感鸽子中的增殖作为 人类动脉粥样硬化。