HDL Function in Human Disease

HDL 在人类疾病中的功能

基本信息

批准号：
10089335
负责人：
MACRAE F LINTON
金额：
$ 262.1万
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 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10089335
关键词：
Acceleration Apoproteins Arterial Fatty Streak Arteries Atherosclerosis Bioinformatics Biometry Biostatistics Core Cardiovascular system Cell Death Cholesterol Chronic Chronic Kidney Failure Data Analyses Development Disease Endocytosis Ensure Environment Event Experimental Designs Familial Hypercholesterolemia Functional disorder Gene Expression Goals High Density Lipoproteins Human Impairment Inflammation Inflammatory Intestines Kidney Lesion Lipid Peroxidation Lipids Lipoproteins Low Density Lipoprotein oxidation Lymphatic Lysine Measurement MicroRNAs Modeling Modification Molecular Multiomic Data Mus Myocardial Infarction NAPE-PLD Necrosis Output Pathogenicity Phospholipids Plasma Proteins Research Residual state Resolution Rheumatoid Arthritis Risk Role Small RNA Stroke Structure TLR7 gene Testing Untranslated RNA adduct analog atherogenesis atheroprotective atherosclerosis risk cardiovascular risk factor chemical synthesis functional loss high density lipoprotein-3 human disease improved in vivo locked nucleic acid lymphatic dysfunction macrophage mesenteric lymphatics microbial microbiome novel novel therapeutic intervention particle programs receptor small molecule transcriptome sequencing

项目摘要

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 diseases associated with increased risk for atherosclerotic cardiovascular disease (ASCVD): Familial Hypercholesterolemia (FH), Chronic Kidney Disease (CKD) and Rheumatoid Arthritis (RA). A major hypothesis of the PPG is that dysfunctional HDL contributes to the residual inflammatory risk of cardiovascular events. Reactive dicarbonyls including MDA, IsoLG, and ONE are highly reactive species that rapidly adduct to apoAI and HDL phospholipids impairing HDL function. A major recent advance by our PPG is the discovery that two different small molecule dicarbonyl scavengers, 2-HOBA and PPM, improve HDL function, reduce LDL oxidation, and dramatically reduce atherosclerosis in Ldlr-/- deficient mice, a model of FH, in the absence of changes in plasma lipid levels. The atherosclerotic lesions showed a dramatic decrease in necrosis and inflammation and had evidence for reduced efferocytosis. Projects 1 and 4 will both explore the hypothesis that reactive carbonyl- induced HDL dysfunction will impair macrophage efferocytosis. Project 1 will test the hypothesis that dicarbonyl scavengers promote remodeling of established atherosclerosis with resolution of inflammation. These studies will set the stage for a translational proof of concept study to test the hypothesis that the dicarbonyl scavenger 2-HOBA will inhibit modification of apoAI and HDL and improve HDL functions in humans with heterozygous FH and subjects with CAD without FH. Interestingly, we have recently discovered that lipoproteins are highly- enriched with small RNAs derived from bacterial and fungal species in the microbiome and environment (msRNA). Another major theme is that msRNA carried by HDL influence HDL function and atherogenesis. Project 2 will examine the hypothesis that CKD increases mesenteric lymphatic output and apoAI harboring harmful bioactive substances (IsoLG, miRNA, msRNA) that contribute to the increased risk of ASCVD. Importantly, microbial sRNAs are present in human and mouse atherosclerotic lesions. Project 3 will examine the hypothesis that HDL removes microbial sRNAs from lesion macrophages and suppresses pro-inflammatory gene expression through retro-endocytosis and msRNA acceptance. In addition, we will target macrophage TLR7/8 activation in vivo using non-targeting locked-nucleic acids (ntLNA) to inhibit atherosclerosis progression and promote regression. Project 4 will elucidate mechanisms whereby dicarbonyl modified lipoproteins potentiate inflammation and cell death in macrophages and determine if these alterations contribute to reduced efferocytosis. Overall, the proposed studies will advance our understanding of the role of HDL function in human disease and identify new therapeutic approaches for the treatment of ASCVD. There are 4 Cores: Core A. Administrative and Biostatistics; Core B Lipoprotein and HDL Function; Core C Chemical Synthesis and Lipid Peroxidation Analytical Core; and Core D Non-Coding RNA and Bioinformatics.

我们 PPG 的中心主题是 HDL 功能是动脉粥样硬化和心血管疾病的关键决定因素人类慢性疾病的风险。我们研究的目标是确定 HDL 功能丧失的机制与动脉粥样硬化性心血管疾病 (ASCVD) 风险增加相关的疾病：家族性高胆固醇血症 (FH)、慢性肾病 (CKD) 和类风湿性关节炎 (RA)。一个主要假设 PPG 的一个特点是，功能失调的 HDL 会导致心血管事件的残余炎症风险。反应性二羰基（包括 MDA、IsoLG 和 ONE）是高反应性物质，可快速加合到 apoAI HDL 磷脂会损害 HDL 功能。我们 PPG 最近的一项重大进展是发现两个不同的小分子二羰基清除剂2-HOBA和PPM，改善HDL功能，减少LDL氧化，在 Ldlr-/- 缺陷小鼠（FH 模型）中，在没有变化的情况下，显着减少动脉粥样硬化血浆脂质水平。动脉粥样硬化病变的坏死和炎症显着减少，有证据表明胞吞作用减少。项目 1 和 4 都将探讨反应性羰基- 诱导的 HDL 功能障碍会损害巨噬细胞的胞吞作用。项目 1 将检验二羰基的假设清除剂促进已形成的动脉粥样硬化的重塑并消除炎症。这些研究将为概念研究的转化验证奠定基础，以测试二羰基清除剂的假设 2-HOBA 将抑制 apoAI 和 HDL 的修饰并改善杂合子 FH 人类的 HDL 功能以及患有 CAD 而没有 FH 的受试者。有趣的是，我们最近发现脂蛋白具有高度- 富含源自微生物组和环境中细菌和真菌物种的小 RNA (msRNA)。另一个主要主题是 HDL 携带的 msRNA 影响 HDL 功能和动脉粥样硬化形成。项目 2 将检验 CKD 增加肠系膜淋巴输出和 apoAI 含有有害物质的假设导致 ASCVD 风险增加的生物活性物质（IsoLG、miRNA、msRNA）。重要的是，微生物 sRNA 存在于人和小鼠的动脉粥样硬化病变中。项目 3 将检验假设 HDL 可去除病变巨噬细胞中的微生物 sRNA 并抑制促炎基因通过逆转录内吞作用和 msRNA 接受来表达。此外，我们还将靶向巨噬细胞TLR7/8 使用非靶向锁定核酸（ntLNA）在体内激活以抑制动脉粥样硬化进展促进回归。项目 4 将阐明二羰基修饰脂蛋白增强的机制巨噬细胞中的炎症和细胞死亡，并确定这些改变是否有助于减少胞吞作用。总体而言，拟议的研究将增进我们对 HDL 功能在人类中的作用的理解疾病并确定治疗 ASCVD 的新治疗方法。有 4 个核心：核心 A。行政和生物统计学；核心B脂蛋白和HDL功能；核心C化学合成与脂质过氧化分析核心；和 Core D 非编码 RNA 和生物信息学。