The Genetic and Molecular Basis of Cholesterol Efflux

项目摘要 低高密度脂蛋白胆固醇(HDLC)是动脉粥样硬化的主要危险因素 心血管疾病(ASCVD)是主要的死亡原因。然而，改进的策略 通过提高高密度脂蛋白胆固醇水平来保护动脉粥样硬化并不能改善结果。巨噬细胞- 特定的胆固醇外流是胆固醇反向转运的第一个关键步骤，这是一个关键 动脉粥样硬化保护途径。胆固醇外流与ASCVD发病呈负相关 然而，胆固醇流出变化背后的机制尚不清楚。 迫切需要确定调节胆固醇外流的因素以促进 对反向胆固醇转运途径的理解，这是一种具有广泛意义的生物过程 对包括动脉粥样硬化在内的各种疾病状态的影响。总的目标是 这项建议是为了系统地确定控制变异的遗传和分子因素。 在胆固醇外流中。我们建议使用两个庞大的人口来实现我们的目标- 基于多种族队列的达拉斯心脏研究(DHS)和 动脉粥样硬化(MESA)追求以下目标：1)确定遗传因素的贡献 影响胆固醇流出的个体间变异性的因素以及这些因素是否是因果关系 与ASCVD相关；以及2)确定胆固醇外流的代谢物和蛋白质特征 以特定于性别和种族的方式。我们希望描述基因、代谢和 胆固醇外流的蛋白质调节剂以支持未来针对操纵 逆转胆固醇转运途径。

Project Summary Low high-density lipoprotein cholesterol (HDL-C) is a major risk factor for atherosclerotic cardiovascular disease (ASCVD), the leading cause of death. However, strategies to improve atheroprotection by raising HDL-C levels have failed to improve outcomes. Macrophage- specific cholesterol efflux is the first critical step of reverse cholesterol transport, a key atheroprotective pathway. Cholesterol efflux is inversely associated with incident ASCVD events; however, the mechanisms that underlie variation in cholesterol efflux are unknown. There is a critical need to identify factors that regulate cholesterol efflux to advance understanding of the reverse cholesterol transport pathway, a biological process that has broad implications across a variety of disease states including atherosclerosis. The overall objective of this proposal is to systematically ascertain the genetic and molecular factors governing variation in cholesterol efflux. We propose to carry out our objective by using two large, population- based multi-ethnic cohorts, the Dallas Heart Study (DHS) and the Multi-Ethnic Study of Atherosclerosis (MESA) to pursue the following aims: 1) determine the contribution of genetic factors to inter-individual variability in cholesterol efflux and whether these factors are causally associated with ASCVD; and 2) identify the metabolite and protein signature of cholesterol efflux in a sex- and ethnicity-specific manner. We expect to characterize the genetic, metabolic, and protein regulators of cholesterol efflux to support future studies targeting manipulation of the reverse cholesterol transport pathway.