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Cardiac Circadian Clock and Dilated Cardiomyopathy

心脏生物钟和扩张型心肌病

基本信息

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
项目类别：
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

项目摘要

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.

项目总结/文摘