EPS8通过EGFR通路调控胆道梗阻肝切后肝脏再生的机制研究

肝脏再生能力是影响患者肝部分切除术后恢复的重要因素。短期胆道梗阻虽未引起肝纤维化等损伤，但仍能减弱肝切后肝再生能力，而具体机制不明。既往研究报道，EGFR通路在肝切后肝再生过程中起着关键作用；而EPS8可通过与EGFR直接结合影响EGFR通路的激活。前期实验发现：相比于正常小鼠，胆道梗阻小鼠肝脏EPS8表达降低，EGFR通路抑制；胆道梗阻小鼠肝切后的肝再生能力减弱，EGFR通路激活减弱。因而推测，短期胆道梗阻可通过抑制EPS8表达，减弱EGFR通路的激活，进而减慢肝切后的肝再生过程。本项目将构建EPS8基因敲除小鼠，建立胆道梗阻、肝部分切除等模型，结合胆盐刺激肝脏细胞等，从动物与细胞水平阐明EPS8介导的EGFR通路改变在此过程中的作用与分子机制；使用临床标本分析EPS8、EGFR等与胆道梗阻临床特征相关性，为胆道梗阻背景下肝部分切除患者术前评估及术后并发症防治提供新的理论依据与干预靶点。

The ability of liver regeneration is an important factor affecting the recovery of patients after partial hepatectomy. Although short-term biliary obstruction does not cause liver fibrosis and other serious liver damage, it can still weaken the ability of liver regeneration after hepatectomy, and the underlying mechanism has not been fully elucidated. Previous studies have reported that EGFR pathway plays a critical role in the process of liver regeneration after hepatectomy, and EPS8 affects the activation of EGFR pathway through direct binding with EGFR. Previous experiment found that, compared with normal mice, the expression of EPS8 in the liver of biliary obstruction mice was reduced, and the EGFR pathway was inhibited. And the ability of liver regeneration and the activation of EGFR pathway in mice with biliary obstruction were significantly weakened after partial hepatectomy. Therefore, it is speculated that short-term biliary obstruction reduces the activation of the EGFR pathway by inhibiting the expression of EPS8, thereby slowing the liver regeneration process after hepatectomy. This project will construct EPS8 gene knockout mice, establish models such as biliary obstruction and partial hepatectomy, and stimulate liver cells with bile salt to clarify the regulatory role and molecular mechanism of EPS8 mediated EGFR pathway change in this process from animal and cell levels. In addition, this project will use clinical specimens to analyze the correlation between expression of EPS8 etc. and clinical characteristics of biliary obstruction, so as to provide new theoretical basis for the preoperative assessment and the prevention and treatment of postoperative complications for patients with biliary obstruction that undergo partial hepatectomy.