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。与低密度脂蛋白不同，高密度脂蛋白水平与动脉粥样硬化的风险呈负相关。高密度脂蛋白通过几种可能的机制发挥其保护作用，在很大程度上是通过促进所谓的反向胆固醇运输途径。动脉粥样硬化和炎症有着密切的联系，动脉粥样硬化的过程表现出慢性炎症的特征。众所周知，炎症可以显著改变高密度脂蛋白的结构和组成，以及血浆高密度脂蛋白和载脂蛋白的水平，但这些变化对动脉粥样硬化性疾病的潜在机制和后果尚不清楚。因此，在研究高密度脂蛋白对动脉粥样硬化的影响时，了解炎症是如何改变高密度脂蛋白的，无论是系统性的还是在动脉粥样硬化病变的炎症微环境中都是至关重要的。该计划项目的中心统一主题是了解炎症如何改变高密度脂蛋白的结构和代谢，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来解决这些问题：项目1，“炎症期间的高密度脂蛋白结构和新陈代谢”(PI，Frederick C.de Beer)，将解决炎症如何通过分泌的磷脂酶、SAA和CETP的作用改变高密度脂蛋白重塑；项目2，“炎症，高密度脂蛋白和B类清道夫受体”(PI，van der Weshuyzen)将确定炎症和SAA如何影响B类清道夫受体的细胞脂运输；项目3，“炎症期间巨噬细胞胆固醇外流”(PI，Nancy R.Webb)，将研究炎症修饰高密度脂蛋白对巨噬细胞胆固醇外流和动脉粥样硬化风险的影响。该计划的主要目标是了解炎症过程中高密度脂蛋白的结构和代谢是如何改变的，并确定这种变化如何影响高密度脂蛋白的功能，特别是它在细胞胆固醇外流和血浆胆固醇运输中的作用及其对动脉粥样硬化的影响。预计该计划将对阐明炎症过程如何影响高密度脂蛋白和胆固醇代谢，以及这些影响对动脉粥样硬化性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.