胆汁酸通过TGR5激活CaCC促进结肠蠕动参与IBS动力异常的机制研究

胆汁酸（BAs）是调节胃肠运动的重要信号分子，参与肠易激综合征（IBS）动力异常的发生，但机制不明。我们新近发现：BAs调控肠道动力的关键靶点G蛋白偶联受体5（TGR5）在肌间Cajal间质细胞（ICC-MY）自发性钙瞬变活动中起重要作用；BAs通过TGR5活化ICC-MY表面的钙激活氯离子通道（CaCC）影响ICC电活动进而促进平滑肌收缩。我们预实验结果显示IBS模型大鼠结肠总BAs水平和TGR5表达明显升高。因此提出假设：BAs通过TGR5激活ICC-MY表面的CaCC促进结肠平滑肌收缩，参与IBS动力异常的发生。本课题拟采用形态学、分子生物学、功能学、药理学和电生理学方法阐明BAs活化TGR5促进结肠蠕动的细胞途径和分子机制，并借助IBS大鼠模型明确BAs/TGR5信号系统在IBS动力异常中的作用。本研究将从理论上揭示IBS动力异常发生的新机制，为IBS药物研发提供新思路。

Bile acids (BAs) act as important signaling molecules to regulate gastrointestinal (GI) motility. There is much evidence show that BAs are closely related to the abnormal GI motility of irritable bowel syndrome (IBS), but the underlying mechanism is still unclear. Recently, we found that G-protein-coupled bile acid receptor 5 (TGR5) played an important role in spontaneous calcium transient activity of interstitial cells of Cajal in myenteric plexus (ICC-MY). Furthermore, calcium activated chloride channel (CaCC) was involved in excitation on ICC induced by BAs/TGR5. Our pre-experimental results show that the expression levels of total BAs and TGR5 in colon of IBS rat model induced by water avoidance stress were significantly increased compared to the control group. Therefore, we hypothesize that activation of TGR5 by BAs can promote the contraction of smooth muscle to enhance the peristalsis of colon and participate in the motility disturbance of IBS by regulating the CaCC on ICC-MY. The present project intends to build the IBS rat model and apply morphological, molecular biological, functional, pharmacological and electrophysiological methodologies to study the cellular pathways and molecular mechanisms of BAs/TGR5 signaling system and the role of BAs in IBS dysmotility. This study will theoretically explain the new mechanism of IBS dysmotility, and provide clues for the development of new drugs in IBS.