HDL Function in Human Disease

描述(由申请人提供)： 高密度脂蛋白(高密度脂蛋白)的抗动脉粥样硬化作用包括调节胆固醇的反向运输、减少氧化和炎症。越来越多的证据支持这样的概念，即功能失调的高密度脂蛋白失去了其有益的特性，实际上导致了动脉粥样硬化的发展。我们PPG的中心主题是，在慢性人类疾病中，高密度脂蛋白功能是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与动脉粥样硬化性心血管疾病风险增加相关的三种疾病的高密度脂蛋白功能丧失的机制：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)。我们建议的一个主要假设是炎症和氧化应激损害了高密度脂蛋白的功能。血浆F2-异前列腺素(F2-lsoP)水平是体内脂质过氧化的准确标记物。有趣的是，高密度脂蛋白是血浆中F2-lsoP的主要载体。我们在RA受试者中的研究表明，F2-lsoP可能是高密度脂蛋白功能的生物标志物。异丙肾上腺素(Isolevuglandins，IsoLG)是一组高活性的氧化损伤介质，是IsoP途径的产物。我们将检验新的假设，即IsoLG形成与高密度脂蛋白和脂类的加合物，从而损害高密度脂蛋白的功能。FH患者的高密度脂蛋白中F2-lsoP和IsoLG蛋白加合物水平升高，抗炎高密度脂蛋白功能显著受损。慢性肾脏疾病(CKD)与血浆F2-lsoP水平升高和从终末期肾病患者分离的高密度脂蛋白胆固醇外流能力降低有关。高密度脂蛋白也是血浆中microRNAs(MiRNAs)的主要载体，并将其输送到影响基因表达的细胞中。我们将检验这一新的假设，即高密度脂蛋白-miRNA谱随着疾病状态的不同而被氧化应激改变，并影响高密度脂蛋白的功能。项目1和2将分别研究FH和CKD中功能失调的高密度脂蛋白形成的机制。项目3将研究IsoP产品对高密度脂蛋白功能的影响。这些项目将严重依赖于为高密度脂蛋白功能、异前列腺素产品、miRNAs和生物信息学提供分析的核心。最终，我们的目标是为功能障碍的高密度脂蛋白开发新的生物标记物和治疗方法，改变临床范式。

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.