Effect of isolevuglandin in HDL structure-function in atherosclerosis

项目摘要 心血管疾病（CVD）占美国每三例死亡中的一例， 被列为全球死亡的主要原因。虽然已作出重大努力， 阐明控制CVD的起始和进展的机制仍有许多不清楚的地方。高 密度脂蛋白（HDL）由于其许多抗动脉粥样硬化性质而被认为是对CVD的保护， 例如从细胞中去除多余的胆固醇、防止炎症和防止细胞死亡。电流 有证据表明，CVD的风险更多地取决于HDL颗粒的功能，而不是HDL- 胆固醇（HDL-C）水平。 心血管疾病的危险因素包括肥胖、高胆固醇血症和高血压， 压力和脂质二羰基的形成。氧化应激产生异evuglandins（isoLG），一个家族， 与蛋白质的赖氨酸残基和 磷脂酰乙醇胺（PE）。重要的是，在动脉粥样硬化中异LG加合物水平升高， 与心血管疾病风险的相关性比低密度脂蛋白（LDL）和胆固醇水平更强。有趣的是， 这些isoLG加合物与LDL没有显著的相关性，提高了isoLG 优先修饰HDL并损害其抗动脉粥样硬化功能。 给定 的许多重要功能 HDL，确定HDL结构，组成和功能上的异LG修饰的后果， 这对于开发新的治疗方法来预防动脉粥样硬化是必要的。 我的研究计划将利用结构生物学、质谱、体外和体内相结合的方法 方法和小分子清除剂，以：i）确定异LG的功能后果 修饰HDL亚群; ii）定义HDL结构上异LG加合物的特异性定位 iii）确定负责炎症的HDL的特定组分（蛋白质与脂质）; iv）测试异LG清除剂在体内减少动脉粥样硬化中的功效; 清除剂在体外保持HDL结构-功能的能力。我所有目标的目标是发展一个 了解HDL的脂质二羰基修饰在动脉粥样硬化形成中的作用。我的长期 研究目标是确定氧化脂质在改变脂蛋白功能和代谢中的作用 (LDL，高密度脂蛋白，乳糜微粒），并制定有效的战略，以针对具体的机制，有助于 动脉粥样硬化的发生和发展。这个奖学金将帮助我建立一个研究项目， 作为CVD中脂蛋白氧化修饰的独立研究者的富有成效的职业生涯。

Project Summary Cardiovascular diseases (CVD) account for one of every three deaths in the United States and are ranked as the leading cause of mortality worldwide. While significant effort has been directed towards elucidating the mechanisms governing the initiation and progression of CVD, much remains unclear. High density lipoprotein (HDL) is regarded to be protective against CVD due to its many anti-atherogenic properties, such as removing excess cholesterol from cells, preventing inflammation, and preventing cell death. Current evidence suggests that the risk for CVD depends more on HDL particle functionality, rather than HDL- cholesterol (HDL-C) levels. Risk factors for CVD including obesity, hypercholesterolemia, and hypertension increase oxidative stress and the formation of lipid dicarbonyls. Oxidative stress generates isolevuglandins (isoLGs), a family of high reactive lipid dicarbonyls that react with lysine residues of proteins and headgroups of phosphatidylethanolamines (PEs). Importantly, isoLG adduct levels are elevated in atherosclerosis, and correlate with CVD risk more strongly than low-density lipoprotein (LDL) and cholesterol levels. Interestingly, these isoLG adducts are not associated with LDL to a significant degree, raising the possibility that isoLG preferentially modifies HDL and impairs its anti-atherogenic functions. Given the many important functions of HDL, determining the consequences of isoLG modification on HDL structure, composition, and function is imperative for developing novel therapeutics to protect against atherosclerosis. My research plan will utilize a combination of structural biology, mass spectrometry, in vitro and in vivo approaches, and small molecule scavengers to: i) determine the functional consequences of isoLG modification on HDL subpopulations; ii) define the specific localization of isoLG adducts on HDL structural proteins; iii) determine the specific component of HDL (protein versus lipid) that is responsible for inflammation; iv) test the efficacy of isoLG scavengers in reducing atherosclerosis in vivo; v) compare analogues of scavengers in their abilities to preserve HDL structure-function in vitro. The goal of all my aims is to develop an understanding of the contribution of lipid dicarbonyl modification of HDL in atherogenesis. My long-term research goals are to identify the contributions of oxidized lipids in altering lipoprotein function and metabolism (LDL, HDL, chylomicrons), and to develop effective strategies to target specific mechanisms that contribute to atherosclerosis initiation and progression. This fellowship will help me build a research program that will lead to a productive career as an independent investigator of oxidative modifications of lipoproteins in CVD.