高胆固醇作用于胆囊Cajal细胞引起胆囊收缩功能障碍的研究

The research of gallbladder contractile dysfunction in the formation of cholesterol calculus was a hotspot of healing gallstone disease. It was understood that SCF/c-kit signaling pathway plays an important role in maintaining for the occurrence, development and phenotype of ICC by studying on kinetics of gastrointestinal. The lack of ICC generally appears in the motility disorders of various gastrointestinal and biliary tract diseases. The reasons of SCF/c-kit signaling pathway disorder causing ICC deletion in the gallbladder and the mechanism of SCF promoting the recovery of the missing ICC were explored by using the animal model of ICC deletion which was constructed by blocking the function of C-kit receptors in this project. By application of cholelithiasis animal model, the mechanism of missing ICC in the gallbladder caused by high cholesterol effecting on SCF/c-kit signaling pathway was studied and reasons of high cholesterol inducing gallbladder contractile dysfunction diminishing via treating of SCF were explored. Through this research we can develop new drugs to improve SCF/c-kit signaling pathway disorder in the future and restore the deletion of ICC in gallbladder and finally improve the contraction function of gallbladder. The new method will be provided for Clinical prevention and treatment of cholelithiasis if this project was carried out.

胆囊收缩功能障碍在胆固醇结石形成中的作用是目前胆石病防治的研究热点。胃肠道动力学研究发现 SCF/c-kit 信号通路对于 ICC 的发生、发育及表型维持具有重要作用，许多胃肠道和胆道疾病动力紊乱都存在 ICC 的缺失。本课题通过阻断 C-kit 受体的作用构建 ICC 缺失动物模型，应用此模型研究 SCF/c-kit 通路障碍导致胆囊 ICC 缺失的原因以及 SCF 促进缺失 ICC 恢复的机理。同时应用胆石症动物模型研究高胆固醇对 SCF/c-kit 信号通路的作用，导致胆囊 ICC 缺失的机制以及 SCF 对高胆固醇所致胆囊收缩功能障碍的影响。通过此研究为将来研发出改善SCF/c-kit 通路障碍的药物，以此用来恢复胆囊缺失的ICC，提高胆囊收缩功能，为临床防治胆石病提供一个新方法。

胆固醇结石病是临床常见疾病，本研课题主要研究了胆囊结石形成中，胆囊Cajal细胞改变与胆囊粘膜改变的关系。获得的主要结果如下：（1）小鼠结石形成过程中，胆囊粘膜病理改，从胆囊粘膜及肌层可以分离到Cajal细胞。进而通过单细胞测序分析显示，熊脱氧胆酸具有增进胆囊Cajal的作用，进而可能在改善胆囊功能中起到一定作用。（2）成石饲料喂养小鼠，肠道菌群发生改变，特别是特别与胆汁酸代谢关系密切的Clostridium菌属，提示了肠道微生态在成石过程中的潜在作用。（3）检测发现人体有机氯类农药残留物含量高的胆石病患者，其肝脏胆固醇转运蛋白ABCG5/G8表达较高，且证实了OCP具有促进肝脏脂肪酸合成的作用。综上所述，本研究从胆囊Cajal细胞的改变阐明了胆囊功能变化在结石形成中的作用，及药物熊脱氧胆酸的治疗效应。