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: 8949279
• 负责人: Michelle Jane Ormseth
• 金额: $ 8.98万
• 依托单位: VANDERBILT UNIVERSITY
• 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 2016-04-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8949279
• 关键词: Affect; Applications Grants; Area; Atherosclerosis; Autoimmune Diseases; Bioinformatics; Biology; Cardiovascular Diseases; Career Choice; Cell Adhesion Molecules; Cell physiology; Cells; Cessation of life; Chronic; Clinical; Clinical Research; Core Facility; Data; Development; Distant; Endothelial Cells; Environment; Fellowship; Funding; Future; Gene Expression; Goals; Grant; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Immunity; Inflammation; Inflammatory; Knowledge; Laboratories; Lipids; Lipoproteins; Literature; Master of Science; Measures; Mediating; Medicine; Mentors; Metabolism; MicroRNAs; Nitric Oxide; Oxidative Stress; Pathogenesis; Patients; Play; Population; Production; RNA; Records; Regulator Genes; Research; Research Personnel; Research Proposals; Resources; Rheumatism; Rheumatoid Arthritis; Rheumatology; Risk Factors; Role; Site; Small RNA; Societies; Systems Biology; Techniques; Technology; Testing; Therapeutic; Thinking; Time; Training; Translational Research; United States; Universities; Untranslated RNA; base; cardiovascular risk factor; career; career development; cell type; clinical investigation; cytokine; differential expression; high density lipoprotein-1; innovation; intercellular communication; macrophage; novel; protein expression; public health relevance; response; skills; targeted treatment; trafficking; transcriptome sequencing

 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，与心血管风险增加两倍相关，与脂蛋白浓度和其他传统风险因素无关。一些证据表明，受损的高密度脂蛋白（HDL）的功能，而不是改变浓度有助于增加心血管疾病的风险;在RA高HDL胆固醇是与矛盾的高炎症或氧化应激的设置心血管疾病的风险增加。HDL功能受损的潜在机制尚不清楚，但最近发现HDL在细胞之间转运微小RNA（miRNA）提供了一种新机制，HDL可以通过这种机制以高度特异性的方式调节细胞间通讯。miRNAs是小的非编码RNA，是免疫和炎症的强大基因调控因子。例如，我们发现HDL将miRNA转运到内皮细胞，改变粘附分子的表达。目前对RA中高密度脂蛋白（HDL）的miRNA负载尚不清楚，这是一种潜在机制，一个部位的炎症可能会产生远处的有害影响。总体假设是，在RA中，改变的HDL-miRNA货物被递送至动脉粥样硬化发展的关键细胞，导致细胞反应改变，为RA患者的CV风险增加提供了机制。在初步数据的基础上，Aim 1将通过对来自RA患者和对照组的纯化HDL的小RNA进行测序，进一步确定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。将定量差异miRNA转移和促炎细胞因子表达的结果变化。在目标3中，将用RA和对照HDL处理内皮细胞。将定量差异miRNA转移和由此产生的粘附分子表达和一氧化氮产生的变化。这种通过HDL-miRNA传递的细胞间通讯的新机制将为RA的治疗提供新的途径，以降低心血管风险。申请人Ormseth博士在临床和转化研究方面具有很强的背景，并致力于风湿病学的学术生涯。在范德比尔特获得临床流变学奖学金后，她获得了临床研究硕士学位，并完成了由T-32资助的另外两年的研究奖学金。她的职业目标是成为脂质和miRNA生物学领域的独立研究者，该领域与炎症性风湿性疾病患者加速动脉粥样硬化的机制和治疗有关。在系统生物学和脂蛋白代谢等主题方面的额外指导研究时间和培训将有助于扩展她的实验室和与她的职业道路相关的生物信息学技能。范德比尔特大学提供了一个特殊的发展环境。亮点是纽曼协会，它旨在为年轻的研究人员提供独立性，核心设施，如Vantage与国家的最先进的RNAseq技术，以及大学的坚定承诺，以支持年轻的研究人员。医学系和流变学系支持Ormseth博士的计划。她的导师，斯坦博士，林顿，维克斯，是国际公认的，有成功的学员的跟踪记录，并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沿着优秀的指导和出色的环境将共同帮助她在独立的R 01资金方面具有竞争力。