Transcriptomics, pathobiology, and cardiac event in hypertrophic cardiomyopathy

肥厚型心肌病的转录组学、病理学和心脏事件

• 批准号: 10638722
• 负责人: Yuichi Shimada
• 金额: $ 75.75万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10638722
• 关键词: Affect; Age; Animals; Arrhythmia; Biological; Biological Markers; Cardiac; Cardiomyopathies; Cardiovascular system; Clinical; Clinical Data; Clinical Management; Clinical Markers; Data; Development; Devices; Disease; Disease Progression; Enrollment; Event; Family; Gene Mutation; Genetic; Goals; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Heterogeneity; Human; Hypertrophic Cardiomyopathy; Image; In Situ Hybridization; Intervention; Interview; Knowledge; Left; Left Ventricular Hypertrophy; MAP Kinase Gene; Matched Case-Control Study; Mediating; Medical Records; Messenger RNA; MicroRNAs; Modeling; Molecular; Molecular Target; Myocardial dysfunction; Myocardium; National Heart, Lung, and Blood Institute; Pathogenesis; Pathway interactions; Patient Selection; Patients; Persons; Pharmacotherapy; Phenotype; Plasma; Preventive therapy; Prospective Studies; Prospective cohort; Proteomics; Quantitative Reverse Transcriptase PCR; RNA; Recording of previous events; Reporting; Research; Research Personnel; Risk; Role; Sampling; Signal Pathway; Specific qualifier value; Strategic Planning; Stroke; System; Testing; Time; Transcript; Untranslated RNA; Up-Regulation; Validation; Ventricular; Work; biobank; circulating microRNA; clinical heterogeneity; clinical phenotype; cohort; disorder prevention; drug development; evidence base; experience; follow-up; high risk; hypertensive; implantation; improved; inhibitor; insight; microRNA biomarkers; molecular drug target; novel; novel strategies; prevent; preventive intervention; prospective; response; retention rate; risk stratification; sex; sudden cardiac death; targeted treatment; transcriptome sequencing; transcriptomic profiling; transcriptomics

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 result in 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 pathobiology 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 prospective cohort that enrolled 615 patients with HCM during 2014-2022. In this large multi-center HCM biorepository, investigators have collected high-quality biospecimens – i.e., 615 plasma and 120 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 transcriptomically profiling both myocardium and plasma samples in parallel, 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 qRT-PCR, single-transcript RNA-FISH, and RNA-Seq. In Aim 2, we will specify signaling pathways and plasma circulating microRNAs that predict new-onset MACE using transcriptomic profiling. Finally, using an unsupervised clustering-based approach, Aim 3 will define HCM subtypes by integrating genetic, transcriptomic, proteomic, and clinical data, and determine their associations with MACE. Our prior studies 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 pathobiology and progression to MACE through examining signaling pathways by applying transcriptomic profiling to paired myocardium and plasma. Moreover, the proposed study will also derive a novel risk stratification system in HCM, which will allow us to precisely identify high-risk HCM subtypes 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 complementary and integrated 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。可以使用以防止MACE的侵入性干预措施，但可能会导致 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病理生物学的信号通路 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 在2014 - 2022年期间，正在进行的3中心前瞻性队列招募了615例HCM患者。在 这个大型的多中心HCM生物座席，研究人员收集了高质量的 生物测量 -​​ 即615血浆和120个左心室心肌。后续数据包括 每年一次的双年度访谈，病历评论和面对面的考试，> 85％的跟随 - 最新的（中值随访，3。1年）。目前的R01项目将扩展这一大型福祉 通过转录分析心肌和等离子体来表征HCM生物座 并行样本，并检查其与HCM疾病状况和MACE的关系。在 AIM 1，我们将检查心肌中信号通路失调的关联 使用QRT-PCR，单转录RNA-FISH和RNA-SEQ具有HCM疾病状态。在AIM 2中， 我们将指定信号通路和等离子体循环的microRNA，以预测新发行 使用转录组分析的痕迹。最后，使用基于无监督聚类的方法， AIM 3将通过整合遗传，转录组，蛋白质组学和临床来定义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HCM病理生物学和进展的分子机制 通过将转录组分析应用于配对的心肌和 等离子体。此外，拟议的研究还将在HCM中得出一个新的风险分层系统， 这将使我们能够精确地识别高风险的HCM亚型，这将受益于 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。调查人员在所有人方面都拥有完整而综合的专业知识 相关字段。该研究与HCM研究的NHLBI战略计划非常匹配。