YAP-R124me2a在肝星状细胞-ECM机械力信号传导中的作用及机制

机械力微环境在肝纤维化中的作用愈受重视。YAP介导的机械力信号传导通路是调控ECM刚度与HSCs活化相互作用的关键机制。翻译后修饰调节YAP蛋白的亚细胞定位及共转录功能，然而它们在肝纤维化中的作用未见研究。我们首次发现YAP-R124存在非对称性双甲基化修饰，HSCs活化后核内增多，更为重要的是该修饰特异性结合STAT3并影响其转录活性。STAT3是调控肝纤维化进展的重要转录因子。本课题拟以YAP-R124me2a为靶点，探讨该修饰对肝纤维化进程的影响；利用质谱分析、ChIP-seq及Biacore等探索该修饰影响YAP与STAT3结合及协同转录机制；并通过刚度梯度及3D细胞培养等探索其调控HSCs与ECM相互作用的细胞学机制。本课题将阐明YAP-R124me2a在肝纤维化中的作用及机制，初步明确纠正ECM-HSCs机械力传导失衡对肝纤维化的疗效，有望为临床治疗慢性肝病提供新的靶点与策略。

Mechanical microenvironment has become increasingly important in the development of hepatic fibrosis. YAP-mediated mechanotransduction pathway is a critical mechanism regulating the interaction between HSCs activation and ECM stiffness. Post-translational modifications regulate the subcellular localization and co-transcriptional function of YAP, but their roles in liver fibrosis have not been studied. For the first time, we found that YAP-R124 had an intrinsic asymmetric dimethylation modification, which increased in the nucleus after the activation of HSCs, and more importantly, this modification could specifically bind to STAT3 and affect its transcriptional activity. STAT3 is an important transcription factor that regulates the progression of liver fibrosis. In this study, YAP-R124me2a would be served as the target to explore its effect on the progression of hepatic fibrosis; Mass spectrometry, ChIP-seq and Biacore were used to investigate the mechanism of YAP binding to STAT3 and synergistic transcription, and the cytological mechanism of regulating the interaction between HSCs and ECM was explored by stiffness gradient and 3D cell culture. This study will elucidate the role and mechanism of YAP-R124me2a in hepatic fibrogenesis, preliminarily clarify the effect of correcting the mechanotransduction imbalance of HSCs-ECM on the progression of hepatic fibrosis, and hopefully provide new targets and strategies for clinical treatment of chronic liver diseases.