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: 10600983
• 负责人: Yuichi Shimada
• 金额: $ 69.94万
• 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/10600983
• 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; 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; Non-Invasive Detection; Pathogenesis; Pathway interactions; Patients; Persons; Pharmacotherapy; Plasma; Preventive therapy; Prospective cohort; Prospective, cohort study; Proteins; Proteomics; Quantitative Reverse Transcriptase PCR; 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; Up-Regulation; Validation; Ventricular; Western Blotting; Work; biobank; circulating biomarkers; clinical phenotype; cohort; disorder prevention; drug development; evidence base; experience; follow-up; genetic analysis; high risk; implantation; improved; inhibitor; insight; invention; 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 肥厚性心肌病（HCM）是最常见的遗传性心脏病，原因是 主要的不良心血管事件（MACE） - 例如心律不齐，心力衰竭和突然 心脏死亡。可以提供防止狼牙棒的侵入性干预措施，但可能导致 并发症。当前的风险分层策略的能力有限预测哪个患者 将发展狼牙棒，并从预防性干预中受益最大。此外，几乎没有 知道基因突变培养基HCM发病机制的信号传导途径 和狼牙棒。这些主要的知识差距阻碍了防止HCM中的MACE的努力。这 哈佛哥伦比亚多中心肥厚心肌病（HCM2）生物座是一种 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。在这个 大型多中心HCM生物座位，研究人员已经收集了高质量的生物测量 -​​ 例如，血浆，左心室心肌。后续数据包括双年度访谈，医疗 每年的记录评论和面对面考试，迄今为止的随访> 85％（中位随访， 3。1年）。目前的R01项目将扩展这个大型良好的HCM生物座 通过蛋白质组学分析血浆和心肌样品，并检查其 与HCM疾病状况和MACE的关系。在AIM 1中，我们将研究 使用分子的心肌的信号通路途径失调，具有HCM疾病状态 生物学方法（例如mRNA，ELISA的RT-PCR）和蛋白质组学分析。在AIM 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 分析并指定预测事件MACE的信号通路。最后，使用系统 生物学方法，AIM 3将通过整合蛋白质组学，遗传和临床来定义HCM亚型 数据，并确定其与狼牙棒的关联。我们先前的研究和初步工作借用 令人信服的支持我们的假设。当前的R01项目将提供独特的机会 揭示了HCM发病机理和进展的分子机制 使用血浆和心肌中的蛋白质组学分析检查信号通路。 此外，拟议的研究还将在HCM中发明一种新型的风险分层系统，该系统 将使我们能够精确地识别高风险的HCM亚群，这些亚群将受益 预防性干预措施。该项目将为开发目标提供强大的证据基础 通过调节的调节，可以防止HCM发病机理和MACE的药物疗法 信号通路。调查人员在所有人中都融合了互补的专业知识 相关字段。该研究与HCM研究的NHLBI战略计划非常匹配。