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 心源性死亡有创干预可预防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病理学的信号通路 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中心前瞻性队列研究，在2014-2022年期间招募了615例HCM患者。在 在这个大型多中心HCM生物储存库中，研究人员收集了高质量的 生物标本--即，615例血浆和120例左心室心肌。随访数据包括 一年两次的面谈、医疗记录审查和每年的亲自检查，>85%的人遵循- 截至目前（中位随访时间为3.1年）。目前的R 01项目将延长这口大井- 通过心肌和血浆的转录组学分析表征HCM生物储存库 平行样本，并通过检查它们与HCM疾病状态和MACE的关系。在 目的1，我们将研究心肌中信号通路失调的相关性， 使用qRT-PCR、单转录RNA-FISH和RNA-Seq检测HCM疾病状态。在目标2中， 我们将详细说明信号通路和血浆循环microRNAs， 使用转录组学分析的MACE。最后，使用基于无监督聚类的方法， 目的3将通过整合遗传学、转录组学、蛋白质组学和临床来确定HCM亚型 数据，并确定其与MACE的关联。我们先前的研究和初步工作 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， 通过以下方式揭示HCM病理生物学的分子机制和进展为MACE 通过对成对心肌应用转录组学分析来检查信号通路， 等离子体此外，拟议的研究还将得出一个新的HCM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， 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方面都具有互补和综合的专门知识， 相关领域。该研究与NHLBI HCM研究战略计划相匹配。