Circulating Exosome microRNA as Markers of Severe Sarcoidosis Phenotypes

循环外泌体 microRNA 作为严重结节病表型的标志物

• 批准号: 9434044
• 负责人: ELLIOTT D CROUSER
• 金额: $ 12.26万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-12 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9434044
• 关键词: Acute; Adult; Affect; Biological Markers; Biology; Blood Circulation; Blood specimen; Brain; Cardiac; Cardiac Sarcoidosis; Cell membrane; Cells; Cellular Stress; Characteristics; Clinical; Clinical Management; Clinical Research; Data; Detection; Diagnosis; Diagnostic; Diagnostic tests; Disease; Endosomes; Genomics; Goals; Granulomatous; Health; Heart; Heart Diseases; Inflammatory; Knowledge; Laboratories; Lead; Lipids; Localized Malignant Neoplasm; Lung; Lung nodule; MicroRNAs; Mission; Modeling; Morbidity - disease rate; Myocardial Ischemia; National Heart, Lung, and Blood Institute; Nervous system structure; Neuraxis; Neurologic; Nucleic Acids; Organ; Parents; Patients; Pattern; Phenotype; Plasma; Polymerase Chain Reaction; Proteins; Public Health; Pulmonary Sarcoidosis; Research; Resources; Sampling; Sarcoidosis; Small RNA; Specificity; Testing; Thoracic Radiography; Time; Tissues; Translating; United States National Institutes of Health; adverse outcome; alpha 1-Antitrypsin Deficiency; base; burden of illness; candidate marker; circulating biomarkers; clinical practice; cohort; design; differential expression; disability; disease phenotype; exosome; experimental study; high risk; human disease; improved; innovation; ischemic cardiomyopathy; microRNA biomarkers; mortality; myocardial damage; neurosarcoidosis; next generation sequencing; prospective; repository; response; specific biomarkers

PROJECT SUMMARY Sarcoidosis is an adult onset systemic inflammatory disease that can compromise the function of vital organs. The lungs are most commonly affected, a manifestation that is readily detected with conventional diagnostic tests (e.g., chest radiography). However, sarcoidosis of the heart [cardiac sarcoidosis (CS)] and central nervous system [neurosarcoidosis (NS)] is present in a significant subset of sarcoidosis patients and these manifestations are more difficult to detect. It is important to identify CS and NS because involvement of these organs contributes significantly to the overall morbidity and mortality of sarcoidosis. Preliminary studies in our laboratory indicate that circulating subcellular components, referred to as exosomes, contain small RNA (microRNA) that can serve as biomarkers of sarcoidosis, and may be able to identify which organs are affected. We posit that exosome-derived microRNA will allow us to specifically detect CS and NS. In Aim 1 we propose to use plasma samples obtained from sarcoidosis patients with well-documented cardiac involvement to determine if circulating endosome-derived microRNA reliably detects CS, and we will further determine the specificity of circulating exosome-derived microRNA in CS patients relative to patients with ischemic heart disease. Aim 2 of the proposal will establish if circulating exosome-derived microRNA can be used as biomarkers of NS, and will further determine if these biomarkers can distinguish NS from CS. These studies will be performed using banked samples provided by the NIH BioLINCC repository, and banked samples available from the recently completed NIH sponsored Genomic Research of Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) trial. For each research Aim exosome-derived microRNA expression will be assessed quantitatively in a smaller test cohort using next-generation sequencing and the most promising microRNA biomarkers will be validated in a second cohort using quantitative real-time polymerase chain reaction (qRT-PCR). These studies will guide the design of subsequent prospective trials that would establish circulating exosome-derived microRNA as organ-specific sarcoidosis biomarkers.

项目概要 结节病是一种成人发病的全身炎症性疾病，可损害重要器官的功能。 肺部最常受到影响，这种表现很容易用传统的诊断方法检测出来 测试（例如胸部X光检查）。然而，心脏结节病 [心脏结节病 (CS)] 和中枢性结节病 神经系统[神经结节病 (NS)] 存在于结节病患者的一个重要亚群中，这些患者 的表现更难被发现。识别 CS 和 NS 很重要，因为这些涉及 器官对结节病的总体发病率和死亡率有显着影响。我们的初步研究 实验室表明循环亚细胞成分（称为外泌体）含有小 RNA （microRNA）可以作为结节病的生物标志物，并且可能能够识别哪些器官是 做作的。我们假设外泌体衍生的 microRNA 将使我们能够特异性检测 CS 和 NS。目标 1 我们建议使用从结节病患者获得的血浆样本，该患者患有有充分记录的心脏疾病 参与以确定循环内体衍生的 microRNA 是否可靠地检测 CS，我们将进一步 确定 CS 患者相对于患有其他疾病的患者循环外泌体衍生的 microRNA 的特异性 缺血性心脏病。该提案的目标 2 将确定循环外泌体衍生的 microRNA 是否可以 用作NS的生物标志物，并将进一步确定这些生物标志物是否可以区分NS和CS。这些 研究将使用 NIH BioLINCC 存储库提供的存储样本进行，并存储 样品来自最近完成的 NIH 资助的 Alpha-1 抗胰蛋白酶基因组研究 缺乏症和结节病（GRADS）试验。对于每项研究，外泌体衍生的 microRNA 表达将 使用下一代测序和最有希望的方法在较小的测试队列中进行定量评估 microRNA 生物标志物将在第二组中使用定量实时聚合酶链进行验证 反应（qRT-PCR）。这些研究将指导后续前瞻性试验的设计，这些试验将建立 循环外泌体衍生的 microRNA 作为器官特异性结节病生物标志物。