昼夜节律对梗死后心肌修复和重构的影响：生物钟核受体RORα信号通路的关键作用

心血管事件发生有明显昼夜节律性，但其机制及临床意义尚未阐明。本中心EARLY-MYO临床研究(NCT01930682)多模态影像亚组分析发现，心梗发病昼夜节律与早期心肌损伤和慢性期左室重构密切相关。申请者前期研究首先发现生物钟核受体RORα在心肌中存在并具有独特的功能活性，是一种新的内源性保护性受体，但RORα是否参与心梗发病的昼夜节律及对梗死后重构的调控，国内外均无报道。我们的最新预实验结果提示，RORα信号通路可能是联结生物昼夜节律与梗死心肌修复和重构的重要节点，可能通过调控细胞生存关键通路而改变心脏细胞命运，最终影响梗死后早期心脏破裂和慢性期重构及心衰发生。本课题拟利用前期构建的心肌活体评价和核受体功能研究平台，结合分子生物学和多模态影像，综合应用动物、细胞与临床标本等研究模型，探讨生物钟核受体RORα作为新的分子靶点对梗死后修复与重构的影响及机制，为梗死后心力衰竭的防治提供新思路。

Occurrence of adverse cardiac events follows a circadian rhythm as evinced in our previous studies documenting a close association between time-of-day oscillation in MI onset and post-infarction early-phase myocardial impairment and chronic-phase left ventricular remodeling (CMR subgroup analysis of EARLY-MYO trial), and a novel functional role for nuclear circadian receptor RORα as an endogenous myocardial protective factor. We therefore hypothesized that by regulating the functions and fates of cardiomyocytes and cardiac fibroblasts, the RORα signaling pathway might link circadian rhythm and post-infarction myocardial healing and remodeling, thereby eventually affecting the incidence of early-phase cardiac rupture, and chronic-phase ventricular remodeling and heart failure. By using the in vivo cardiac imaging and nuclear receptor research platforms established at our center, along with molecular biology and multi-modality imaging techniques, the present project seeks novel insight into the prevention and treatment of post-infarction heart failure by exploring the potential roles and underlying mechanisms of the nuclear circadian receptor RORα in the pathogenesis of post-infarction healing and remodeling.