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: 9140517
• 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/9140517
• 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; Clinical Trials; 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; 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; endothelial dysfunction; innovation; macrophage; novel; protein expression; public health relevance; response; targeted treatment; 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，人们发现高密度脂蛋白 (HDL) 可以将 microRNA 转运至细胞，从而导致 HDL-miRNA 货物的基因表达发生改变，并且其向靶细胞的递送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。类风湿性关节炎 (RA) 的常见疾病后遗症是心血管 (CV) 疾病，其发病率增加两倍，但潜在的机制尚不清楚，其中一个潜在的机制是将改变的 HDL-miRNA 转运至细胞，从而促进血管炎症和炎症。目前，关于 HDL-miRNA 货物及其在 RA 中的转移尚不清楚，总体假设是，在 RA 中，改变的 HDL-miRNA 货物转移可调节细胞的反应，从而促进血管炎症和内皮功能障碍，这在 RA 中很常见。该研究的基本原理是，miRNA 是强大的基因表达调节因子，并且在 RA 和 HDL 疾病中，一些 miRNA 发生改变，仅与一小部分相互作用。此外，HDL 能够在初步基础上将 miRNA 特异性递送至免疫系统细胞和内皮细胞。 数据，目标 1 将通过比较无冠状动脉疾病 (CAD) 的 RA 患者、患有 CAD 的 RA 患者和对照受试者的货物，并确定哪些 miRNA 与炎症和内皮细胞相关，来定义 RA 中的 HDL-miRNA 货物目标 2 将定义 HDL-miRNA 向巨噬细胞的差异转移（RA 与对照）及其对巨噬细胞炎症细胞因子表达以及斑块炎症和动脉粥样硬化的影响。图 3 将定义 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。这项研究具有重要意义，因为它从机制上解决了细胞功能的问题，这一点很重要。在 CV 疾病的发病机制中，通过一种可以修改的新机制（HDL-miRNA 转移）来改变。此外，该提案具有创新性，因为它将是第一个进行检查的提案。 HDL-miRNA 在 RA 中的应用，对未来的研究具有广泛的影响，不仅限于 RA 中心血管疾病的发展，这项研究具有很高的影响力，因为它可以确定促进 RA 中心血管疾病的早期血管变化的基本、可靶向的机制，并且可能会导致靶向 miRNA 治疗。