MicroRNA Profile in Peripheral Artery Disease

外周动脉疾病中的 MicroRNA 谱

• 批准号: 8301065
• 负责人: Naomi Miriam Hamburg
• 金额: $ 22.09万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8301065
• 关键词: Activities of Daily Living; Affect; Age; American; Amputation; Angiogenesis Modulating Agents; Angiography; Animal Model; Arteries; Automobile Driving; Biological Markers; Biology; Biopsy; Blood; Blood Vessels; Cardiac Death; Cardiovascular Diseases; Cardiovascular system; Cell Separation; Clinical; Complication; Congestive Heart Failure; Coronary; Coronary artery; Cross-Sectional Studies; Data; Disease; Endocrine; Endothelial Cells; Enrollment; Epidemiologic Studies; Evaluation; Event; Experimental Models; Funding; Gene Expression; Inflammation; Inflammatory; Injury; Intervention; Ischemia; Isolated limb perfusion; Limb structure; Link; Lower Extremity; Measurement; Measures; Medicine; Methodology; Methods; MicroRNAs; Molecular Profiling; Myocardial Infarction; National Heart, Lung, and Blood Institute; Outcome; Patients; Pattern; Peripheral; Peripheral arterial disease; Pharmaceutical Preparations; Phenotype; Plasma; Prevalence; Prevention strategy; Procedures; Process; Research; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Sampling; Severity of illness; Signal Transduction; Source; Specialist; Stroke; Symptoms; Techniques; Testing; Time; Tissues; Translational Research; United States; Unstable angina; Vascular Diseases; Work; aging population; angiogenesis; base; cardiovascular disorder epidemiology; cardiovascular risk factor; cohort; cytokine; disability; experience; follow-up; functional disability; human subject; improved; innovation; insight; longitudinal design; novel; novel therapeutic intervention; outcome forecast; prospective; research study; response; response to injury; restenosis; therapeutic target; treatment strategy

DESCRIPTION (provided by applicant): Peripheral artery disease (PAD) is increasingly prevalent and leads to disability and high cardiovascular risk. The determinants of clinical status and prognosis in PAD are not well understood. Emerging evidence from experimental models identifies microRNAs (miRNAs) as regulators of cellular responses to limb ischemia and as potential therapeutic targets. Altered miRNA expression may contribute to PAD by modulating angiogenesis, inflammation and endothelial injury response, but little is known about these mechanisms in patients. MiRNAs circulate in the blood, hold potential as biomarkers, and may function as endocrine signaling factors. Endothelial cells are a potential source for circulating miRNA. We have developed methods to perform comprehensive quantitative RT-PCR based miRNA profiling in plasma. In addition, we have established the ability to characterize miRNA expression in freshly isolated endothelial cells. The proposed research aims to define circulating and arterial endothelial miRNAs in PAD to provide insight into the mechanisms driving clinical disease in PAD. We will accomplish Aims 1 and 2 by studying our well-characterized, National Heart Lung and Blood Institute-funded PAD cohort and controls (306 PAD patients, 50 CAD patients and 50 controls) with longitudinal outcome evaluation and Aim 3 by enrolling 90 patients (30 each PAD, CAD alone and control) for endothelial cell isolation. In Aim 1, we will test the hypothesis that PAD alters circulating miRNA expression by comparing PAD patients to CAD and healthy controls. In Aim 2, we will relate circulating miRNAs to disease severity, inflammatory cytokines, and circulating angiogenesis modulators in PAD. Further, we will use previously collected 2-year follow-up data to test the hypothesis that circulating miRNAs are associated with coronary and peripheral disease events in PAD. In Aim 3, we will collect arterial endothelial cells at the time of angiography by J-wire biopsy from the iliofemoral arteries. We relate endothelial cell miRNA expression to circulating miRNAs and PAD status. These studies will provide new information regarding circulating and endothelial miRNAs in PAD and may stimulate innovative treatment strategies. PUBLIC HEALTH RELEVANCE: Peripheral arterial disease (PAD) affects over 8 million Americans and leads to physical disability, limb amputation, heart attack and stroke. The determinants of the clinical status and prognosis in PAD are not well understood. This application focuses on microRNAs to understand the mechanisms of cardiovascular risk in PAD and may generate novel therapeutic approaches for PAD.

描述（由申请人提供）：外周动脉疾病（PAD）越来越普遍，并导致残疾和高心血管风险。临床状态的决定因素 PAD 的发病率和预后尚不清楚。来自实验模型的新证据表明 microRNA (miRNA) 是细胞对肢体缺血反应的调节因子，也是潜在的治疗靶点。改变的 miRNA 表达可能通过调节血管生成、炎症和内皮损伤反应而导致 PAD，但人们对患者的这些机制知之甚少。 miRNA 在血液中循环，具有作为生物标志物的潜力，并且可能作为内分泌信号因子发挥作用。内皮细胞是循环 miRNA 的潜在来源。我们开发了在血浆中进行基于 miRNA 综合定量 RT-PCR 分析的方法。此外，我们还建立了表征新鲜分离的内皮细胞中 miRNA 表达的能力。拟议的研究旨在定义 PAD 中的循环和动脉内皮 miRNA，以深入了解 PAD 临床疾病的驱动机制。我们将通过研究我们由国家心肺和血液研究所资助的特征明确的 PAD 队列和对照（306 名 PAD 患者、50 名 CAD 患者和 50 名对照）并进行纵向结果评估来实现目标 1 和 2，并通过招募 90 名患者（每个 PAD、CAD 和对照各 30 个）用于内皮细胞分离。在目标 1 中，我们将通过将 PAD 患者与 CAD 和健康对照进行比较来检验 PAD 改变循环 miRNA 表达的假设。在目标 2 中，我们将把循环 miRNA 与 PAD 中的疾病严重程度、炎症细胞因子和循环血管生成调节剂联系起来。此外，我们将使用之前收集的 2 年随访数据来检验循环 miRNA 与 PAD 中的冠状动脉和外周疾病事件相关的假设。在目标 3 中，我们将在血管造影时通过 J 线活检从髂股动脉收集动脉内皮细胞。我们将内皮细胞 miRNA 表达与循环 miRNA 和 PAD 状态联系起来。这些研究将提供有关 PAD 中循环和内皮 miRNA 的新信息，并可能激发创新的治疗策略。 公共卫生相关性：外周动脉疾病 (PAD) 影响着超过 800 万美国人，并导致身体残疾、截肢、心脏病发作和中风。 PAD 临床状态和预后的决定因素尚不清楚。该应用重点关注 microRNA，以了解 PAD 心血管风险机制，并可能产生新的 PAD 治疗方法。