MOLECULAR GENETIC APPROACHES IN ATHEROSCLEROSIS RESEARCH

在过去的5年里，在以下方面取得了显著的进展 了解健康人群脂代谢的分子机制 和疾病。这一进展提供了工具来现在确定 影响动脉粥样硬化发展的遗传因素 以及这种影响产生的分子机制。 使用多学科方法，我们将不会专注于广泛的 在脂质运输中起作用的各种候选基因， 包括编码载脂蛋白的结构基因和 酶和决定血脂的调节基因 饮食挑战的水平和反应。基本信息 将提供理解分子机制所必需的信息 通过详细的分子、遗传和生理特征 在脂类运输分解代谢中起关键作用的两种酶， 脂蛋白脂肪酶和肝脂酶。两种酶都是 在前一个授权期内已成功克隆。我们也会 继续努力从根本上了解apo是如何 脂蛋白B与甘油三酯的包装形成有关 极低密度脂蛋白和乳糜粒。 项目I将重点研究人类载脂蛋白B的遗传多态， 试图对各种人类同种异型进行分类，以检查如何 这些都会影响脂质代谢，并构建全面的 模特。项目II和项目VI将探索该中心的结构、功能和 脂蛋白脂肪酶和肝脂酶的调节。项目III 将利用小鼠模型来识别调节血浆的基因 血脂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，以及 它们实际参与了人类动脉粥样硬化。项目IV将 关注分子机制，特别是那些涉及载脂蛋白B的分子机制。 用于形成富含甘油三酯的脂蛋白。 参与该项目的研究人员提供了必要的 分子生物学、人类和小鼠遗传学、分子生物学专业知识 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.