HUMAN LIPOPROTEIN PATHOPHYSIOLOGY

年轻高脂血症受试者中仍有早产儿血管疾病 一个尚未解决的重大健康问题，在发病机制和 治疗。最近的研究进展导致了新的标记物 研究脂蛋白代谢的新方法--遗传分析 动脉粥样硬化性疾病的进展和消退，以及 高脂血症的诊断参考值。有了这些 进步，现在存在进一步深入聚焦的机会 大鼠脂蛋白生理学和病理生理学研究 具有遗传性特征的患者的目标是 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， 遗传性的遗传和病理生理学基础 家族性合并脂蛋白血症 高脂血症(FCHL)与脂蛋白基础研究 生理学，特别是关于高密度脂蛋白，即脂质的蛋白质 运输和巨噬细胞-脂蛋白的相互作用。研究对象将 以脂蛋白的遗传性为特征 异常，包括载脂蛋白限制性片段长度 多态(项目2)与载脂蛋白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 分离的高密度脂蛋白亚类的结构、功能和代谢 通过免疫亲和层析(项目4)，以及脂质的作用 转运蛋白在调节脂蛋白组成中的作用 血管内脂蛋白代谢(项目3)，项目5 建议评估氧化修饰的机理 细胞对修饰的脂蛋白的摄取 巨噬细胞，花生四烯酸向巨噬细胞的传递，以及 胆固醇反向转运调节剂的定义。这个 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术的进展/退化将 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助核心组成 实验室，一个多学科的调查小组将 结合他们在生理学、分子生物学、 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 不同水平的脂蛋白生理学和病理生理学 从基础分子生物学和细胞生物学谈生物组织 从人体活体研究到种群研究。

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.