代谢重构是研究心力衰竭的新靶点，组蛋白去乙酰化酶（HDAC）对环境相关心肌重塑有重要作用，我们已发现肌肉特异性敲除HDAC3（MCH3-KO）可导致高脂饮食所诱发的心衰。本项目拟在前期建立MCH3-KO小鼠基础上，明确脂代谢异常可致心肌代谢重构，阐明HDAC3可影响心肌线粒体功能；Co-IP检测HDAC3敲除后雌激素受体（ER）存在状态；结合启动子基因工程及FLEX系统的重组AAV载体技术，特异性诱导心肌过表达雌激素相关受体（ERR），在体验证ERR是否介导HDAC3调节心肌脂代谢；利用腺病毒shRNA载体，建立小鼠心肌细胞原代培养的体外HDAC3敲除体系，研究HDAC3对ERR、ER与DNA相互作用的调控机制；建立小鼠去势及激素替代模型，结合ChIP-seq及RNA-seq，探讨雌激素在小鼠ERR相关脂代谢调控中的作用机理；以期揭示HDAC3通过ERR信号通路影响心肌脂代谢的表遗传机制。

Metabolic remodeling underlies cardiomyopathy and heart failure. Histone deacetylases (HDACs) play important roles on environment-dependent myocardial remodeling. We have found muscle-specific HDAC3 knockout cause fatal heart failure only when mice are fed high fat diet, providing a unique model for dietary lipid-induced heart failure. In the proposed study, we will address how HDAC3 regulates myocardial lipid metabolism and mitochondrial function through estrogen related receptor (ERR). We will determine whether hyperlipidemia is the major causative environmental factor for myocardial remodeling; test whether heart-specific overexpression of ERR could rescue lipid-induced fatal heart failure; characterize molecular interplays between estrogen receptor (ER), ERR, and HDAC3 using Co-IP and ChIP in primary cardiomyocytes with adenovirus-mediated genetic manipulation; address the role of estrogen in lipid-induced myocardial remodeling using ovariectomy and hormone replacement approaches; investigate how estrogen and ERR regulates cardiac lipid metabolism using ChIP-seq and RNA-seq. Our study will provide novel insights into epigenomic mechanisms of how HDAC3 regulates myocardial lipid metabolism through ERR, which has profound clinical implications given availability of many small molecule estrogen modulators and HDAC inhibitors.