Lipoprotein Metabolism in Atherosclerosis

描述(由申请人提供)： 在我们的社会中，冠心病是主要的死亡原因。这种疾病的潜在原因是 称为动脉粥样硬化的病理过程。本计划的中心主题是定义以下方面 脂蛋白代谢在动脉粥样硬化形成中起重要作用。当血浆低密度时发生动脉粥样硬化 脂蛋白(LDL)沉积在动脉壁中。富含胆固醇酯的动脉粥样硬化病变是对低密度脂蛋白沉积的反应。该计划项目中的研究将有助于确定低密度脂蛋白前体在细胞内实际是如何生成的(项目2)，如何控制浓度，以及使其更容易导致动脉粥样硬化的低密度脂蛋白的特性。我们已经在肝脏和肠道中发现了一种名为ACAT2的酶，它在这方面似乎很重要，我们将使用不再具有这种酶的基因工程小鼠来展示这种酶如何改变肝脏和肠道中的胆固醇代谢(项目1)。我们将测试这一假设，即随着低密度脂蛋白的增加，胆固醇油酸盐在血浆中积累会促进动脉粥样硬化，我们将尝试进行研究，以确定是否可以将胆固醇油酸盐确定为人类ACAT2的生物标志物。高密度脂蛋白(高密度脂蛋白)是一类有助于从动脉中清除胆固醇的脂蛋白。我们将进行研究，以帮助确定高密度脂蛋白颗粒是如何形成的。我们知道，高密度脂蛋白的主要蛋白质，称为载脂蛋白A-L，是在没有脂的情况下分泌到血浆中，然后与一种名为ABCA1的转运蛋白相互作用后在细胞表面组装脂质，这种转运蛋白主要在肝脏中发现。将衡量影响这种互动的因素(项目3)。此外，高密度脂蛋白的主要蛋白质，称为载脂蛋白A-L的性质，负责其在脂肪同化和运输中的有效功能，将在项目4中进行评估。将通过研究蛋白质的自然突变来确定蛋白质的重要特征，使用确定蛋白质结构的技术。在所有这些项目中，基因工程小鼠将提供对分子生理学的具体见解。总体而言，该计划项目将提供基本信息，帮助我们了解脂蛋白代谢在动脉粥样硬化中的作用，以便更容易地实现冠心病的预防。(摘要结束)

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)