Lipoprotein Metabolism in Atherosclerosis

描述（由申请人提供）： 冠心病是导致人类死亡的主要原因。这种疾病的基础是称为动脉粥样硬化的病理过程。该计划的中心主题是确定以下方面： 脂蛋白代谢在动脉粥样硬化形成中重要。动脉粥样硬化发生在血浆低密度 脂蛋白（LDL）沉积在动脉壁上。富含胆固醇酯的动脉粥样硬化病变是对LDL沉积的反应。该计划项目的研究将有助于确定LDL前体脂蛋白实际上是如何在细胞内产生的（项目2），如何控制浓度，以及LDL的特性使其更具致动脉粥样硬化性。我们已经确定了肝脏和肠道中的一种酶，称为ACAT 2，在这种情况下似乎很重要，我们将使用基因工程小鼠，不再有这种酶，以显示这种酶如何改变肝脏和肠道中的胆固醇代谢（项目1）。我们将检验胆固醇油酸酯在血浆中的积累作为LDL促进动脉粥样硬化的假设，并且我们将尝试研究以确定我们是否可以鉴定胆固醇油酸酯作为人类ACAT 2的生物标志物。高密度脂蛋白（HDL）是一类脂蛋白，有助于清除动脉中的胆固醇。我们将进行研究以帮助确定HDL颗粒是如何形成的。我们知道HDL的主要蛋白质，称为apoA-I，在没有脂质的情况下分泌到血浆中，然后在细胞表面上与主要在肝脏中发现的称为ABCA 1的转运蛋白相互作用后组装脂质。将测量影响这种相互作用的因素（项目3）。此外，HDL的主要蛋白质（称为apoA-I）的性质将在项目4中评估，apoA-I负责其在脂质同化和转运中的有效功能。蛋白质的重要特征将通过研究蛋白质的自然突变来确定，使用技术来定义蛋白质结构。在所有这些项目中，基因工程小鼠将为分子生理学提供具体的见解。总的来说，这个项目将提供基本的信息，帮助我们了解脂蛋白代谢在动脉粥样硬化中的作用，从而更容易地预防冠心病。(End摘要）

DESCRIPTION (provided by applicant): Coronary Heart Disease is the leading cause of death in our society. Underlying this disease is the pathologic process known as atherosclerosis. The central theme of this Program is to define aspects of lipoprotein metabolism important in atherogenesis. Atherosclerosis occurs when plasma low density lipoproteins (LDL) get deposited in the artery wall. Atherosclerotic lesions rich in cholesteryl esters develop in response to LDL deposition. Studies in this program project will help define how LDL precursor lipoproteins are actually made inside cells (Project 2), how concentrations are controlled, and properties of LDL that make them more atherogenic. We have identified an enzyme in the liver and intestine, termed ACAT2, that appears to be important in this context, and we will use genetically engineered mice that no longer have this enzyme to show how this enzyme alters cholesterol metabolism in the liver and in the intestine (Project 1). We will test the hypothesis that cholesteryl oleate accumulation in plasma as LDL promotes atherosclerosis, and we will attempt studies to determine if we can identify cholesteryl oleate as a biomarker for ACAT2 in humans. High density lipoproteins (HDL) are the class of lipoproteins that help remove cholesterol from arteries. We will do studies to help determine how HDL particles are made. We know that the principal protein of HDL, called apoA-l, is secreted without lipid into plasma and then assembles lipid after interaction on the surface of cells with a transporter termed ABCA1 found mostly in the liver. Factors influencing this interaction will be measured (Project 3). Further, the properties of the major protein of HDL, termed apoA-l, which are responsible for its efficient function in lipid assimilation and transport will be assessed in Project 4. Important characteristics of the protein will be identified through the study of natural mutations of the protein using techniques to define protein structure. In all of these projects, genetically engineered mice will provide specific insights into molecular physiology. Overall, this program project will provide basic information that will help us understand the role of lipoprotein metabolism in atherosclerosis so that prevention of CHD can be more readily achieved. (End of Abstract)