肝细胞源外泌体LncRNA H19调控let-7/LIN28B轴促进胆道闭锁胆管增生的作用机制研究

肝内胆管异常增生是造成胆道闭锁（BA）患儿肝纤维化进展迅速及肝衰竭的重要原因，其发生机制不明，临床防治困难。我们前期研究结果提示肝细胞源外泌体长链非编码RNA H19及LIN28B在BA肝内胆管增生中起重要作用，但作用机制不明。生物信息学预测H19能海绵吸附微小RNA let-7调控LIN28B表达水平。据此我们提出假说：肝细胞能借助外泌体把H19传递给胆管上皮细胞，H19以分子海绵形式调控let-7/LIN28B信号轴，促进BA肝内胆管增生。为了验证这一假说，本课题拟从分子、细胞、组织和动物整体水平等多层面明确H19在BA肝内胆管增生中的具体作用；探讨H19表达的调控机制；确定H19对肝内胆管增生相关基因的调控；揭示H19调控LIN28B表达的分子机制。本研究将从细胞通讯这个新视点探讨H19在BA肝内胆管异常增生中的分子机制，为BA肝脏纤维化发生机制奠定基础，为临床防治提供新思路。

Hyperplasia of intrahepatic bile duct contributes to the rapid progress of liver fibrosis and liver failure in biliary atresia (BA) infants. Since the involved mechanisms are unclear, it is very hard to prevent or treat the biliary hyperplasia. Our previous studies have suggested that the hepatocyte-derived long non-coding RNA H19 and LIN28B are essential to the hyperplasia of intrahepatic bile duct in BA patients, but involved mechanisms are still unclear. Bioinformatics predicts that H19 can regulate the expression of LIN28B by sponge microRNA let-7 members. We thus propose that hepatocytes transmit the H19 into cholangiocytes via exosomal delivering. H19 acts as sponges to absorb the let-7 and regulates the let-7/LIN28B pathway, and further to promotes the intrahepatic bile duct hyperplasia of BA. To test this hypothesis, we will analyze the roles of H19 in the intrahepatic bile duct hyperplasia of BA on the levels of molecules, cells, tissues and even whole animal; We next to explore the regulatory mechanism of H19 expression; We further to determine the effect of H19 on intrahepatic bile duct hyperplasia related genes; Finally, we will reveal the molecular mechanism of H19 in regulating the expression of LIN28B. This study will explore the pathogenesis of the abnormal hyperplasia of bile duct of BA patients. Our study will be helpful in revealing the mechanism of for BA liver fibrosis and provide new ideas for clinical prevention and treatment from a new perspective new viewpoint of cellular communication.