肝内胆管异常增生是胆汁性肝纤维化发生的关键病理环节，Notch信号通路活化是其关键信号转导机制，但目前尚缺乏有效的干预措施，成为亟需解决的关键科学问题。本课题基于前期对Notch信号促进胆汁性肝纤维化发生，以及黄芪汤对Notch信号及其负调控因子Numb影响的研究，提出“Numb对胆汁性肝纤维化的发生可能具有重要的干预作用，黄芪汤干预胆汁性肝纤维化的作用机制与抑制肝祖细胞Notch信号通路的活化有关，而Numb可能是其关键作用靶点”假说。以肝祖细胞Numb基因水平与胆汁性肝纤维化的发生及其对黄芪汤抗纤维化作用的影响为主要研究内容，拟采用胎肝祖细胞基因改造移植技术，分离绿色荧光蛋白转基因SD大鼠胎肝祖细胞，使Numb基因过表达或表达下降后植入胆总管结扎SD大鼠肝脏，并予黄芪汤干预，结合体外实验，揭示Numb与肝纤维化的关系以及黄芪汤治疗胆汁性肝纤维化的效应机制，为该方的临床应用提供科学依据。

Abnormal proliferation of bile duct is a key pathological process in cholestatic liver fibrosis and Notch signal activation is the major signal transduction mechanism in this process. So far there are no an effective therapeutics for cholestatic liver fibrosis which is an urgent scientific problem need to be resolved. Based on our previous research, Notch signaling promotes cholestatic liver fibrogenesis, as well as effects of Huangqi decoction on Notch signaling and its negative regulator Numb, we hypothesized that " Numb might play an important role in preventing cholestatic liver fibrogenesis. Huangqi decoction could prevent cholestatic liver fibrosis by inhibiting activation of Notch signaling in hepatic progenitor cells; While Numb, an inhibitor of Notch signaling, might be a key target of this decoction". Our study will focus on the association between Numb expression in hepatic progenitor cells and cholestatic liver fibrogenesis, as well as anti-fibrotic effects of Huangqi decoction on regulating Numb expression. The fetal hepatic progenitor cells (HPCs) are isolated from GFP-transgene Sprague Dawley (SD) rats, and the HPCs with Numb over expression or Numb-knockdown by genetic modification will be transplanted into livers of common bile duct ligation (BDL) rats respectively; and these rats are treated with Huangqi decoction at the same time. By combining results with in vitro experiments, the relationship between Numb expression and liver fibrosis, and effect of Huangqi Decoction against cholestatic liver fibrosis through regulating Numb expression will be revealed. The project will elucidate the molecular mechanism of Huangqi decoction against cholestatic liver fibrosis and provide scientific evidence for its clinical application.