Transcriptional regulation of cardiac pathological remodeling by REV-ERBα

项目摘要 心力衰竭（HF）与50%的5年死亡率相关，并且发病率仍在上升。识别 临床上迫切需要新的治疗HF的策略。一个错过的机会是HF与一种 然而，常规的基因表达程序，目前的治疗集中在改善血液动力学和 在神经激素环境中，已经承诺的基因程序不会逆转。我们已经确定了一个昼夜节律 阻遏物REV-ERBα，其在心脏中结合病理驱动转录因子MEF 2附近， HF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HF，作为预防和晚期疾病 稳定化心脏REV-ER B α和B缺失导致压力超负荷后加重心力衰竭 并且随着年龄的增长而自发地产生。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抑制心脏病理性 通过异常激活的MEF 2增强子的转录抑制进行重构。我们的长期目标 了解REV-ERBα如何抑制心肌细胞中的基因程序， 增强作为HF的新治疗策略。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心肌细胞中的作用;（2）确定REV-ERB在静息和心脏应激状态下心肌细胞中的作用。 心脏重塑过程中REV-ERBα和MEF 2c相互作用的分子基础。完成本提案 将对理解病理性重塑过程中心脏的基因调控产生重大影响， 潜在地扩展了我们用于HF治疗的治疗策略。

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.