Functional Impact of HDL transport of miRNA in rheumatoid arthritis

HDL 转运 miRNA 对类风湿性关节炎的功能影响

• 批准号: 9251585
• 负责人: Michelle Jane Ormseth
• 金额: $ 3.51万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9251585
• 关键词: Functional; Impact; HDL; transport; miRNA

 DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is an inflammatory autoimmune disease associated with a two-fold increased cardiovascular risk independent of lipoprotein concentrations and other traditional risk factors. Several lines of evidence suggest that impaired high-density lipoprotein (HDL) function rather than altered concentrations contributes to increased cardiovascular risk; in RA high HDL cholesterol is associated paradoxically with increased cardiovascular risk in the setting of high inflammation or oxidative stress. Mechanisms underlying impaired HDL function are unclear, but a recent discovery that HDL transports microRNAs (miRNAs) between cells provides a novel mechanism by which HDL can regulate intercellular communication in a highly specific manner. miRNAs are small non-coding RNAs that are powerful gene regulators of immunity and inflammation. For example, we found that HDL transports miRNAs to endothelial cells altering adhesion molecule expression. Nothing is known about miRNA cargo of HDL in RA, a potential mechanism whereby inflammation at one site may have distant deleterious effects. The overarching hypothesis is that in RA an altered HDL-miRNA cargo is delivered to cells key to the development of atherosclerosis leading to altered cellular responses providing a mechanism for increased CV risk in patients with RA. Building on preliminary data, Aim 1 will further define HDL-miRNA cargo in RA by sequencing small RNAs from purified HDL from patients with RA and controls. These findings will help select those HDL-miRNAs most closely associated with inflammation and endothelial function in RA. In Aim 2, macrophages will be treated with RA and control HDL. The differential miRNA transfer and resultant change in pro-inflammatory cytokine expression will be quantified. In Aim 3, endothelial cells will be treated with RA and control HDL. The differential miRNA transfer and resultant change in adhesion molecule expression and nitric oxide production will be quantified. This novel mechanism of intercellular communication by HDL-miRNA delivery will offer new avenues of therapeutics for RA to decrease cardiovascular risk. The applicant, Dr. Ormseth, has a strong background in clinical and translational research and is committed to an academic career in rheumatology. Following her clinical rheumatology fellowship at Vanderbilt, she obtained a Master of Science in Clinical Investigation degree and completed an additional two year research fellowship, funded by a T-32 grant. Her career goal is to become an independent investigator in the area of lipid and miRNA biology pertaining to mechanisms and treatment of accelerated atherosclerosis in patients with inflammatory rheumatic diseases. Additional mentored research time and training in topics such as systems biology and lipoprotein metabolism will help expand her laboratory and bioinformatics skills relevant to her career path. Vanderbilt University provides an exceptional environment in which to develop. Highlights are the Newman Society, which seeks to equip young investigators for independence, core facilities like VANTAGE with state- of-the-art RNAseq technology, and the deep commitment of the University to support young investigators. The Department of Medicine and Division of Rheumatology support Dr. Ormseth's plans. Her mentors, Drs. Stein, Linton, and Vickers, are internationally recognized, have track records of successful mentees, and have the necessary resources to train her and develop her career. Dr. Ormseth's innovative research proposal along with excellent mentoring and an outstanding environment will together help her to be competitive for independent R01 funding.

 描述（由申请人提供）：类风湿性关节炎（RA）是一种炎症性自身免疫性疾病，与脂蛋白浓度和其他传统危险因素无关的心血管风险增加两倍相关。多项证据表明，高密度脂蛋白 (HDL) 功能受损而非浓度改变会导致心血管风险增加。在 RA 中，在高炎症或氧化应激的情况下，高 HDL 胆固醇与心血管风险增加存在矛盾的关系。 HDL 功能受损的机制尚不清楚，但最近发现 HDL 在细胞之间转运 microRNA (miRNA)，这提供了一种新机制，HDL 可以通过该机制以高度特异性的方式调节细胞间通讯。 miRNA 是小型非编码 RNA，是免疫和炎症的强大基因调节剂。例如，我们发现 HDL 将 miRNA 转运至内皮细胞，从而改变粘附分子的表达。关于 RA 中 HDL 的 miRNA 货物，我们一无所知，这是一种潜在机制，使某一部位的炎症可能产生遥远的有害影响。总体假设是，在 RA 中，改变的 HDL-miRNA 货物被传递到对动脉粥样硬化发展至关重要的细胞，导致细胞反应改变，从而为 RA 患者的心血管风险增加提供了一种机制。基于初步数据，目标 1 将通过对来自 RA 患者和对照的纯化 HDL 中的小 RNA 进行测序，进一步定义 RA 中的 HDL-miRNA 货物。这些发现将有助于选择那些与 RA 炎症和内皮功能最密切相关的 HDL-miRNA。在目标 2 中，将用 RA 和对照 HDL 处理巨噬细胞。差异性 miRNA 转移和促炎细胞因子表达的变化将被量化。在目标 3 中，将用 RA 和对照 HDL 处理内皮细胞。差异性 miRNA 转移以及由此产生的粘附分子表达和一氧化氮产生的变化将被量化。这种通过 HDL-miRNA 传递进行细胞间通讯的新机制将为 RA 降低心血管风险的治疗提供新途径。申请人Ormseth博士在临床和转化研究方面拥有深厚的背景，并致力于风湿病学的学术事业。在范德堡大学获得临床风湿病学奖学金后，她获得了临床研究理学硕士学位，并完成了由 T-32 拨款资助的额外两年研究奖学金。她的职业目标是成为脂质和 miRNA 生物学领域的独立研究者，该领域涉及炎症性风湿性疾病患者加速动脉粥样硬化的机制和治疗。额外的指导研究时间和系统生物学和脂蛋白代谢等主题的培训将有助于扩展她与职业道路相关的实验室和生物信息学技能。范德比尔特大学提供了优越的发展环境。亮点包括纽曼学会（Newman Society），该协会致力于为年轻研究人员提供独立性、配备最先进 RNAseq 技术的 VANTAGE 等核心设施，以及大学对支持年轻研究人员的坚定承诺。医学系和风湿病科支持 Ormseth 博士的计划。她的导师，博士。斯坦因、林顿和维克斯获得了国际认可，拥有成功受训者的记录，并拥有必要的资源来培训她和发展她的职业生涯。 Ormseth 博士的创新研究提案以及出色的指导和出色的环境将共同帮助她在独立 R01 资助方面具有竞争力。