Hippo信号通路调控肝星状细胞活化机制研究

肝星状细胞是肝纤维化过程中肌成纤维细胞的主要来源。肝纤维化过程中，静息的肝星状细胞如何激活分化成为肌成纤维细胞是亟待回答的重要科学问题。YAP转录因子是Hippo信号通路中主要的效应蛋白。基于前期工作发现，我们提出肝星状细胞活化过程中Hippo信号通路发挥复杂的调控功能，依赖于TEAD的经典Hippo信号通路抑制肝星状细胞活化，而不依赖于TEAD的非经典Hippo信号通路促进肝星状细胞活化。本项目中，我们将利用CCl4、TAA、BDL等肝纤维化小鼠模型、静息与活化肝星状细胞特异性基因敲除小鼠模型、原代肝星状细胞体外活化模型，研究肝星状细胞活化过程中Hippo-YAP信号通路的动态变化，及其在肝星状细胞活化与肝纤维化过程中时空特异性的功能与作用机制，以期为发展有效的肝纤维化治疗策略和药物提供线索。

Hepatic stellate cells (HSCs) are the major source of myofibroblasts in liver fibrosis. It remains to be elucidated how quiescent HSCs are activated and trans-differentiated to myofibroblasts during liver fibrosis development. YAP transcription factor is the major effector of Hippo signaling pathway. We hypothesize that TEAD-dependent and -independent Hippo signaling plays distinct roles in regulating HSC activation. In this project, we will utilize liver fibrosis mouse models, quiescent and activated HSC-specific gene knockout mouse model and primary HSCs in vitro activation model to study the dynamic changes of Hippo-YAP signaling, and how Hippo-YAP signaling regulates HSC activation and liver fibrosis.