Proteomics profiling in hypertrophic cardiomyopathy and cardiac event prediction

肥厚型心肌病和心脏事件预测的蛋白质组学分析

• 批准号: 10372158
• 负责人: Yuichi Shimada
• 金额: $ 70.99万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10372158
• 关键词: Affect; Age; Animal Model; Area Under Curve; Arrhythmia; Cardiac; Cardiomyopathies; Cardiovascular system; Characteristics; Clinical; Clinical Data; Clinical Management; Clinical Markers; Cohort Studies; Cross-Sectional Studies; Data; Development; Devices; Diagnosis; Dilatation - action; Disease; Disease Progression; Enrollment; Enzyme-Linked Immunosorbent Assay; Event; Exhibits; Family; Gene Mutation; Genetic; Goals; Heart; Heart Atrium; Heart Diseases; Heart failure; Human; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertrophic Cardiomyopathy; Image; Intervention; Interview; Knowledge; Left; Life Expectancy; MAP Kinase Gene; Matched Case-Control Study; Measures; Mediating; Medical Records; Messenger RNA; Meta-Analysis; Molecular; Molecular Biology; Molecular Target; Myocardium; National Heart, Lung, and Blood Institute; Pathogenesis; Pathway interactions; Patients; Persons; Pharmacotherapy; Plasma; Preventive therapy; Prospective cohort; Prospective cohort study; Proteins; Proteomics; Recording of previous events; Research; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Risk; Role; Sampling; Signal Pathway; Specific qualifier value; Strategic Planning; Stroke; Symptoms; System; Systems Biology; Testing; Time; To specify; Up-Regulation; Validation; Ventricular; Western Blotting; Work; base; biobank; circulating biomarkers; clinical phenotype; cohort; disorder prevention; drug development; evidence base; experience; follow-up; genetic analysis; high risk; implantation; improved; insight; member; molecular drug target; novel; novel strategies; phenotypic data; predictive modeling; prevent; preventive intervention; prospective; retention rate; risk stratification; sex; sudden cardiac death; targeted treatment

PROJECT SUMMARY Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiac disease and causes major adverse cardiovascular events (MACE) – e.g., arrhythmias, heart failure, and sudden cardiac death. Invasive interventions to prevent MACE are available but can cause complications. Current risk stratification strategy has limited power to predict which patient would develop MACE and benefit most from preventive interventions. Furthermore, little is known about the signaling pathways through which gene mutations mediate HCM pathogenesis and MACE. These major knowledge gaps have hindered efforts to prevent MACE in HCM. The Harvard-Columbia Multi-center Hypertrophic Cardiomyopathy (HCM2) Biorepository is an ongoing 3-center cohort study that enrolled 560 patients with HCM during 2014-2020. In this large multi-center HCM biorepository, investigators have collected high-quality biospecimens – e.g., plasma, left ventricular myocardium. Follow-up data include biannual interviews, medical record reviews, and in-person exam every year, with >85% follow-up to date (median follow-up, 3.1 years). The present R01 project will extend this large well-characterized HCM biorepository by proteomically profiling both plasma and myocardium samples, and by examining their relations to both HCM disease status and MACE. In Aim 1, we will examine the association of signaling pathway dysregulation in the myocardium with HCM disease status using molecular biology approach (e.g., RT-PCR of mRNA, ELISA) and proteomics profiling. In Aim 2, we will determine the association of signaling pathway dysregulation with MACE using proteomics profiling, and specify signaling pathways that predict incident MACE. Finally, using a systems biology approach, Aim 3 will define HCM subtypes by integrating proteomic, genetic, and clinical data, and determine their associations with MACE. Our prior study and preliminary work lend compelling support to our hypotheses. The present R01 project will provide a unique opportunity to reveal the molecular mechanisms of HCM pathogenesis and progression to MACE through examining signaling pathways using proteomics profiling in both plasma and myocardium. Furthermore, the proposed study will also invent a novel risk stratification system in HCM, which will allow us to precisely identify high-risk HCM subpopulations that would benefit from preventive interventions. The project will provide a strong evidence base for developing targeted pharmacotherapies to prevent HCM pathogenesis and MACE through the modulation of specific signaling pathways. The investigators have integrated and complementary expertise in all relevant fields. The study matches well with the NHLBI strategic plan for HCM research.

项目摘要 肥厚型心肌病（HCM）是最常见的遗传性心脏病， 主要心血管不良事件（MACE）-例如，心律失常、心力衰竭和突发性 心源性死亡可进行侵入性干预以预防MACE，但可能导致 并发症目前的风险分层策略在预测哪些患者 将发生MACE，并从预防干预中获益最多。此外， 已知基因突变介导HCM发病机制的信号通路 的MACE。这些主要的知识差距阻碍了HCM中预防MACE的努力。的 哈佛-哥伦比亚多中心肥厚型心肌病（HCM 2）生物储存库是一个 正在进行的3中心队列研究，在2014-2020年期间招募了560例HCM患者。在这 大型多中心HCM生物储存库，研究人员收集了高质量的生物标本- 例如，在一个实施例中，血浆，左心室心肌。随访数据包括一年两次的访谈， 记录审查和每年的亲自检查，迄今为止随访率>85%（中位数随访， 3.1年）。目前的R 01项目将扩大这个大型的HCM生物储存库， 通过对血浆和心肌样品进行蛋白质组学分析，并通过检查它们的 与HCM疾病状态和MACE的关系。在目标1中，我们将研究 HCM疾病状态心肌中信号通路失调的分子生物学研究 生物学方法（例如，mRNA的RT-PCR，ELISA）和蛋白质组学分析。在目标2中，我们将 使用蛋白质组学确定信号通路失调与MACE的关联 分析，并指定预测MACE事件的信号通路。最后，使用系统 目标3将通过整合蛋白质组学、遗传学和临床学方法来定义HCM亚型 数据，并确定其与MACE的关联。我们的前期研究和前期工作， 有力地支持了我们的假设目前的R 01项目将提供一个独特的机会， 揭示HCM发病机制和进展为MACE的分子机制， 在血浆和心肌中使用蛋白质组学分析来检查信号通路。 此外，拟议的研究还将发明一种新的HCM风险分层系统， 将使我们能够精确地识别高风险HCM亚群， 预防性干预。该项目将为制定有针对性的计划提供强有力的证据基础 通过调节特异性药物治疗来预防HCM发病机制和MACE 信号通路调查人员在所有领域都有综合和互补的专门知识， 相关领域。该研究与NHLBI HCM研究战略计划相匹配。