FXR受体通过线粒体途径诱导心肌缺血/再灌注损伤的新机制：孤儿受体SHP的关键作用

我们前期研究发现核受体FXR是一种新的心肌细胞凋亡的调控因子并参与缺血/再灌注损伤（Eur Heart J, 2012），但其潜在机制不明。我们在预实验中发现，孤儿受体SHP可被FXR受体诱导出核并靶向作用于线粒体，可能在FXR受体介导的心肌缺血/再灌注损伤中扮演关键角色。在前期工作基础上，本项目将首次对FXR-SHP核受体级联通路在缺血心肌再灌注及心梗后重塑中的作用进行研究，拟通过在体和离体实验，应用分子荧光探针结合激光扫描共聚焦、在体/离体基因沉默或敲除技术以及活体小动物影像技术等先进实验方法，重点研究这条新的核受体信号通路参与缺血心肌再灌注损伤的深入机制，阐明 FXR下游靶蛋白SHP受体介导的信号通路在诱导心肌线粒体功能失调、细胞凋亡和缺血/再灌注损伤等一系列病理过程中所起的关键作用，为治疗缺血性心脏病提供新的技术路线和筛选新的基因靶点。

Our previous studies suggested that nuclear receptor farnesoid-X-receptor (FXR) is a novel apoptosis mediator and contributes to the myocardial ischemia/reperfusion injury (Eur Heart J, 2012). However, the underlying signaling mechanism has not been clearly elucidated. In the preliminary experiment, we found that the FXR downstream target protein, small heterodimer partner (SHP), could be activated and translocate from the nucleus to mitochondria, which might play a critical role in the FXR-induced apoptotic pathway in the setting of myocardial ischemia/reperfusion injury. The present study was designed to investigate the role of FXR-SHP cascade pathway in the setting of myocardial ischemia/reperfusion injury and post-infarction remodeling, using molecuar fluorecent probe combined with laser scanning confocal microscope, in vivo/in vitro siRNA gene silencing or gene knockout, and in vivo small animal image techniques. The results of our study would highlight the importance of FXR-SHP cascade signaling pathway in the setting of myocardial ischemia/reperfusion injury and post-infarction remodeling, and provide novel target in treating ischemic heart diseases.