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 发病机制的信号通路 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 中心队列研究，在 2014 年至 2020 年期间招募了 560 名 HCM 患者。 大型多中心HCM生物样本库，研究人员采集了高质量的生物样本—— 例如，血浆、左心室心肌的随访数据包括每年两次的访谈、医疗。 每年进行记录审核和现场检查，迄今为止随访率超过 85%（中位随访率、 3.1 年）目前的 R01 项目将扩展这个大型的特征良好的 HCM 生物样本库。 通过对血浆和心肌样本进行蛋白质组学分析，并检查它们 与 HCM 疾病状态和 MACE 的关系 在目标 1 中，我们将检查 HCM 疾病状态和 MACE 之间的关联。 使用分子技术研究 HCM 疾病状态下心肌信号通路失调 在目标 2 中，我们将采用生物学方法（例如 mRNA 的 RT-PCR、ELISA）和蛋白质组学分析。 使用蛋白质组学确定信号通路失调与 MACE 的关联 最后，使用系统来分析并指定预测事件 MACE 的信号通路。 生物学方法，目标 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。 通过揭示 HCM 发病机制和进展为 MACE 的分子机制 使用血浆和心肌中的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，该系统 将使我们能够准确识别高风险 HCM 亚群，这些亚群将受益于 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拥有整合和互补的专业知识。 该研究与 NHLBI 的 HCM 研究战略计划非常吻合。