HUMAN LIPOPROTEIN PATHOPHYSIOLOGY

年轻高血压患者的早发性血管疾病仍然存在 在发病机制方面，这是一个尚未解决的重大健康问题， 治疗 最近的研究进展导致了新的标志物， 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。 与这些 现在，我们有机会进一步深入研究， 脂蛋白生理和病理生理学的研究 基因特征的患者，目的是 了解疾病机制，开发更好的治疗方法， 识别和预防早期血管疾病。 这将是 通过把我们的注意力集中在1）分子上， 遗传和病理生理基础的遗传 异常脂蛋白血症，特别涉及家族性合并 高脂血症（FCHL）和脂蛋白的基础研究 生理学，特别是关于HDL，脂质的蛋白质 转运和巨噬细胞-脂蛋白相互作用。 受试者将 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 多态性（项目2）和载脂蛋白B- 含脂蛋白，包括代谢产物-产物关系 （项目1）。 脂蛋白生理学的基础研究将包括 HDL亚类结构、功能和代谢 免疫亲和层析（项目4），脂质的作用 调节脂蛋白组成的转移蛋白， 血管内脂蛋白代谢（项目3），项目5 建议评估氧化改性的机制， 脂蛋白的细胞，修饰的脂蛋白的摄取 巨噬细胞，花生四烯酸向巨噬细胞的递送，以及 胆固醇逆向转运调节剂的定义。 的 饮食和药物干预对动脉粥样硬化的影响 使用定量冠状动脉血管造影进行进展/消退将 在项目8中进行评估。 因此，在本项目中， 包括六个协调项目和六个支助核心项目， 实验室，一个多学科的研究小组将 联合收割机结合他们在生理学，分子生物学， 生物化学，遗传学，免疫化学，营养学，内分泌学， 代谢，心脏病学，流行病学和生物数学，研究 脂蛋白生理学和病理生理学在几个水平上， 从基本的分子和细胞生物学的生物组织 从人体内研究到人群研究。

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.