肝纤维化是各种慢性肝病向肝硬化及终末期肝病发生发展过程中的关键步骤，是影响肝病预后的重要环节。该进程中肝祖细胞(HPC)如何定向分化为肝细胞分子机制尚不清楚。我们发现沉默YB-1和过表达YB-1分别促进和抑制白蛋白等肝细胞标志物表达；沉默自噬相关基因7（Atg7）降低自噬活化，从而降低白蛋白等表达，说明YB-1和Atg7均可影响HPC向肝细胞分化，ChIP-seq表明Atg7启动子区有YB-1结合域。基于此本课题拟从细胞水平探索YB-1如何调控Atg7影响自噬并对HPC向肝细胞分化发挥作用并从体内水平论证这一过程，阐明YB-1和Atg7表达水平与肝损伤、肝纤维化相关性。最后观察慢性乙肝和非酒精性脂肪性肝炎肝纤维化临床标本中YB-1和Atg7表达水平同HPC分化、肝损伤及肝纤维化程度的关联。为高效促进HPC向肝细胞分化及临床应用HPC治疗肝纤维化提供理论及实验依据。

Liver fibrosis is considered to be the critical step during the progression to the advanced stage of cirrhosis in any chronic liver disease （CLDs）which affects the prognosis of CLDs.It is unclear that the exact molecular mechanisms underling how hepatic progenitor cells (HPC) differentiate into hepatocytes during liver fibrosis. In our study, we found that knockdown and overexpression of Y-box binding protein-1（YB-1）might reduce and facilitate albumin expression of hepatocytic markers, respectively. Knockdown of autophagy-related gene 7(Atg7) repressed activation of autophagy, and then reduced albumin expression of hepatocytic markers. It implied that both of YB-1 and Atg7 had effect on hepatic differentiation of HPC. ChIP-seq assay demonstrated that the binding site of YB-1 locates in the region of Atg7 promotor. The aim of our study is to examine how YB-1 effect autophagy by regulating Atg7, and then effect hepatic differentiation of HPC in vitro and in vivo, respectively. We will also clarify the correlation of expression of YB-1, Atg7 and liver injury, fibrosis. Finally, the expression of YB-1, Atg7 and their association with hepatic differentiation of HPC, liver injury and fibrosis observed in patients with chronic hepatitis B or nonalcoholic steatohepatitis will be elucidated. The results of the study will contribute to further the molecular mechanisms of YB-1regulates Atg7 in the process of hepatic differentiation of HPC and effection of it on liver injury,thus provides a new theoretical and experimental basis for promoting hepatic differentiation of HPC and appling HPC to treatment of chronic liver diseases.