肝内胆管细胞癌发生的分子调控机制是胆管癌研究中的关键科学问题。申请人长期从事肝癌和肝内胆管癌的临床诊治和基础研究，在主持的前两个国自然面上项目支持下，发现在肝细胞特异性NcoR1敲除小鼠中，肝细胞癌发生显著降低，本工作申请人以共同通讯作者于2018年发表于Hepatology（IF：14.1）。在此研究过程中，我们同时也构建了胆管细胞特异性NcoR1敲除小鼠，并采用TAA诱导胆管细胞癌肿瘤发生小鼠模型，检测胆管细胞特异性NcoR1敲除是否调控了胆管癌的肿瘤发生。有意思的是，与肝癌发生相反，胆管细胞特异性NcoR1敲除显著增强了胆管细胞癌的肿瘤发生，并且我们发现此小鼠中胆管细胞增殖显著增强。此外，我们在胆管癌临床组织样本中也发现了NcoR1表达的显著降低，并与较差预后密切相关。据此，本工作拟探求胆管细胞中NcoR1的敲除导致胆管癌发生的作用和机制，以期为其肿瘤发生提出新机制和干预思路。

The molecular regulatory mechanism of cholangiocarcinoma carcinogenesis is an important scientific issue in the study of cholangiocarcinoma. The subscriber focused on the clinical treatment and basic research of hepatocellular carcinoma and cholangiocarcinoma, and under the support of our previous NSFC grants, we found that hepatocyte specific knockout of NcoR1 significantly decreased the carcinogenesis of hepatocellular carcinoma, and have published the paper in Hepatolygy (IF: 14.1) in the year 2018 as co-corresponding author. During this work, we have also constructed the NcoR1 cholangiocyte specific knockout mice, and used TAA model to induce cholangiocarcinoma. Interestingly, which is different form that in hepatocellular caicinoma, NcoR1 deletion in cholangiocyte significantly increased the carcinogenesis of cholangiocarcinoma, and we also found that the cell proliferation of cholangiocytes under TAA administration was markedly increased by NcoR1 cholangiocyte specific knockout. Moreover, in the clinical cholangiocacinoma tissues, the expression of NcoR1 was also significantly decreased, and lower NcoR1 expression was significantly correlated with decreased survival of cholangiocacinoma patients. Thus, we intended to investigate the roles and inderlying mechanisms of NcoR1 in the regulation of cholangiocacinamo carcinogenesis, so as to provide new mechanism of pathogenesis and intervention of cholangiocarcinoma.