HDL Function in Human Disease

HDL 在人类疾病中的功能

基本信息

批准号：
9044811
负责人：
MACRAE F LINTON
金额：
$ 238.86万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9044811
关键词：
Affect Anti-Inflammatory Agents Anti-inflammatory Antiatherogenic Atherosclerosis Bioinformatics Biological Assay Biological Markers Cells Cholesterol Chronic Chronic Kidney Failure Clinical Collaborations Coronary Arteriosclerosis Data Development Disease End stage renal failure Exhibits F2-Isoprostanes Familial Hypercholesterolemia Functional disorder Gene Expression Goals Hemodialysis High Density Lipoprotein Cholesterol High Density Lipoproteins Human Inflammation Isoprostanes Lipid Peroxidation Lipids Mediation Mediator of activation protein MicroRNAs Oxidation-Reduction Oxidative Stress Pathway interactions Phospholipids Plasma Property Proteins Publishing Research Rheumatoid Arthritis Risk adduct atherogenesis atheroprotective cardiovascular risk factor cholesterol transporters functional loss human disease in vivo loss of function macrophage member monocyte novel novel marker novel therapeutic intervention oxidative damage particle prevent reverse cholesterol transport

项目摘要

DESCRIPTION (provided by applicant): Anti-atherogenic functions of high-density lipoproteins (HDL) include mediation of reverse cholesterol transport and reduction of oxidation and inflammation. Mounting evidence supports the concept that dysfunctional HDL loses its beneficial properties and actually contributes to the development of atherosclerosis. The central theme of our PPG is that HDL function is a critical determinant of atherogenesis and cardiovascular risk in chronic human disease. The goal of our research is to define the mechanisms for HDL functional loss in three diseases associated with increased risk for atherosclerotic cardiovascular disease: Familial Hypercholesterolemia (FH), Chronic Kidney Disease (CKD) and Rheumatoid Arthritis (RA). A major hypothesis of our proposal is that inflammation and oxidative stress impair HDL function. Plasma levels of F2-isoprostanes (F2-lsoP) are accurate in vivo markers of lipid peroxidation. Interestingly, HDL is the main carrier of F2-lsoP in plasma. Our studies in RA subjects suggest that F2-lsoP may be a biomarker for HDL function. Isolevuglandins (IsoLG) are a group of highly reactive mediators of oxidative damage that are formed as products of the IsoP pathway. We will examine the novel hypothesis that IsoLG forms adducts to HDL proteins and lipids, impairing HDL function. Subjects with FH have elevated levels of F2-lsoP and IsoLG protein adducts in their HDL and strikingly impaired anti-inflammatory HDL function. Chronic kidney disease (CKD) has been associated with increased plasma F2-lsoP levels and reduced cholesterol efflux capacity of HDL isolated from subjects with ESRD. HDL is also the major carrier of microRNAs (miRNAs) in plasma and delivers them to cells impacting gene expression. We will examine the novel hypothesis that the HDL-miRNA profile differs with disease state is altered by oxidative stress, and impacts HDL function. Projects 1 and 2 will examine mechanisms of dysfunctional HDL formation in FH and CKD, respectively. Project 3 will examine the impact of IsoP products on HDL function. The projects will rely heavily on Cores providing assays for HDL function, isoprostane products, miRNAs and bioinformatics. Ultimately, we aim to develop novel biomarkers and therapeutic approaches for dysfunctional HDL, shifting the clinical paradigm.

描述（由申请人提供）：高密度脂蛋白（HDL）的抗动脉粥样硬化功能包括介导反向胆固醇运输以及氧化和炎症的减少。越来越多的证据支持了功能失调的HDL失去其有益特性的概念，实际上有助于动脉粥样硬化的发展。我们PPG的中心主题是HDL功能是慢性人类疾病中动脉粥样硬化和心血管风险的关键决定因素。我们研究的目的是确定与动脉粥样硬化心血管疾病风险增加的三种疾病中HDL功能丧失的机制：家族性高胆固醇血症（FH），慢性肾脏疾病（CKD）和类风湿性节关节炎（RA）。我们建议的一个主要假设是炎症和氧化应激会损害HDL功能。 F2-异前列腺（F2-LSOP）的血浆水平在脂质过氧化的体内标记中是准确的。有趣的是，HDL是血浆中F2-LSOP的主要载体。我们对RA受试者的研究表明，F2-LSOP可能是HDL功能的生物标志物。 Isolevuglandins（Isalg）是一组高度反应性的氧化损伤介质，形成为ISOP途径的产物。我们将研究以下新的假设，即Iselg形成对HDL蛋白和脂质的加合物，从而损害HDL功能。 FH的受试者的HDL中具有升高的F2-LSOP和ISLEG蛋白加合物，并且抗炎HDL功能受损。慢性肾脏疾病（CKD）与血浆F2-LSOP水平的升高以及从患有ESRD受试者分离的HDL的胆固醇外排能力降低有关。 HDL也是血浆中microRNA（miRNA）的主要载体，并将其传递给影响基因表达的细胞。我们将研究新的假设，即HDL-MIRNA谱与疾病状态不同，会因氧化应激而改变，并影响HDL功能。项目1和2将分别检查FH和CKD中功能失调的HDL形成机制。项目3将检查ISOP产品对HDL功能的影响。这些项目将在很大程度上依赖于提供HDL功能，异丙烷产品，miRNA和生物信息学测定法的核心。最终，我们旨在开发新型的生物标志物和功能障碍HDL的治疗方法，从而改变临床范式。