The Genetic and Molecular Basis of Cholesterol Efflux

项目摘要 低高密度脂蛋白胆固醇（HDL-C）是动脉粥样硬化的主要危险因素 心血管疾病（ASCVD）是导致死亡的主要原因。然而，改善战略 通过提高HDL-C水平来预防动脉粥样硬化并不能改善预后。巨噬细胞- 特异性胆固醇流出是胆固醇逆向转运的第一个关键步骤， 动脉粥样硬化保护途径胆固醇流出与ASCVD事件呈负相关 事件;然而，胆固醇流出变化的机制尚不清楚。 有一个关键的需要，以确定因素，调节胆固醇流出，以促进 了解胆固醇逆向转运途径，这是一个具有广泛生物学意义的过程。 包括动脉粥样硬化在内的多种疾病状态的影响。的总体目标 这一建议是系统地确定控制变异的遗传和分子因素 胆固醇流出量我们建议利用两个人口众多的- 基于多种族的队列，达拉斯心脏研究（DHS）和多种族研究， 运动疗法（梅萨）追求以下目标：1）确定遗传的贡献， 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; 2）确定胆固醇流出的代谢产物和蛋白质特征 以性别和种族的方式。我们希望能描述遗传、代谢和 胆固醇流出的蛋白质调节剂，以支持未来的研究， 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.