TRPC通道对ICC的调控机制及对胃肠道运动功能的影响

Irritable bowel syndrome (IBS) is a kind of common clinical gastrointestinal disorders, but the etiology and pathogenesis of IBS is unclear. Our preliminary results suggested that TRPC3 and TRPC4 were expressed on ICC cells, and the ICC pacemaking currents in TRPC3 (-/-) mice were abnormal. So we propose the following hypothesis: TRPC channels may affect the ICC pacemaking currents by influencing the calcium ion and the slow wave potential of smooth muscle cells, furthermore affect the rhythms of gastrointestinal motility; TRPC channels may also directly affect the rhythms of gastrointestinal motility, then lead to gastrointestinal disorders in IBS. Moreover TRPC channels may regulate the gastrointestinal tract ICC, smooth muscle and other gastrointestinal motility by Mch. The effect of TRPC channel on ICC pacing currents was studied by using the methods of electrophysiology, cell biology and molecular biology, then the effect of TRPC channel on muscle strips and single smooth muscle was studied. The regulation of TRPC channel was further observed in IBS-C, IBS-D animal models. It is useful to understand the ICC pace-making mechanism and further elucidate the pathogenesis of IBS gastrointestinal motility disorder according to this project, furthermore to provide a potential therapeutic target for the study of new IBS therapeutic drugs.

肠易激综合征(IBS) 是临床上常见的一种胃肠道功能紊乱性疾患，其病因和发病机制尚不清楚。前期预实验发现，在ICC细胞上有TRPC3、TRPC4的表达，而且TRPC3(-/-)小鼠的ICC起搏电流表现异常。为此我们提出如下假说：TRPC通道可能通过对钙离子影响ICC，继而影响平滑肌细胞的慢波电位，影响胃肠运动的节律；TRPC通道也可能直接影响胃肠运动的节律，导致胃肠功能紊乱，产生IBS。还有可能影响Mch对胃肠道ICC、平滑肌等胃肠运动的调节。本项目拟采用电生理、细胞和分子生物学等手段深入研究TRPC通道对ICC起搏电流的调控作用、TRPC通道对离体肌条及单个平滑肌的影响、观察TRPC通道在IBS-C、IBS-D 动物模型发生发展中的可能作用。本项目的研究为深刻理解ICC的起搏机制、阐明IBS胃肠动力障碍及IBS发生发展提供新的理论，也为开发新型IBS治疗药物提供一个有潜力的治疗靶点。

肠易激综合征是临床常见的胃肠道紊乱性疾病，严重影响患者生活质量，常兼有严重的精神心理压力，给社会和家庭造成一定的经济压力，其病因和发病机制尚不清楚。根据本研究结果可知，基本可以明确TRPC3和TRPV4通道对胃肠道运动功能和内脏敏感性及疼痛有明显的影响，但是具体的调控过程和机制还需要进一步实验证实。通过不同动物模型，基本可以确定TRPC3和TRPV4的通道的拮抗剂对IBS-D及IBS-C都有改善作用，尤其师TRPC3可以改善肠易激综合征的疼痛和腹泻情况。而TRPV4得阻断剂，则可以降低一些促炎因子的量， Cajal 间质细胞的数量减少及结构、功能的异常在 IBS 发病机制起重要影响。采用新的药物制剂对 C-kit 基因进行靶向定位治疗，改变 IBS 肠道降低 C-kit 的表达，恢复肠道动力，降低内脏敏感性，将会给肠道紊乱性疾病的治疗带来新的方向。本项目的研究为深刻理解ICC的起搏机制、阐明IBS胃肠动力障碍及IBS发生发展提供新的理论，也为开发新型IBS治疗药物提供一个有潜力的治疗靶点。