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: 10171416
• 负责人: Lilei Zhang
• 金额: $ 47.47万
• 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/10171416
• 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; 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.

项目摘要 心力衰竭(HF)与50%的5年死亡率有关，而且发病率仍在上升。识别 治疗心力衰竭的新策略是临床上迫切需要的。错过的一个机会是，HF与一种 常规基因表达计划，然而，目前的治疗侧重于改善血流动力学和 神经激素环境，已经承诺的基因程序不会被逆转。我们发现了一种昼夜节律 抑制子REV-ERBα，它与心脏中接近病理驱动转录因子MEF2s结合，防止 心衰时病理基因程序激活。我们证明了REV-ERBα的药理激动剂 作为预防和晚期疾病，在各种应激状态下改善心肌肥厚和心力衰竭 稳定状态。心脏REV-ERBα和b基因缺失导致压力超负荷后心力衰竭加重 而且随着年龄的增长而自发地。此外，我们发现REV-ERBα激动剂在人类诱导的 多能干细胞来源于心肌细胞。因此，我们假设REV-ERBα抑制心脏病理 通过转录抑制异常激活的MEF2增强子进行重塑。我们的长期目标 目的是了解REV-ERBα如何抑制心肌细胞中的基因程序，并发展REV-ERBα 增强治疗心力衰竭的新策略。在这项建议中，我们有两个具体目标 目的：(1)明确REV-ERB在静息和心脏应激状态下对心肌细胞的作用；(2)确定REV-ERB在静息和心脏应激状态下对心肌细胞的作用 REV-ERBα和MEF2C在心脏重塑过程中相互作用的分子基础。完成本建议书 将对理解心脏病理重塑过程中的基因调控有重大影响 有可能扩大我们治疗心力衰竭的治疗策略。