Transcriptional regulation of cardiac pathological remodeling by REV-ERBα

REV-ERBα 对心脏病理重塑的转录调节

基本信息

批准号：
9927666
负责人：
Lilei Zhang
金额：
$ 48.98万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
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/9927666
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 therapeutics pressure prevent programs recruit stem cell differentiation tool transcription factor transcriptomics young adult

项目摘要

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。临床迫切需要治疗心力衰竭的新策略，而错过的一个机会是心力衰竭与一种疾病有关。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 REV-ERBα 和 b 的心脏缺失会导致压力超负荷后严重的心力衰竭。此外，我们发现 REV-ERBα 激动剂在人体诱导中具有类似的效果。多能干细胞衍生的心肌细胞因此截获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这项提案中，我们有两个具体目标。目标：(1) 确定 REV-ERB 在静息和心脏应激状态下心肌细胞中的作用；(2) 确定 REV-ERB 在心肌细胞中的作用；心脏重塑过程中 REV-ERBα 和 MEF2c 相互作用的分子基础完成该提案。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。