AORTIC PROTEOGLYCANS AND ATHEROSCLEROSIS

主动脉蛋白聚糖和动脉粥样硬化

• 批准号: 3337975
• 负责人: WILLIAM D WAGNER
• 金额: $ 10.69万
• 依托单位: WAKE FOREST UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1979
• 资助国家: 美国
• 起止时间: 1979-12-01 至 1989-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3337975
• 关键词: aorta; atherosclerosis; chemical aggregate; chemical bond; conformation; disease /disorder proneness /risk; electron microscopy; electron spin resonance spectroscopy; human tissue; membrane permeability; molecular pathology; monoclonal antibody; nuclear magnetic resonance spectroscopy; pathologic process; proteoglycan

The known atherosclerosis "risk factors" such as hyperlipoproteinemia and hypertension do not fully explain the atherosclerotic process, suggesting that the artery wall itself exerts a major influence. A vital unanswered question concerns the mechanism of lipid accumulation in the artery wall. One current hypothesis involves the interaction of arterial wall intercellular polyanionic complex carbohydrates, the proteoglycans (PG) and plasma lipoprotein as the plasma lipoproteins traverse the arterial wall. This proposal involves studies of arterial wall PG, specifically chondroitin sulfate (CS) and dermatan sulfate (DS) PG monomers to test the hypothesis that compositional and/or conformational changes and thus function are important factors in the initiation and/or perhaps more importantly, in influencing the rate of atherosclerosis development. The studies involve dissociative extraction, purification of CS-PG and DS-PG and characterization of monomer structure. The model systems used will be the normal human aorta, areas of fatty streak and atherosclerotic plaque, and the arteries from genetically selected atherosclerosis-susceptible White Carneau and -resistant Show Racer pigeons. Studies are designed to provide detailed information on the structure, especially the oligosaccharides of the CS-PG. For DS-PG, monomer size, number of glycosaminoglycan chains, carbohydrate composition of glycosaminoglycan chains, and the nature and composition of the oligosaccharide component will be examined in an attempt to relate the structural features to a potential for greater plasma low density lipoprotein binding. Through electron microscopic studies of isolated DS-PG and CS-PG monomers and CS-PG-hyaluronic acid complexes we will assess structural characteristics, relate these observations to the biochemically defined structure and determine the significant changes in monomers in both the White Carneau pigeon artery and in the human atherosclerotic plaque. Several in situ localization studies of PG monomers using polyclonal and specific monoclonal antibodies will be used to localize CS-PG and DS-PG in the artery wall and to investigate changes during atherosclerosis progression. The significance of the project lies in a better understanding of the structure and function of PG in normal artery and a further definition of how these matrix components may influence the development of atherosclerosis. Ultimately the research could provide a further understanding of the initiation and progression of the atherosclerotic plaque.

已知的动脉粥样硬化“危险因素”，如高脂蛋白血症和 高血压不能完全解释动脉粥样硬化的过程，提示 动脉壁本身会产生很大的影响 一个重要的未答复 问题涉及动脉壁中脂质积聚的机制。 目前的一个假说涉及动脉壁的相互作用 细胞间聚阴离子复合碳水化合物，蛋白聚糖（PG）和 当血浆脂蛋白穿过动脉壁时，血浆脂蛋白被释放。 这项建议涉及动脉壁PG的研究，特别是 硫酸软骨素（CS）和硫酸皮肤素（DS）PG单体，以测试 假设组成和/或构象变化， 功能是启动的重要因素， 重要的是，影响动脉粥样硬化发展的速度。 的 研究涉及CS-PG和DS-PG的解离提取、纯化 和单体结构的表征。 使用的模型系统将是 正常人主动脉，脂肪条纹和动脉粥样硬化斑块的区域， 动脉粥样硬化易感基因的动脉 白色赛鸽，耐赛. 研究旨在 提供有关结构的详细信息，特别是 对于DS-PG，单体大小、寡糖的数目、单体的分子量、寡糖的分子量、寡糖的分子量和寡糖的分子量都是影响CS-PG的分子量的重要因素。 糖胺聚糖链，糖胺聚糖的碳水化合物组成 链，以及寡糖组分的性质和组成 将进行审查，试图将结构特征与 血浆低密度脂蛋白结合率可能更高。 通过 分离的DS-PG和CS-PG单体的电子显微镜研究 我们将评估CS-PG-透明质酸复合物的结构特征， 将这些观察结果与生物化学定义的结构联系起来， 测定两种白色样品中单体的显著变化 鸽子动脉和人类动脉粥样硬化斑块中的动脉粥样硬化。 几个在原地 PG单体的定位研究，使用多克隆和特异性 单克隆抗体将用于定位CS-PG和DS-PG， 动脉壁，并研究动脉粥样硬化进展过程中的变化。 该项目的意义在于更好地了解 正常动脉PG结构和功能及PG的进一步定义 这些基质成分如何影响 动脉粥样硬化 最终，这项研究可以提供一个更深入的 了解动脉粥样硬化的发生和发展 斑块