MOLECULAR GENETIC APPROACHES IN ATHEROSCLEROSIS RESEARCH

在过去五年中， 了解健康中脂质代谢的分子机制 和疾病 这一进展提供了工具， 影响动脉粥样硬化发展的遗传因素 以及产生这种影响的分子机制。 使用多学科的方法，我们将不会专注于广泛的 多种在脂质转运中起作用的候选基因， 包括编码载脂蛋白的结构基因， 酶和决定血脂的调节基因 水平和对饮食挑战的反应。 基本面信息 将提供必要的了解分子机制 通过详细的分子遗传和生理特征 在脂质转运催化剂中起关键作用的两种酶中， 脂蛋白脂肪酶和肝脂肪酶。 两种酶 在上一个授权期间成功克隆。 我们也将 继续努力从根本上了解非洲警察组织如何 脂蛋白B与甘油三酯的包装有关， VLDL和乳糜微粒。 项目I将集中于人类载脂蛋白B的遗传多态性， 试图对各种人类同种异型进行分类， 这些影响脂质代谢，并构建一个全面的 模型 项目二和项目六将探讨 调节脂蛋白脂酶和肝脂酶。 项目三 将使用小鼠模型来鉴定调节血浆的基因， 脂质水平及其对饮食挑战的反应，而项目 IV将尝试识别相应的人类基因， 它们与人类动脉粥样硬化的关系 项目四将 侧重于分子机制，特别是那些涉及载脂蛋白B， 用于形成富含甘油三酯的脂蛋白。 参与该计划的研究人员提供了必要的 分子生物学、人类和小鼠遗传学、分子生物学、 遗传学，免疫化学，生物化学，生物物理学，酶学， 分子生理学和医学。

During the last 5 years, remarkable progress has been made in understanding the molecular machinery of lipid metabolism in health and disease. This progress provides the tools to now identify genetic factors which influence the development of atherosclerosis and the molecular mechanisms by which this influence is exerted. Using a multidisciplinary approach, we will not focus on a wide variety of candidate genes which play roles in lipid transport, including structural genes coding for the apo lipoproteins and the enzymes, and the regulatory genes which determine plasma lipid levels and response to dietary challenge. Fundamental information essential for understanding molecular mechanisms will be provided by a detailed molecular, genetic and physiologic characterization of tow enzymes which play key roles in lipid transport catabolism, lipoprotein lipase and hepatic lipase. Both enzymes were successfully cloned during the previous grant period. Also we will continue efforts to understand at a fundamental level how apo lipoprotein B is related to the packaging of triglycerides to form the VLDL and chylomicrons. Project I will focus on the genetic polymorphism of human apo B, attempting to classify the various human allotypes, to examine how these affect lipid metabolism, and to construct a comprehensive model. Projects II and VI will explore the structure, function and regulation of lipoprotein lipase and hepatic lipase. Project III will employ the mouse model to identify genes regulating plasma lipid levels and their response to dietary challenge, while Project IV will attempt to identify the corresponding human genes, and their actual involvement in human atherosclerosis. Project IV will focus on molecular mechanisms, especially those involving apo B, utilized in the formation of the triglyceride-rich lipoproteins. The researchers involved in this program provide the necessary expertise in molecular biology, human and mouse genetics, molecular genetics, immunochemistry, biochemistry, biophysics, enzymology, molecular physiology and medicine.