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（由适用提供）：类风湿关节炎（RA）是一种炎症自身免疫性疾病，与脂蛋白浓度无关的心血管风险增加了两倍，而与脂蛋白浓度无关。几条证据表明，高密度脂蛋白（HDL）功能受损而不是浓度改变会导致心血管风险增加。在RA中，高HDL胆固醇在高感染或氧化应激的情况下与心血管风险增加有关。 HDL功能受损的机制尚不清楚，但是最近发现，HDL在细胞之间传输MicroRNA（miRNA）提供了一种新型机制，通过该机制，HDL可以以高度特定的方式调节细胞间通信。 miRNA是小型非编码RNA，是免疫学和注射的强大基因调节剂。例如，我们发现HDL将miRNA转运到改变粘合分子表达的内皮细胞。 RA中HDL的miRNA货物一无所知。总体假设是，在RA中，将HDL-MIRNA货物的变化传递到了动脉粥样硬化发展的关键的细胞，从而导致细胞反应改变，从而为RA患者的CV风险增加了一种机制。在初步数据的基础上，AIM 1将通过对RA和对照患者的纯化HDL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与RA中炎症和内皮功能最紧密相关的HDL-MIRNA。在AIM 2中，将用RA和对照HDL处理巨噬细胞。将量化miRNA转移和促炎细胞因子表达的结果变化。在AIM 3中，内皮细胞将用RA和对照HDL处理。将量化miRNA转移和粘合分子表达和一氧化氮产生的变化。 HDL-MIRNA递送的细胞间通信的这种新型机制将为RA提供新的疗法途径，以降低心血管风险。申请人Ormseth博士在临床和翻译研究方面具有强大的背景，并致力于风湿病学的学术生涯。在范德比尔特（Vanderbilt）的临床风湿病学奖学金之后，她获得了临床调查学位的科学硕士学位，并完成了由T-32赠款资助的另外两年研究奖学金。她的职业目标是成为脂质和miRNA生物学领域的独立研究者，与机制和治疗炎症性风湿病患者的加速动脉粥样硬化有关。在系统生物学和脂蛋白代谢等主题中进行的额外指导的研究时间和培训将有助于扩大她的实验室和生物信息学技能与她的职业道路相关。范德比尔特大学（Vanderbilt University）提供了一个特殊的环境。亮点是纽曼学会（Newman Society），该协会旨在为年轻的调查人员提供独立性，诸如Vantage之类的核心设施与The-Art RNASEQ技术的核心设施，以及大学对支持年轻调查人员的深刻承诺。医学和风湿病学系支持Ormseth博士的计划。她的导师斯坦（Stein），林顿（Linton）和维克斯（Vickers）在国际上得到认可，具有成功的训练记录，并拥有训练她并发展职业生涯的必要资源。 Ormseth博士的创新研究建议以及出色的指导和出色的环境将有助于她获得独立R01资金的竞争力。