HDL Function in Human Disease

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。我们研究的目的是确定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）和风湿性关节炎（RA）。一个主要的假设 PPG的一个重要特征是功能失调的HDL有助于心血管事件的残余炎症风险。 包括MDA、IsoLG和ONE在内的反应性二羰基是快速加合至apoAI的高反应性物质 和损害HDL功能的HDL磷脂。我们PPG最近的一个主要进展是发现， 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， 并显著减少Ldlr-/-缺陷小鼠（FH模型）的动脉粥样硬化， 血脂水平动脉粥样硬化病变显示坏死和炎症显著减少， 有证据表明红细胞增多症减少项目1和4都将探讨反应性羰基- 诱导的HDL功能障碍将损害巨噬细胞巨噬细胞增多。项目1将测试二羰基 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证明奠定基础，以测试二羰基清除剂 2-HOBA将抑制apoAI和HDL的修饰，并改善杂合FH患者的HDL功能 和无FH的CAD受试者。有趣的是，我们最近发现脂蛋白是高度- 富含来自微生物组和环境中的细菌和真菌物种的小RNA （msRNA）。另一个主要的主题是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携带有害的apoAI的假设。 生物活性物质（IsoLG，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将检验假设 HDL从病变巨噬细胞中清除微生物sRNAs， 通过逆转录内吞作用和msRNA接受来表达。此外，我们将靶向巨噬细胞TLR 7/8， 使用非靶向锁定核酸（ntLNA）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 炎症和细胞死亡，并确定这些改变是否有助于减少 红细胞增多症。总的来说，这些研究将促进我们对HDL功能在人类中的作用的理解。 疾病，并确定新的治疗ASCVD的治疗方法。有4个核心：核心A。 管理和生物统计学;核心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。

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.