胆酸排泌蛋白OATP3A1抗胆汁淤积性胆管损伤的效应及机制研究

胆汁淤积是多因素所致肝损害的常见临床综合症，易致肝硬化肝衰竭等。胆酸转运蛋白是维持胆酸肝肠循环稳态及对抗胆汁淤积肝损害的重要因素。申请人前期已阐明新鉴定的胆酸排泌蛋白OATP3A1抗肝细胞损伤的效应及机制，同时发现OATP3A1高表达可对抗胆管炎症，但机制不清。预实验发现OATP3A1与TNFα、SP1、NFκB呈正相关，可摄取维生素D3，而文献报道维生素D3在抗胆管损伤及炎症方面起重要作用。故假设：胆汁淤积时胆管细胞分泌TNFα激活JNK- SP1/NFκB-p65信号通路上调OATP3A1表达，促进外排胆汁酸和摄入维生素D3，共同对抗胆汁淤积性胆管损伤的重要机制。本课题拟构建OATP3A1胆管特异敲除小鼠、培养原代胆管细胞、同源蛋白建模等，在体内外水平阐明OATP3A1对抗胆汁淤积性胆管损伤的效应及调控机制，进一步明确OATP3A1在胆汁淤积性肝病的重要作用，为其临床治疗找到关键靶点。

Cholestatic is a common clinical syndrome of liver damage caused by multiple factors, and is easy to cause liver cirrhosis and liver failure. The bile acid transporter is an important factor in maintaining the homeostasis of bile acid circulation in gut-liver axis and preventing liver damage in cholestasis. The applicant had previously elucidated the effect and mechanism of the newly identified bile acid excretion protein OATP3A1 against hepatocyte injury, and found that high expression of OATP3A1 can prevent bile duct inflammation, but the mechanism was unclear. Pre-experiment found that OATP3A1 is positively correlated with TNFα, SP1, NFκB, and can take up vitamin D3. The literature reports that vitamin D3 plays an important role in anti-biliary injury and inflammation. Therefore, it is hypothesized that biliary cell secretion of TNFα activates JNK-SP1/NFκB-p65 signaling pathway to up-regulate OATP3A1 expression, promote efflux of bile acid and vitamin D3, and fight against cholestatic bile duct injury. This study aims to construct OATP3A1 bile duct-specific knockout mice, culture primary cholangiocarcinoma cells, homologous protein modeling, etc., to elucidate the effect and regulation mechanism of OATP3A1 against cholestatic bile duct injury in vivo and in vitro, and further clarify the significant role of OATP3A1 in cholestasis. The results gained through this study may advance our understanding of the OATP3A1 gene and help in the development of novel treatments for cholestasis.