肠道HCN通道在IBS发病中的作用

项目名称： 肠道HCN通道在IBS发病中的作用

项目编号： No.81500416

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 陈瑜

作者单位： 福建医科大学

项目金额： 18万元

中文摘要： 肠易激综合征（IBS）表现为反复腹痛与排便习惯异常，发病机制不明。先前研究表明传入神经末梢HCN通道的活化可引发痛觉敏化，最近研究提示肠道Cajal间质细胞（ICC）HCN通道控制肠道运动节律，据此我们假设HCN通道功能异常是引发IBS腹痛与排便习惯异常的重要原因。我们拟建立IBS大鼠模型，首先从整体水平探讨HCN通道对IBS大鼠脊髓背根感觉传入、内脏痛敏反应、在体和离体肠道平滑肌运动功能的影响；然后从细胞水平明确HCN通道在肠神经系统与ICC中的分布和表达；最后从分子水平用膜片钳技术观察模型大鼠肠神经系统神经元与ICC本身的电生理学特性及HCN通道在其上的表达及功能是否发生变化，以期揭示肠道HCN通道在IBS慢性内脏痛与肠道动力异常中的作用及起主要作用的亚型，旨在进一步揭示IBS发病机理，为IBS治疗提供新思路。开展本项目研究不仅具有重要的理论意义和科学价值，而且具有潜在的应用前景。

中文关键词： 肠易激综合征；慢性内脏痛；肠神经系统；HCN；通道；Cajal；间质细胞

英文摘要： Irritable bowel syndrome (IBS) is characterized by recurrent visceral pain and abnormal bowel evacuation habit. The pathogenesy of IBS is unclear. Previous study indicate neuropathic pain is initiated by HCN-driven action potential firing in nociceptors. A recent research suggests HCN channels in colonic ICCs participate in regulation of pacemaking activity. From above we propose HCN channel function abnormality can lead to not only visceral hypersensitivity, but also intestinal movement abnormality due to alteration of smooth muscle autorhythmicity. We plan to construct IBS rat model by colon irritation in neonatal rat. First, behavioral and electrophysiology testings are used to determine effects of HCN channel antagonists and antagonists on visceral afferent nerve discharge, visceral pain intensity and enteric motor function. Second, immunohistochemistry and Western blot/RT-PCR are used to determine the distribution and subtype of HCN channels in enteric nervous system and ICC. Last, patch clamp are performed in enteric nervous system neurons and ICC to find out their electrophysiology characteristics, and whether HCN channel expression and function are changed in them. These experiments are performed to identify the role of enteric nervous system and ICC HCN channels in chronic visceral pain and enteric motor disorder in patients with IBS, and the main HCN channel subtype, thus providing a new way for therapeutic intervention in patients with IBS.

英文关键词： Irritable bowel syndrome;Chronic visceral pain;Enteric nervous system;HCN channel;Interstitial cells of Cajal