Cajal间质细胞自噬调控在高原胃肠动力紊乱中的保护作用研究

项目名称： Cajal间质细胞自噬调控在高原胃肠动力紊乱中的保护作用研究

项目编号： No.81500411

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： 邓尚新

作者单位： 中国人民解放军联勤保障部队第九四〇医院

项目金额： 18万元

中文摘要： 高原胃肠动力紊乱常见且危害大，但发病机制不祥，尚无有效防护措施。Cajal间质细胞（ICC）在胃肠道平滑肌起搏和运动中起关键作用，受c-Kit基因、细胞内钙离子等调控，易被外界因素影响而导致其损害，出现胃肠动力紊乱。研究发现：高原缺氧等因素可使胃肠粘膜受损，诱发自噬；自噬(包括线粒体自噬)是确保细胞功能稳定、存活的重要机制。但目前尚不清楚高原损伤因素所诱发的自噬是否作为损伤因素，进一步引起c-Kit表达异常、ICC结构和功能破坏、线粒体过度自噬损伤，进而导致高原胃肠动力障碍的形成。为此我们采用高原大鼠为研究对象，分析c-Kit表达变化，电镜下观察ICC超微结构、数目和网络结构，线粒体自噬状态，细胞内钙离子变化，在体和离体分析肠道运动功能；最后通过自噬干预、ICC保护等手段，观察上述指标和功能的变化。综合分析高原环境诱发胃肠动力紊乱的形成及保护机制，为高原胃肠动力紊乱的防治提供基础理论依据。

中文关键词： 胃肠动力障碍；高海拔；Cajal间质细胞；自噬；保护机制

英文摘要： Gastrointestinal motility disorders are common phenomenon at high altitudes and may cause greatly body harm. However, the pathogenesis is unknown. There are no effective preventions against the damage. Interstitial cells of Cajal(ICC) play a key role in the control of gastrointestinal motility and are regulated by c-Kit gene and levels of intracellular calcium. They are susceptible to the harmful factors, which may cause them structural and functional damage and result in dysfunction. Previous researches showed that gastrointestinal mucosa barrier function could be damaged at high altitude environment and induced gastrointestinal autophagy. Moderate autophagy is some kind of cellular protection. But there is uncertain that if hypoxia at high altitudes would act as an injury factor to cause excessive autophagy, which would furtherly result in abnormal expression of c-Kit, structural or functional damage in ICC, excess mitochondrial autophagy and finally lead to the plateau gastrointestinal motility disorders. Would it be possible that a moderate autophagy could reduce the severity of gastrointestinal motility disorders? To illustrate our hypothesis, rat model of high altitude is in used. Research targets include the following: analysis the expression of c-Kit gene, observation the ultrastructure and network of ICC by electron microscopy, the autophagy in mitochondrion, levels of intracellular calcium, analysis of intestinal motility function in vivo and vitro; meanwhile intervention of ICC’s function through interfering drugs and autophagy controlling are also involved. A comprehensive analysis of high altitude-induced gastrointestinal motility disorder will be done according to the above indicators. These results will give us a clear view of gastrointestinal motility disorders in plateau and show some indications in prevention or treatment of gastrointestinal motility disorders.

英文关键词： Gastrointestinal motility disorder;High altitude;Interstitial cells of Cajal;Autophagy;Protection mechanism