Lipoprotein Metabolism in Atherosclerosis

描述（由申请人提供）：冠心病是我们社会的主要死亡原因。这种疾病的病理过程被称为动脉粥样硬化。该计划的中心主题是确定在动脉粥样硬化发生中重要的脂蛋白代谢方面。动脉粥样硬化发生时，血浆低密度脂蛋白（LDL）沉积在动脉壁。富含胆固醇酯的动脉粥样硬化病变是对LDL沉积的反应。本项目的研究将有助于确定细胞内LDL前体脂蛋白是如何生成的（Shelness项目），LDL的浓度是如何控制的，以及使其更容易致动脉粥样硬化的特性。我们已经在肝脏和肠道中发现了一种酶，称为ACAT2，它在这种情况下似乎很重要，我们将使用不再具有这种酶的基因工程小鼠来显示对动脉粥样硬化的保护（Rudel项目）。我们将检验胆固醇油酸在血浆中积累作为LDL促进动脉粥样硬化的假设。高密度脂蛋白（HDL）是一类帮助清除动脉胆固醇的脂蛋白。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HDL的主要蛋白，apoa - 1，在没有脂质的情况下分泌到血浆中，然后在细胞表面与转运体ABCA1相互作用后组装脂质。这种相互作用的特征将被测量（Parks的项目）。此外，apoA-I的特性决定了该载脂蛋白在脂质同化和运输中的有效功能，将在Sorci-Thomas项目中进行评估。在这两个项目中，基因工程小鼠将为分子生理学提供具体的见解。最后，在Project 5中，我们将研究胆固醇在体内的主要分解产物——胆汁酸。我们将研究这些分子进行肠肝再循环的效率，以及这可能如何影响血浆脂蛋白浓度和动脉粥样硬化。已经建立了一种缺乏肠道胆汁酸转运蛋白的小鼠模型，该模型可以从肠道中恢复胆汁酸，并且将对该小鼠进行研究，以帮助确定该代谢轴调节的特定方面。总的来说，该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，从而更容易实现冠心病的预防。

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 by Shelness), 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 protection against atherosclerosis (Project by Rudel). We will test the hypothesis that cholesteryl oleate accumulation in plasma as LDL promotes atherosclerosis. 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-I, is secreted without lipid into plasma and then assembles lipid after interaction on the surface of cells with a transporter termed ABCA1. The characteristics of this interaction will be measured (Project by Parks). Further, the properties of apoA-I that determine efficient function of this apolipoprotein in lipid assimilation and transport will be assessed in Project by Sorci-Thomas. In both of these projects, genetically engineered mice will provide specific insights into molecular physiology. Finally, in Project 5, we will study the main breakdown product of cholesterol in the body, bile acids. We will examine the efficiency with which these molecules undergo enterohepatic recirculation and how this may affect plasma lipoprotein concentrations and atherosclerosis. A mouse model has been created that lacks the intestinal bile acid transporter protein that recovers the bile acids from the intestine, and this mouse will be studied to help define specific aspects of the regulation of this metabolic axis. 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.