Functional impact of HDL transport of microRNA in rheumatoid arthritis

HDL 转运 microRNA 对类风湿性关节炎的功能影响

• 批准号: 9858228
• 负责人: Michelle Jane Ormseth
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9858228
• 关键词: Address; Affect; Area; Atherosclerosis; Autoimmune Diseases; Biological Availability; Blood Vessels; Cardiovascular Diseases; Cell Adhesion Molecules; Cell physiology; Cells; Cessation of life; Chronic; Coronary Arteriosclerosis; Data; Development; Disease; Distant; Drug Targeting; Endothelial Cells; Endothelium; Focal Adhesions; Future; Gene Expression; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Immune system; Inflammation; Inflammatory; Inflammatory Arthritis; Intercellular adhesion molecule 1; Interleukin-6; Investigation; Lead; Lipids; Measures; MicroRNAs; Modeling; Mus; Nitric Oxide; Pathogenesis; Patients; Phase I Clinical Trials; Phase II Clinical Trials; Play; Population; Production; RNA; Regulator Genes; Research; Rheumatoid Arthritis; Role; Serum; Testing; Therapeutic; Time; United States; Vasodilation; Veterans; cardiovascular disorder risk; cardiovascular risk factor; cell type; cytokine; disorder control; disorder prevention; innovation; macrophage; novel; protein expression; public health relevance; response; targeted treatment; therapeutic miRNA; vascular endothelial dysfunction; vascular inflammation

 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.

 描述（由申请人提供）： 最近，发现高密度脂蛋白（HDL）将microRNA转运至细胞，从而导致基因表达改变。 HDL-MIRNA货物及其向靶细胞的传递可能会因不同的疾病状态而改变，并可能导致某些疾病后遗症。类风湿关节炎（RA）的常见疾病后遗症是心血管（CV）疾病，其增加了两倍，但潜在的机制尚不清楚。潜在的机制是将改变的HDL-MIRNA货物传递到促进血管感染和内皮功能障碍的细胞。目前，HDL-MIRNA货物及其在RA中的转移尚无。总体假设是，在RA中，HDL-MIRNA货物转移调节了促进血管感染和内皮功能障碍的细胞反应，这在RA中很常见，并且在CV疾病发展的早期发生。拟议的研究的理由是miRNA是强大的基因表达调节剂，在RA和CV疾病中，几种miRNA都改变了。 HDL仅与一小部分细胞相互作用，支持miRNA的独特积累。此外，HDL能够针对免疫系统和内皮细胞细胞的靶向miRNA递送。基于初步 数据，AIM 1将通过比较没有冠状动脉疾病的RA患者（CAD），CAD患者和对照受试者的RA患者的货物来定义RA中的HDL-MIRNA货物，并确定哪些miRNA与RA中的炎症和内皮功能有关。 AIM 2将定义HDL-miRNA向巨噬细胞的差异转移（RA与控制）及其对巨噬细胞炎症细胞因子表达以及对斑块炎症和动脉粥样硬化的影响。 AIM 3将定义HDL-MIRNA对内皮细胞的差异转移（RA与控制）及其对粘合分子表达和一氧化氮生物利用度以及对动脉粥样硬化的影响。拟议的研究之所以重要，是因为它通过机械地解决了在CV疾病发病机理中重要的细胞功能如何通过可以修改的新机制（HDL-MIRNA转移）来改变。此外，该提案具有创新性，因为它将是第一个在RA中检查HDL-MIRNA的人，并且对未来不限于RA中CV疾病发展的未来研究具有广泛的影响。这项研究具有很大的影响，因为它可以鉴定出早期血管变化的基本，可靶向的机制，从而促进RA中的CV疾病，并可能导致靶向miRNA治疗。