肝祖细胞作为双潜能肝干细胞，在肝脏再生中发挥重要作用，进一步分化为肝细胞和胆管细胞。两者的协调增殖及肝内胆管通道的有效形成，是肝脏组织结构和功能恢复的重要保证。Notch-RBPJ通路对维持肝祖细胞的稳态，调控其分化增殖，尤其对胆管的再生重建、损伤至关重要。我们前期研究发现肝脏特异性敲除RBPJ基因的小鼠，在围生产期存在胆管发育异常，出现胆汁淤积。为此，我们提出假说：Notch-RBPJ信号通路通过调控肝祖细胞增殖分化，介导胆管再生与重建，是肝脏再生的关键机制。为验证这一假说，我们拟通过基因敲除小鼠的体内模型和体外细胞实验，采用谱系示踪技术在小鼠中转入Rosa26报告基因来示踪肝祖细胞；Cre-loxP技术在肝脏特异性敲除RBPJ基因等手段，探讨该通路对肝祖细胞的增殖分化、胆管再生与重建的作用，并明确其下游靶基因调控机制。为探索肝脏再生，尤其是胆管再生与重建提供新的靶点及分子机制。

Liver progenitor cells are bipotentiality cells that can differentiate to hepatocytes and biliary epithelial cells.In the setting of liver injury and diseases, liver progenitor cells play an improtant role in the liver regeneration and repair process. The coordinated proliferation of hepatocytes and biliary epithelial cells to efficiently form intrahepatic biliary ducts is pivotal to the structure and funciton of liver regeneration. Notch-RBPJ is very important in the maintance of hepatic progenitor cells homeostasis, proliferation, differentiation, especially in bile duct injury and regeneration. In previous study we found that liver specific RPBJ knockout would lead to bile duct develop abnormalities in perinatal and cholestasis. Therefore, we hypothesize that Notch-RBPJ plays a significant role in the progress in liver disease by regulating the proliferation and differentiation of liver progenitor cells, bile duct rebuild and mediate the bile duct injury and cholestasis. To test this hypothesis, we will apply genetic mice models, cre-loxp system for lineage tracing by Rosa 26 gene report and RBPJ gene knockout especially in liver. We will explore the mechanism of Notch-RBPJ pathway in regulating liver progenitor cells and bile duct reconstruction, and analyze the effect of the pathway in regulating of target genes. It would not help us to understand the machinery in liver regeneration, but also provide the evidence for therapeutic target and pathogenesis of bile duct reconstruction and regeneration.