胆盐沉积与胆管纤维化等是肝胆管结石病（HL）的关键致病因素。胆盐膜受体TGR5是胆盐重要清除受体，其结构或功能改变与HL的发生密切相关。我们近期研究发现，在HL人群中TGR5受体存在多点高频率单核苷酸多态型并形成错义突变(Q77E，W83R)，体外实验显示错义突变受体对胆盐的结合能力明显下降，虽然突变受体结合胆盐后对PKA信号的活化作用减弱，但活化持续时间显著延长。结合文献，我们推测，TGR5受体点突变可以导致其对清除胆盐功能低下，而过量的胆盐则可持续活化TGR5受体，进而通过下游PKA信号通路在胆管纤维化与结石的形成发挥重要作用。本研究拟通过细胞及动物水平系统深入阐明错义突变对TGR5受体摄取胆盐功能的影响，同时采用荧光素酶报告载体、qRT-PCR等技术探讨在胆盐刺激的情况下，TGR5错义突变受体持续活化对胆管上皮成纤维化的影响。本研究将为深入认识HL发病机制及其预防与治疗提供新思路。

Bile salt deposition and biliary duct fibrosis are the key pathogenic factors of hepatolithiasis (HL). Takeda G protein-coupled receptor 5 (TGR5) plays an important role in scavenging bile salts. Its structural or functional changes are closely related to the occurrence of HL. Our recent research has found that in HL population, the TGR5 receptor has high frequency of multiple single nucleotide polymorphisms, thereby forming missense mutations (Q77E, W83R). In vitro experiments have shown that the binding ability of missense mutation-mediated TGR5 to bile salts is significantly decreased. Although the activation of PKA signaling pathway has been weakened after missense mutation-mediated TGR5 binding to bile salts, the activation duration has been significantly prolonged. In combination with related literature, we speculate that missense mutation-mediated TGR5 can lead to its low function of scavenging bile salts, while excessive bile salts can continuously activate TGR5 receptor, and then play an important role in the formation of bile duct fibrosis and cholelithiasis formation through the downstream PKA signaling pathway. The purpose of this study is to elucidate the effect of missense mutation-mediated TGR5 on the uptake of bile salts at cellular and animal levels. Meanwhile, the effect of continuous activation of missense mutation-mediated TGR5 on fibrosis of bile duct epitheliums stimulated by biliary salts were also investigated by luciferase reporter vector, qRT-PCR and et al. This study will provide new ideas for further understanding the pathogenesis of HL and its prevention and treatment.