Cardiac Circadian Clock and Dilated Cardiomyopathy

项目总结/摘要 Rev-erbα/β是分子生物钟的药物成分。心脏Rev-erb如何调节心脏 功能尚未在体内研究。我们产生了心肌细胞特异性Rev-erbα/β双敲除（Rev- CKO）小鼠模型。Rev-CKO小鼠表现出导致心力衰竭的进行性扩张型心肌病， 完全致命在成年Rev-CKO小鼠中，可诱导的心肌细胞特异性Rev-erbα再表达， 同相，但不是反相，其内源性振荡模式挽救了收缩缺陷和心力衰竭， 证明了Rev-erb振荡本身在心脏功能中的重要性。RNA-seq，ChIP-seq， 代谢组学和代谢示踪剂研究揭示了线粒体氧化代谢的深刻变化 尤其是在晚上我们假设Rev-erb通过调节心脏功能， 代谢基因的预期表达和昼夜脂质可用性的时间协调 心肌我们将确定心脏Rev-erb如何调节基因表达振荡， 振荡影响心脏功能;描绘心脏Rev-erb介导的分子机制 基因表达调控;探索心脏Rev-erb如何调节心肌代谢;并表征 rev-erb激动剂治疗扩张型心肌病。使用一种新的小鼠模型，一种新的相位限制性受体， 表达技术，和综合多组学方法，我们的目标是提供新的见解，如何 生物钟调节基因表达和“管家”功能，例如能量代谢 心肌细胞在心力衰竭的病理生物学中的作用，这可能为新的 扩张型心肌病的时辰治疗策略

Project Summary/Abstract Rev-erbα/β are druggable components of the molecular circadian clock. How cardiac Rev-erb regulates heart function has not been studied in vivo. We generated a cardiomyocyte-specific Rev-erbα/β double knockout (Rev- CKO) mouse model. Rev-CKO mice display progressive dilated cardiomyopathy that leads to heart failure and complete lethality. In adult Rev-CKO mice, inducible cardiomyocyte-specific re-expression of Rev-erbα that is in-phase, but not anti-phase, with its endogenous oscillation pattern rescued contractile defects and heart failure, demonstrating the importance of the Rev-erb oscillation per se in cardiac functions. RNA-seq, ChIP-seq, metabolomics, and metabolic tracer studies revealed profound alterations in mitochondrial oxidative metabolism in the Rev-CKO heart, particularly at night. We hypothesize that Rev-erb regulates heart function through temporal coordination of anticipatory expression of metabolic genes and the diurnal lipid availability to the myocardium. We will determine how cardiac Rev-erb regulates gene expression oscillation and how the oscillation affects cardiac functions; delineate the molecular mechanism underlying cardiac Rev-erb-mediated gene expression regulation; explore how cardiac Rev-erb regulates myocardial metabolism; and characterize Rev-erb agonist in treating dilated cardiomyopathy. Using a new mouse model, a novel phase-restricted re- expression technique, and integrative multi-omics approaches, we aim to provide new insights into how the circadian clock regulates gene expression and “housekeeping” functions such as energy metabolism in cardiomyocytes in the pathobiology of heart failure, which can potentially lay an intellectual groundwork for novel chronotherapy strategies of dilated cardiomyopathy.