Cardiac Circadian Clock and Dilated Cardiomyopathy

心脏生物钟和扩张型心肌病

• 批准号: 10245139
• 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/10245139
• 关键词: Address; Adult; Affect; Age; Agonist; Binding; Cardiac; Cardiac Myocytes; Cell Respiration; ChIP-seq; Chromatin; Chronotherapy; Closure by clamp; Complex; 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 Contractilities; Heart Hypertrophy; Heart failure; Housekeeping; Human; Isotopes; Knock-out; 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; Signal Transduction; Sleep; Techniques; Time; Tracer; Troponin; XCL1 gene; 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.

项目摘要/摘要 Rev-ERBα/β是分子昼夜节律时钟的可药物成分。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的Rev-ERBα/β双重敲除（Rev- CKO）鼠标模型。 Rev-Cko小鼠表现出逐渐扩张的心肌病，导致心力衰竭和 完全致死。在成年Rev-CKO小鼠中，Rev-ERBα的诱导型心肌细胞特异性重新表达 同一期，但不是反相，其内源性振荡模式返回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。 RNA-Seq，芯片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改变 在Rev-Cko心中，尤其是在晚上。我们假设Rev-erb通过 代谢基因的预期表达和昼夜脂质的临时协调 心肌。我们将确定心脏REV-ERB如何调节基因表达振荡以及如何调节 振荡会影响心脏功能；描述心脏Rev-ERB介导的分子机制 基因表达调节；探索心脏REV-ERB如何调节心肌代谢；和特征 Rev-erb激动剂治疗扩张的心肌病。使用新的小鼠模型，一种新型的相限制重新限制 表达技术和综合多词方法，我们旨在为如何提供有关如何如何提供的见解 昼夜节律时钟调节基因表达和“管家”功能，例如能量代谢 心力衰竭病理生物学中的心肌细胞，这可能为新颖的智力奠定基础 扩张心肌病的年代疗法策略。