HUMAN LIPOPROTEIN PATHOPHYSIOLOGY

人类脂蛋白病理生理学

• 批准号: 3098165
• 负责人: JOHN J ALBERS
• 金额: $ 163.25万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-05-01 至 1993-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3098165
• 关键词: atherosclerosis; blood lipoprotein metabolism; blood lipoprotein transport; coronary disorder; familial hyperlipoproteinemia type I; familial hyperlipoproteinemia type II; human subject

Premature vascular disease in young hyperlipidemic subjects remains a major unsolved health problem in terms of pathogenesis and treatment. Recent research advances have led to new markers for genetic analysis, new methods for studying lipoprotein metabolism and atherosclerotic disease progression and regression, and reference values for diagnosing hyperlipidemia. With these advances, the opportunity now exists for further in depth focused studies of lipoprotein physiology and pathophysiology in genetically characterized patients with the objectives of understanding disease mechanisms, developing better treatments, and identifying and preventing early vascular disease. This will be accomplished by focusing our attention on 1) the molecular, genetic, and pathophysiological basis of the inherited dyslipoproteinemias with particular reference to familial combined hyperlipidemia (FCHL), and on fundamental studies of lipoprotein physiology, particularly in regard to HDL, the proteins of lipid transport and macrophage-lipoprotein interactions. Subjects will be characterized in terms of the heritability of lipoprotein abnormalities, including apolipoprotein restriction fragment-length polymorphisms (Project 2) and the metabolism of the apoprotein B- containing lipoproteins, including precursor-product relationships (Project 1). Basic studies of lipoprotein physiology will include the structure, function and metabolism of HDL subclasses isolated by immunoaffinity chromatography (Project 4), and the role of lipid transfer proteins in modulating lipoprotein composition and intravascular lipoprotein metabolism (Project 3), Project 5 proposes to evaluate the mechanisms of oxidative modification of lipoproteins by cells, the uptake of modified lipoproteins by macrophages, the delivery of arachidonic acid to macrophages, and the definition of modulators of reverse cholesterol transport. The effects of diet and drug interventions on atherosclerosis progression/regression using quantitative coronary angiography will be evaluated in Project 8. Thus, in this Program Project, comprised of six coordinated projects and six supporting core laboratories, a multidisciplinary team of investigators will combine their expertise in physiology, molecular biology, biochemistry, genetics, immunochemistry, nutrition, endocrinology, metabolism, cardiology, epidemiology, and biomathematics, to study lipoprotein physiology and pathophysiology at several levels of biological organization from basic molecular and cell biology through in vivo studies in man to studies in populations.

年轻高脂血症受试者的过早血管疾病仍然存在 就发病机制而言，这是一个尚未解决的重大健康问题 治疗。 最近的研究进展带来了新的标记物 遗传分析，研究脂蛋白代谢的新方法 和动脉粥样硬化疾病的进展和消退，以及 诊断高脂血症的参考值。 有了这些 进展，现在存在进一步深入关注的机会 脂蛋白生理学和病理生理学的研究 具有遗传特征的患者，其目标是 了解疾病机制，开发更好的治疗方法，以及 识别和预防早期血管疾病。 这将是 通过将我们的注意力集中在1）分子上来完成， 遗传的遗传和病理生理学基础 异常脂蛋白血症，特别是家族性联合 高脂血症（FCHL）和脂蛋白的基础研究 生理学，特别是关于高密度脂蛋白（HDL），脂质的蛋白质 运输和巨噬细胞-脂蛋白相互作用。 受试者将 根据脂蛋白的遗传力来表征 异常，包括载脂蛋白限制性片段长度 多态性（项目 2）和脱辅基蛋白 B- 的代谢 含有脂蛋白，包括前体-产物关系 （项目1）。 脂蛋白生理学的基础研究将包括 分离的 HDL 亚类的结构、功能和代谢 通过免疫亲和层析（项目4），以及脂质的作用 调节脂蛋白组成的转移蛋白和 血管内脂蛋白代谢（项目3）、项目5 提议评估氧化修饰的机制 细胞对脂蛋白的摄取，修饰脂蛋白的摄取 巨噬细胞，将花生四烯酸递送至巨噬细胞，以及 胆固醇反向转运调节剂的定义。 这 饮食和药物干预对动脉粥样硬化的影响 使用定量冠状动脉造影的进展/消退将 在项目 8 中进行评估。因此，在本计划项目中， 由六个协调项目和六个支持核心组成 实验室，一个多学科的研究小组将 结合他们在生理学、分子生物学方面的专业知识， 生物化学、遗传学、免疫化学、营养学、内分泌学、 新陈代谢、心脏病学、流行病学和生物数学，以研究 脂蛋白生理学和病理生理学在几个层面上 基础分子和细胞生物学的生物组织 从人体研究到人群研究。