Cardiac Circadian Clock and Dilated Cardiomyopathy

心脏生物钟和扩张型心肌病

• 批准号: 10625462
• 负责人: Zheng Sun
• 金额: $ 48万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10625462
• 关键词: ATAC-seq; Acceleration; Address; Adult; Affect; Age; Agonist; Binding; Cardiac; Cardiac Myocytes; Cell Respiration; ChIP-seq; Chromatin; Chronotherapy; Closure by clamp; Complex; Darkness; Data; Defect; Deterioration; Dietary Fats; Dilated Cardiomyopathy; Energy Metabolism; Functional disorder; Gene Expression; Gene Expression Profiling; Gene Expression Regulation; Genes; Genome; Genomics; Glycolysis; Heart; Heart Hypertrophy; Heart failure; Housekeeping; Human; Isotopes; Knock-out; Knockout Mice; Light; Lipids; Mediating; Medicine; Metabolic; Metabolic dysfunction; Metabolism; Mitochondria; Modeling; Molecular; Morphologic artifacts; Mus; Mutate; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardium; Outcome; Pattern; Phase; Phenotype; Proteins; Proteomics; Reperfusion Therapy; Respiration; Signal Transduction; Sleep; Techniques; Tracer; Troponin; antagonist; carbohydrate metabolism; circadian; circadian pacemaker; experimental study; fatty acid oxidation; heart function; in vivo; insight; metabolomics; mouse model; multiple omics; novel; nuclear respiratory factor; overexpression; oxidation; pressure; transcriptome; transcriptome sequencing

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.

项目概要/摘要 Rev-erbα/β 是分子生物钟的可药物成分 Rev-erb 如何调节心脏。 我们生成了心肌细胞特异性 Rev-erbα/β 双敲除（Rev-）。 Rev-CKO 小鼠模型表现出进行性扩张型心肌病，导致心力衰竭和 在成年 Rev-CKO 小鼠中，Rev-erbα 可诱导心肌细胞特异性重新表达。 同相，但不是反相，以其内源性振荡模式挽救了收缩缺陷和心力衰竭， 证明 Rev-erb 振荡本身在心脏功能中的重要性。 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 Rev-CKO 心脏，尤其是在晚上，我们认为 Rev-erb 通过调节心脏功能。 代谢基因预期表达和每日脂质可用性的时间协调 我们将确定心脏 Rev-erb 如何调节基因表达振荡以及如何 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；探讨心脏 Rev-erb 如何调节心肌代谢； Rev-erb 激动剂治疗扩张型心肌病。 表达技术和综合多组学方法，我们的目标是提供新的见解 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病理学中的作用，这可能为新颖的研究奠定知识基础 扩张型心肌病的时间治疗策略。