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（HDL）被发现可以将microRNA转运到细胞中，从而改变基因表达。HDL-miRNA货物及其向靶细胞的递送可以被不同的疾病状态改变，并且可能是一些疾病后遗症的原因。类风湿性关节炎（RA）的常见疾病后遗症是心血管（CV）疾病，其增加了两倍，但其潜在机制尚不清楚。一个潜在的机制是将改变的HDL-miRNA货物递送到促进血管炎症和内皮功能障碍的细胞。目前，对HDL-miRNA货物及其在RA中的转移一无所知。 总体假设是，在RA中，改变的HDL-miRNA货物转移调节促进血管炎症和内皮功能障碍的细胞反应，这在RA中很常见，并在CV疾病发展早期发生。这项研究的基本原理是，miRNAs是强大的基因表达调控因子，并且在RA和CV疾病中有几种miRNAs发生了改变。HDL仅与一小部分细胞相互作用，促进miRNA的独特积累。此外，HDL能够特异性地将miRNA靶向递送至免疫系统细胞和内皮细胞。 在初步 数据，目标1将通过比较患有RA但无冠状动脉疾病（CAD）的患者、患有RA且有CAD的患者和对照受试者的货物，并通过确定哪些miRNA与RA中的炎症和内皮功能相关，来定义RA中的HDL-miRNA货物。目的2将定义HDL-miRNA向巨噬细胞的差异转移（RA与对照）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将确定HDL-miRNA向内皮细胞的差异转移（RA与对照）及其对粘附分子表达和一氧化氮生物利用度以及动脉粥样硬化的影响。 这项拟议的研究意义重大，因为它从机制上解决了在CV疾病发病机制中至关重要的细胞功能如何通过一种可以修饰的新机制（HDL-miRNA转移）改变。此外，该提案是创新的，因为它将是第一个检查RA中HDL-miRNAs的研究，并对未来的研究具有广泛的意义，这些研究不仅限于RA中CV疾病的发展。这项研究具有很高的影响力，因为它可以确定促进RA CV疾病的早期血管变化的基本靶向机制，并可能导致靶向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.