HDL Function in Human Disease

HDL 在人类疾病中的功能

• 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
• 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

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的关键决定因素 慢性人类疾病的风险。我们研究的目的是定义HDL功能损失的机制 与动脉粥样硬化心血管疾病（ASCVD）的风险增加有关的疾病：家族性 高胆固醇血症（FH），慢性肾脏疾病（CKD）和类风湿关节炎（RA）。一个主要的假设 PPG的HDL功能失调会导致心血管事件的残留炎症风险。 包括MDA，Iselg和一个是高反应性的物种，包括迅速加入ApoAI HDL磷脂会损害HDL功能。我们PPG最近的重大进步是发现两个 不同的小分子双骨清除剂，2-HOBA和PPM，改善HDL功能，减少LDL氧化， 在没有变化的情况下 血浆脂质水平。动脉粥样硬化病变显示坏死和炎症急剧下降 有证据表明肿瘤病减少。项目1和4将探讨反应性羰基的假设 诱导的HDL功能障碍会损害巨噬细胞的肿瘤病。项目1将检验dicarbonyl的假设 清除剂通过解决炎症来促进已建立的动脉粥样硬化的重塑。这些研究 将为转化概念研究奠定阶段 2-HOBA将抑制APOAI和HDL的修饰，并改善杂合FH人类的HDL功能 和带有FH的CAD的受试者。有趣的是，我们最近发现脂蛋白是高度的 在微生物组和环境中富含源自细菌和真菌种类的小rNA （MSRNA）。另一个主要主题是HDL携带的MSRNA会影响HDL功能和动脉粥样硬化。项目 2将检查以下假设：CKD增加肠系膜淋巴输出和有害 生物活性物质（Iselg，miRNA，msRNA），导致ASCVD风险增加。重要的是， 微生物SRNA存在于人和小鼠动脉粥样硬化病变中。项目3将检查假设 HDL从病变巨噬细胞中去除微生物SRNA并抑制促炎基因 通过恢复性细胞增多症和msRNA接受的表达。此外，我们将靶向巨噬细胞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的进展和 促进回归。项目4将阐明机制，从而增强脂蛋白的修饰脂蛋白 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，拟议的研究将促进我们对HDL功能在人类中的作用的理解 疾病并确定用于治疗ASCVD的新治疗方法。有4个核心：核心A。 行政和生物统计学；核B脂蛋白和HDL功能；核心C化学合成和脂质 过氧化分析核心；和核心D非编码RNA和生物信息学。