HDL Function and Metabolism During Inflammation

描述（由申请人提供） 在西方世界，动脉粥样硬化是导致死亡的主要原因。与LDL不同，HDL水平与动脉粥样硬化的风险呈负相关。HDL通过几种假定的机制发挥其保护作用，在很大程度上是通过其促进所谓的胆固醇逆向转运途径的能力。 动脉粥样硬化和炎症有着密切的联系，动脉粥样硬化过程表现出慢性炎症的特征。已知炎症可显著改变HDL结构和组成，以及HDL胆固醇和载脂蛋白的血浆水平，但这些变化对动脉粥样硬化疾病的潜在机制和后果尚不清楚。因此，在研究HDL对动脉粥样硬化的影响时，了解HDL如何作为炎症的结果而被修饰是至关重要的，包括全身性的和动脉粥样硬化病变的炎症微环境内的。该项目的中心统一主题是了解炎症如何改变HDL结构和代谢，以及这些变化如何影响动脉粥样硬化的发展。该计划包括三个相互依赖和协同的项目，以解决这些问题：项目1，“HDL结构和炎症期间的代谢”（PI，弗雷德里克C。de Beer）将阐述炎症如何通过分泌的磷脂酶、SAA和CETP的作用改变HDL重塑;项目2，“炎症、HDL和B类清道夫受体”（PI，货车der Westhuyzen）将确定炎症和SAA如何影响B类清道夫受体的细胞脂质运输;项目3，“炎症期间巨噬细胞胆固醇流出”（PI，Nancy R. Webb），将研究HDL的炎症修饰对巨噬细胞胆固醇流出和动脉粥样硬化风险的影响。该计划的主要目标是了解HDL结构和代谢在炎症过程中如何改变，并确定这些变化如何影响HDL的功能，特别是其在细胞胆固醇流出和血浆胆固醇转运中的作用及其对动脉粥样硬化的影响。该项目有望为阐明炎症过程如何影响HDL和胆固醇代谢以及这些影响对动脉粥样硬化疾病的影响程度做出重大贡献。

DESCRIPTION (provided by applicant) Atherosclerosis is the leading cause of mortality in the western world. Unlike LDL, HDL levels are inversely correlated with the risk of atherosclerosis. HDL exerts its protective effect through several putative mechanisms, in large part through its ability to promote the so-called reverse cholesterol transport pathway. Atherosclerosis and inflammation share intimate associations and the atherosclerotic process exhibits features of a chronic inflammation. Inflammation is known to significantly alter HDL structure and composition, as well as plasma levels of HDL cholesterol and apolipoproteins, but the underlying mechanisms and the consequences of such changes on atherosclerotic disease are not understood. In studying the impact of HDL on atherosclerosis, it is therefore critical to understand how HDL may be modified as a result of inflammation, both systemically and within the inflammatory microenvironment of the atherosclerotic lesion. The Central Unifying Theme of this program project is an understanding of how inflammation alters HDL structure and metabolism and how such changes influence the development of atherosclerosis. The program comprises three inter-dependent and synergistic projects to address these questions: Project 1, "HDL structure and metabolism during inflammation" (PI, Frederick C. de Beer), will address how inflammation alters HDL remodeling through the actions of secreted phospholipases, SAA and CETP; Project 2, "Inflammation, HDL and Class B Scavenger Receptors" (PI, van der Westhuyzen) will determine how inflammation and SAA impact cellular lipid trafficking by Class B scavenger receptors; Project 3, "Macrophage cholesterol efflux during inflammation" (PI, Nancy R. Webb), will investigate the effect of inflammatory modifications of HDL on macrophage cholesterol efflux and atherosclerotic risk. The major goals of the program are to understand how HDL structure and metabolism are altered during inflammation and to determine how such changes influence HDL's function, particularly its roles in cellular cholesterol efflux and plasma cholesterol transport and its influence on atherosclerosis. The program is expected to make significant contributions towards elucidating how the inflammatory process affects HDL and cholesterol metabolism and the extent to which such effects impact atherosclerotic disease.