Transcriptional regulation of cardiac pathological remodeling by REV-ERBα

REV-ERBα 对心脏病理重塑的转录调节

• 批准号: 10447818
• 负责人: Lilei Zhang
• 金额: $ 45.88万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-08 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10447818
• 关键词: Address; Affect; Age; Aging; Agonist; Base Pairing; Binding; Binding Sites; Biotin; Cardiac; Cardiac Myocytes; Cardiac health; Cell Nucleus; Cells; Circadian Rhythms; Clinical; DNA; DNA Binding Domain; Dilated Cardiomyopathy; Disease; Enhancers; Exhibits; Foundations; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genome; Goals; Heart; Heart Hypertrophy; Heart failure; Human; Hypertrophy; Incidence; Intervention; Lead; LoxP-flanked allele; Modeling; Molecular; Mus; Muscle Cells; Neonatal; Output; Pathologic; Periodicity; Pharmaceutical Preparations; Pharmacology; Physiological; Prevention; Rattus; Resolution; Rest; Role; Site; Specificity; Stable Disease; Stress; Structure; Swimming; Switch Genes; Testing; Therapeutic; Time; Tissues; Transcriptional Regulation; Transgenic Organisms; Treatment Failure; Ventricular; base; cell type; chromatin modification; circadian; experimental study; gain of function; gene repression; genetic corepressor; heart function; hemodynamics; improved; in vivo; induced pluripotent stem cell; induced pluripotent stem cell derived cardiomyocytes; loss of function; mortality; mouse model; mutant; novel; novel strategies; novel therapeutic intervention; novel therapeutics; pressure; prevent; programs; recruit; stem cell differentiation; tool; transcription factor; transcriptomics; young adult

Project Summary Heart failure (HF) is associated with a 5-year mortality of 50% and the incidence is still rising. Identifying novel strategies to HF is of urgent clinical need. One missed opportunity is that HF is associated with a stereotypical gene expression program, however, the current therapy focuses on improving hemodynamics and neurohormonal milieu, the already committed gene program is not reversed. We have identified a circadian repressor REV-ERBα, which binds near pathological driver transcription factor MEF2s in the heart and prevents pathological gene program activation during HF. We demonstrated that pharmacological agonist of REV-ERBα ameliorates cardiac hypertrophy and HF during a variety of stresses both as prevention and as late disease stabilization. Cardiac deletion of REV-ERBα and b leads to exaggerated heart failure after pressure overload and spontaneously with aging. Further, we found REV-ERBα agonist has a similar effect in human induced pluripotent stem cells derived cardiomyocytes. We thus hypothesize that REV-ERBα inhibits cardiac pathological remodeling through transcriptional repression at the aberrantly activated MEF2 enhancers. Our long-term goal is to understand how REV-ERBα inhibits gene program in the cardiomyocytes and develop REV-ERBα enhancement as a novel therapeutic strategy for HF. In this proposal, we have two specific aims towards this goal: (1) define the role of REV-ERB in the cardiomyocytes at rest and under cardiac stress; (2) determine the molecular basis of REV-ERBα and MEF2c interaction during cardiac remodeling. Completion of this proposal will have significant impact in understanding gene regulation in the heart during pathological remodeling and potentially expand our therapeutic strategies for HF treatment.

项目概要 心力衰竭 (HF) 与 50% 的 5 年死亡率相关，且发病率仍在上升。识别 临床迫切需要治疗心衰的新策略。一个错失的机会是 HF 与 然而，刻板的基因表达计划目前的治疗重点是改善血流动力学和 在神经激素环境中，已经确定的基因程序不会被逆转。我们已经确定了昼夜节律 阻遏蛋白 REV-ERBα，与心脏中的病理驱动转录因子 MEF2 附近结合并阻止 心衰期间病理基因程序激活。我们证明了 REV-ERBα 的药理学激动剂 在各种压力下改善心脏肥大和心力衰竭，作为预防和晚期疾病 稳定。心脏缺失 REV-ERBα 和 b 会导致压力超负荷后严重心力衰竭 并随着衰老而自发。此外，我们发现 REV-ERBα 激动剂在人类诱导的 多能干细胞衍生的心肌细胞。因此，我们假设 REV-ERBα 抑制心脏病理学 通过异常激活的 MEF2 增强子的转录抑制进行重塑。我们的长期目标 是了解REV-ERBα如何抑制心肌细胞中的基因程序并发展REV-ERBα 增强作为心力衰竭的新治疗策略。在本提案中，我们有两个具体目标 目标：（1）定义REV-ERB在静息和心脏应激下心肌细胞中的作用； (2) 确定 心脏重塑过程中 REV-ERBα 和 MEF2c 相互作用的分子基础。完成本提案 将对理解心脏病理重塑过程中的基因调控产生重大影响 潜在地扩展我们的心力衰竭治疗策略。