HDL Function in Human Disease

我们PPG的中心主题是高密度脂蛋白功能是动脉粥样硬化形成和心血管疾病的关键决定因素 在慢性人类疾病中的风险。我们研究的目标是明确高密度脂蛋白功能丧失的机制。 与动脉粥样硬化性心血管疾病风险增加相关的疾病：家族性 高胆固醇血症(FH)、慢性肾脏疾病(CKD)和类风湿性关节炎(RA)。一个重要的假设 PPG的一个特点是，功能失调的高密度脂蛋白会增加心血管事件的残余炎症风险。 反应性二羰基包括丙二醛、异丙基和一种高活性物种，能快速与载脂蛋白AI加成 高密度脂蛋白磷脂损害高密度脂蛋白功能。我们的PPG最近的一个主要进展是发现了两个 不同小分子二羰基清除剂，2-HOBA和PPM，提高高密度脂蛋白功能，减少低密度脂蛋白氧化， 并显著减少Ldlr/-缺陷小鼠的动脉粥样硬化，这是FH的一个模型，在没有改变的情况下 血脂水平。动脉粥样硬化病变的坏死和炎症显著减少， 有证据表明泡沫化作用减少。项目1和项目4都将探索一种假设，即反应性羰基- 诱导的高密度脂蛋白功能障碍会损害巨噬细胞的泡沫化作用。项目1将检验假设，即二羰基 清道夫通过消解炎症来促进已建立的动脉粥样硬化的重塑。这些研究 将为翻译概念验证研究奠定基础，以测试二羰基清除剂的假设 2-HOBA抑制杂合性FH患者载脂蛋白AI和高密度脂蛋白的修饰并改善高密度脂蛋白功能 无FH的冠心病受试者。有趣的是，我们最近发现脂蛋白是高度- 富含微生物组和环境中细菌和真菌物种的小RNA (MsRNA)。另一个主要论题是高密度脂蛋白携带的msRNA影响高密度脂蛋白的功能和动脉粥样硬化的形成。项目 2将检验CKD增加肠系膜淋巴输出和载脂蛋白AI有害的假设 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存在于人类和小鼠的动脉粥样硬化病变中。项目3将检验这一假设 高密度脂蛋白去除病变巨噬细胞中的微生物sRNA并抑制促炎基因 通过逆转录内吞和msRNA接受来表达。此外，我们还将针对巨噬细胞TLR7/8 使用非靶向锁定核酸(NtLNA)体内激活抑制动脉粥样硬化进展和 促进回归。项目4将阐明二羰基修饰的脂蛋白增强脂蛋白的机制 巨噬细胞的炎症和细胞死亡，并确定这些变化是否有助于减少 泡泡细胞增多症。总体而言，建议的研究将促进我们对高密度脂蛋白功能在人类中的作用的理解 并确定治疗ASCVD的新的治疗方法。有4个核心：核心A。 行政与生物统计学；核心B脂蛋白与高密度脂蛋白功能；核心C化学合成与脂质 过氧化分析核心；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.