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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要肥厚型心肌病 (HCM) 是最常见的遗传性心脏病，其病因主要不良心血管事件 (MACE) – 例如心律失常、心力衰竭和突发事件可以采用侵入性干预措施来预防 MACE，但可能会导致死亡。目前的风险分层策略对于预测哪些患者的能力有限。会发展 MACE 并从预防性干预措施中获益最多。了解基因突变介导 HCM 病理学的信号通路这些主要的知识差距阻碍了 HCM 中预防 MACE 的努力。哈佛-哥伦比亚多中心肥厚性心肌病 (HCM2) 生物样本库是一个正在进行的 3 中心前瞻性队列研究，在 2014 年至 2022 年期间招募了 615 名 HCM 患者。在这个大型多中心 HCM 生物样本库中，研究人员收集了高质量的生物样本 – 即 615 份血浆和 120 份左心室心肌随访数据。每年两次访谈、病历审查和现场检查，跟踪率超过 85% 迄今为止（中位随访时间为 3.1 年），目前的 R01 项目将扩展这个大型油井。通过对心肌和血浆进行转录组学分析来表征 HCM 生物库平行样本，并检查它们与 HCM 疾病状态和 MACE 的关系。目标 1，我们将检查心肌信号通路失调的关联在目标 2 中，使用 qRT-PCR、单转录 RNA-FISH 和 RNA-Seq 来了解 HCM 疾病状态。我们将指定预测新发疾病的信号通路和血浆循环 microRNA 最后，使用基于无监督聚类的方法，目标 3 将通过整合遗传、转录组、蛋白质组和临床来定义 HCM 亚型数据，并确定它们与我们之前的研究和初步工作贷款的关联。目前的 R01 项目将提供一个独特的机会。通过以下方式揭示 HCM 病理学和进展为 MACE 的分子机制通过对配对心肌应用转录组学分析来检查信号通路此外，拟议的研究还将得出一种新的 HCM 风险分层系统，这将使我们能够准确识别高风险 HCM 亚型，这些亚型将受益于该项目将为制定有针对性的预防干预措施提供强有力的证据基础。通过调节特定的药物疗法来预防 HCM 发病机制和 MACE 研究人员在所有信号通路方面都有互补和综合的专业知识。该研究与 NHLBI 的 HCM 研究战略计划非常吻合。