Functional impact of HDL transport of microRNA in rheumatoid arthritis

 描述(由申请人提供)： 最近，高密度脂蛋白(HDLs)被发现可以将microRNAs转运到细胞内，导致基因表达的改变。不同的疾病状态会改变高密度脂蛋白-miRNA的载量及其对靶细胞的输送，这可能是导致一些疾病后遗症的原因。类风湿性关节炎(RA)的一种常见疾病后遗症是心血管(CV)疾病，其发病率增加了两倍，但其潜在机制尚不清楚。一个潜在的机制是将改变的高密度脂蛋白-miRNA货物运送到细胞，促进血管炎症和内皮功能障碍。目前，关于高密度脂蛋白-miRNA的载物及其在RA中的转运尚不清楚。最重要的假设是，在RA中，改变的高密度脂蛋白-miRNA货物转移调节细胞的反应，促进血管炎症和内皮功能障碍，这在RA中很常见，发生在CV疾病发展的早期。这项研究的理论基础是miRNAs是强大的基因表达调节因子，而且几个miRNAs在RA和CV疾病中都发生了改变。高密度脂蛋白只与一小部分细胞相互作用，促进miRNAs的独特积累。此外，高密度脂蛋白能够特异性地将miRNA靶向输送到免疫系统的细胞和内皮细胞。建立在初步的基础上 数据，目标1将通过比较无冠状动脉疾病(CAD)的RA患者、有CAD的RA患者和对照受试者的货物，并通过确定哪些miRNA与RA的炎症和内皮功能相关来定义RA中的高密度脂蛋白-miRNA货物。目的2明确高密度脂蛋白-miRNAs向巨噬细胞的差异转移(RA和对照)及其对巨噬细胞炎性细胞因子表达和斑块炎症和动脉粥样硬化的影响。目的3将明确高密度脂蛋白-miRNAs向内皮细胞的差异转移(RA与对照)及其对黏附分子表达和一氧化氮生物利用度的影响，以及对动脉粥样硬化的影响。这项拟议的研究具有重要意义，因为它从机械上解决了细胞功能是如何通过一种可以修改的新机制(高密度脂蛋白-miRNA转移)改变的，而细胞功能在心血管疾病的发病机制中是重要的。此外，这项建议是创新的，因为它将是第一次检查类风湿关节炎中的高密度脂蛋白-miRNAs，并对未来的研究具有广泛的影响，这些研究并不局限于类风湿关节炎的发展。这项研究具有很高的影响力，因为它可以识别导致RA心血管疾病的早期血管变化的基本的、有针对性的机制，并可能导致靶向的miRNA治疗。

 DESCRIPTION (provided by applicant): Recently, high-density lipoproteins (HDL) were discovered to transport microRNAs to cells, leading to altered gene expression. HDL-miRNA cargo and its delivery to target cells can be altered by different disease states and may be responsible for some disease sequelae. A common disease sequela of rheumatoid arthritis (RA) is cardiovascular (CV) disease, which is increased two-fold, but underlying mechanisms are unclear. A potential mechanism is delivery of altered HDL-miRNA cargo to cells that promote vascular inflammation and endothelial dysfunction. Currently, nothing is known about HDL-miRNA cargo and its transfer in RA. The overarching hypothesis is that in RA altered HDL-miRNA cargo transfer modulates the responses of cells that promote vascular inflammation and endothelial dysfunction, which are common in RA and occur early in CV disease development. The rationale for the proposed research is that miRNAs are powerful gene expression regulators, and several miRNAs are altered in both RA and CV disease. HDL interacts with only a small proportion of cells, facilitating a unique accumulation of miRNAs. Moreover, HDL is capable of targeted miRNA delivery specifically to cells of the immune system and endothelial cells. Building on preliminary data, Aim 1 will define the HDL-miRNA cargo in RA by comparing the cargo of patients with RA without coronary artery disease (CAD), patients with RA with CAD, and control subjects, and by determining which miRNAs are associated with inflammation and endothelial function in RA. Aim 2 will define the differential transfer (RA vs control) of HDL- miRNAs to macrophages and their impact on macrophages inflammatory cytokine expression and on plaque inflammation and atherosclerosis. Aim 3 will define the differential transfer (RA vs control) of HDL-miRNAs to endothelial cells and their impact on adhesion molecule expression and nitric oxide bioavailability, and on atherosclerosis. The proposed research is significant because it mechanistically addresses how cellular functions, which are important in the pathogenesis of CV disease, are altered through a novel mechanism (HDL-miRNA transfer) that could be modified. Moreover, this proposal is innovative because it will be the first to examine HDL-miRNAs in RA and has wide implications for future investigations that are not limited to the development of CV disease in RA. This study is high impact because it could identify fundamental, targetable mechanisms underlying early vascular changes which promote CV disease in RA, and could lead to targeted miRNA therapeutics.