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）受损。功能而不是浓度改变会导致心血管风险增加；在 RA 中，高密度脂蛋白胆固醇在高炎症或氧化应激机制受损的情况下与心血管风险增加存在矛盾的相关性。目前尚不清楚，但最近发现 HDL 在细胞之间运输 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 RA 中 HDL 的 miRNA 表达，这是一种潜在机制，其中一个部位的炎症可能具有远距离有害作用。总体假设是，在 RA 中，改变的 HDL-miRNA 被传递到对动脉粥样硬化发展至关重要的细胞，从而导致细胞反应改变，从而为 RA 患者的心血管风险增加提供了一种机制。通过对来自 RA 患者和对照的纯化 HDL 的小 RNA 进行测序，进一步定义 RA 中的 HDL-miRNA，这些发现将有助于选择与 RA 中的炎症和内皮功能最密切相关的 HDL-miRNA。目标 2，将用 RA 和对照 HDL 处理巨噬细胞，并量化促炎细胞因子表达的差异。在目标 3 中，将用 RA 和对照 HDL 处理内皮细胞。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 传递的细胞间通讯新机制将为 RA 治疗提供新途径。申请人 Ormseth 博士拥有深厚的临床和转化研究背景，在范德比尔特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，并致力于风湿病学的学术生涯。完成了额外的两年研究奖学金，由 T-32 资助，她的职业目标是成为与炎症性风湿病患者加速动脉粥样硬化的机制和治疗相关的脂质和 miRNA 生物学领域的独立研究者。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大与她的职业道路相关的实验室和生物信息学技能，纽曼协会的亮点是她的发展。为了使年轻研究人员能够独立，VANTAGE 等核心设施配备了最先进的 RNAseq 技术，并且大学对支持年轻研究人员的坚定承诺。 Ormseth 的导师 Stein、Linton 和 Vickers 博士获得了国际认可，拥有成功的受训者记录，并拥有培训她和发展她的职业生涯所需的资源以及出色的指导和指导。优秀的环境将共同帮助她在独立R01资助中具有竞争力。