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Effect of isolevuglandin in HDL structure-function in atherosclerosis

异左旋黄素对动脉粥样硬化HDL结构功能的影响

基本信息

批准号：
9767276
负责人：
Linda Zhang
金额：
$ 6.56万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-06 至 2020-09-05
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9767276
关键词：
Animals Antiatherogenic Apolipoprotein A-I Apolipoprotein A-II Apolipoproteins Arterial Fatty Streak Atherosclerosis Biomedical Engineering Cardiovascular Diseases Cell Death Cells Cessation of life Cholesterol Chylomicrons Clinical Development Drug Delivery Systems Endothelial Cells Familial Hypercholesterolemia Family Fellowship Future Goals High Density Lipoprotein Cholesterol High Density Lipoproteins Hypertension Impairment In Vitro Inflammation Inflammatory Inflammatory Response Interleukin-1 beta LDL Cholesterol Lipoproteins Laboratories Link Lipid Biochemistry Lipids Lipoproteins Low-Density Lipoproteins Lysine Mass Spectrum Analysis Mediating Mentors Metabolism Modification Mus Obesity Oxidative Stress Peroxidases Pharmacology Phosphatidylcholine-Sterol O-Acyltransferase Phosphatidylethanolamine Phospholipids Plasma Plasma Proteins Post-Translational Protein Processing Prevention Property Proteins Research Research Personnel Research Project Grants Role Structural Protein Structure Testing Training Training Programs United States adduct analog atherogenesis base cardiovascular disorder risk cardiovascular risk factor career crosslink drinking water efficacy testing experience hypercholesterolemia in vivo lipophilicity macrophage mortality novel therapeutics oxidation oxidized lipid particle preservation prevent programs protein structure response reverse cholesterol transport small molecule structural biology

项目摘要

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.

项目总结