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：
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
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/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

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.

项目摘要心力衰竭（HF）与50％的5年死亡率有关，并且此事件仍在上升。识别 HF的新型策略是紧迫的临床需求。一个错过的机会是HF与然而，刻板印象的基因表达程序，当前的疗法着重于改善血液动力学和神经激素环境，已经承诺的基因程序没有逆转。我们已经确定了昼夜节律抑制器Rev-ERBα，该抗体在病理驱动器转录因子MEF2接近心脏中的结合并防止 HF期间的病理基因程序激活。我们证明了Rev-erbα的药物激动剂在预防和晚期疾病的各种应力期间，可以改善心脏肥大和HF 稳定。 Rev-ERBα和B的心脏缺失导致压力超负荷后夸张的心力衰竭并随着衰老而赞助。此外，我们发现Rev-erbα激动剂对人类诱导的作用相似多能干细胞衍生出心肌细胞。因此，我们假设Rev-ERBα抑制心脏病理通过异常激活的MEF2增强剂的转录表示重塑。我们的长期目标是要了解Rev-ERBα如何抑制心肌细胞中的基因程序并发展Rev-erbα 增强是HF的新型治疗策略。在此提案中，我们有两个具体的目标目标：（1）定义Rev-erb在静止和心脏应激下的心肌细胞中的作用；（2）确定心脏重塑期间Rev-ERBα和MEF2C相互作用的分子基础。完成此提案在病理重塑期间，将对理解心脏中的基因调节产生重大影响有可能扩大我们的HF治疗策略。