核受体FXR-SHP级联通路参与心肌细胞肥大与心肌成纤维细胞增殖的双重调控及其分子机制

我们前期工作在心肌细胞和心肌成纤维细胞中发现一条具有功能活性的核受体FXR-SHP级联通路，预实验提示这条通路可能参与心肌细胞肥大与心肌成纤维细胞增殖的双重调控，但目前尚无关于该通路对心肌肥厚作用的相关报道。在前期工作基础上，本项目拟通过在体和离体实验，对核受体FXR-SHP级联信号通路在心肌肥厚中的作用及其分子机制进行研究：一方面应用基因敲除或基因过表达小鼠，在整体动物水平上研究FXR-SHP级联通路在主动脉缩窄和血管紧张素II诱导的心肌肥厚中的作用及其关键分子通路；另一方面运用原代培养小鼠心肌细胞和心肌成纤维细胞，通过重组腺病毒介导基因过表达或基因沉默技术，在细胞水平上探讨FXR-SHP级联通路对心肌细胞肥大及心肌成纤维细胞增殖的作用及相关机制，研究结果不仅将为心肌肥厚的基础机制增添新的内容，并为心力衰竭的防治提供新思路和新靶点。

In our previous studies we found a novel FXR-SHP nuclear receptor signaling cascade presented in both cardiomyocyte and cardiac fibroblast (Eur Heart J. 2013; 34:1834-45). Our recent preliminary experiment further suggested that FXR-SHP signaling cascade might regulate both cardiomyocyte hypertrophy and cardiac fibroblast proliferation. However, to date, the role of FXR-SHP signaling cascade in pathological myocardial hypertrophy and the underlying mechanisms have not been investigated. Based on our previous findings, we design the present study to investigate the role of FXR-SHP signaling cascade in the setting of pathological myocardial hypertrophy. On one hand, we will use in vivo gene knockout or overexpression techniques to determine the role of FXR-SHP signaling cascade in both transverse aortic constriction and angiotensin II-induced cardiac hypertrophy. On the other hand, we will use the in vitro gene overexpression or siRNA gene silencing techniques to investigate the role of FXR-SHP signaling cascade in the in vitro cardiomyocyte hypertrophy and cardiac fibroblast proliferation models. The results of our study would highlight the critical role of FXR-SHP signaling cascade in the setting of pathological myocardial hypertrophy, and provide novel targets in treatment and prevention of chronic heart failure.