HDL Function in Human Disease

HDL 在人类疾病中的功能

基本信息

批准号：
8667666
负责人：
MACRAE F LINTON
金额：
$ 236.42万
依托单位：
VANDERBILT UNIVERSITY
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/8667666
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 Therapeutic adduct atherogenesis atheroprotective cardiovascular risk factor cholesterol transporters functional loss human disease in vivo loss of function macrophage member monocyte novel 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胆固醇反向转运以及减少氧化和炎症。越来越多的证据支持这样的观点：功能失调的高密度脂蛋白会失去其有益特性，实际上会导致动脉粥样硬化的发展。我们 PPG 的中心主题是 HDL 功能是人类慢性疾病中动脉粥样硬化形成和心血管风险的关键决定因素。我们研究的目标是确定三种与动脉粥样硬化性心血管疾病风险增加相关的疾病中 HDL 功能丧失的机制：家族性高胆固醇血症 (FH)、慢性肾脏病 (CKD) 和类风湿性关节炎 (RA)。我们提议的一个主要假设是炎症和氧化应激会损害高密度脂蛋白功能。 F2-异前列腺素 (F2-lsoP) 的血浆水平是体内脂质过氧化的准确标记。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。异黄兰素 (IsoLG) 是一组高反应性氧化损伤介质，作为 IsoP 途径的产物形成。我们将研究 IsoLG 与 HDL 蛋白质和脂质形成加合物，从而损害 HDL 功能的新假设。 FH 受试者的 HDL 中 F2-lsoP 和 IsoLG 蛋白加合物水平升高，且抗炎 HDL 功能显着受损。慢性肾病 (CKD) 与 ESRD 患者血浆 F2-lsoP 水平升高和 HDL 胆固醇流出能力降低有关。 HDL 也是血浆中 microRNA (miRNA) 的主要载体，并将它们传递到影响基因表达的细胞。我们将研究新的假设，即 HDL-miRNA 谱随疾病状态而变化，氧化应激会改变疾病状态，并影响 HDL 功能。项目 1 和 2 将分别研究 FH 和 CKD 中 HDL 形成功能障碍的机制。项目 3 将研究 IsoP 产品对 HDL 功能的影响。这些项目将严重依赖提供 HDL 功能、异前列烷产品、miRNA 和生物信息学检测的 Cores。最终，我们的目标是开发针对功能失调的 HDL 的新型生物标志物和治疗方法，从而改变临床范式。