克罗恩病中干预TLE1逆转凋亡介导的肠道粘膜自噬紊乱的策略研究

项目名称： 克罗恩病中干预TLE1逆转凋亡介导的肠道粘膜自噬紊乱的策略研究

项目编号： No.81500422

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： 黄美兰

作者单位： 上海交通大学

项目金额： 18万元

中文摘要： 克罗恩病是一种多基因参与并协同作用下的复杂性、自身免疫性疾病，环境因素及遗传基因对其发病亦至关重要。目前克罗恩病发病机制研究最深入的即为NOD2多态性、自噬平衡紊乱及内质网应激三学说，而三者中的关键点又是自噬平衡紊乱学说。本课题组前期实验在表达谱芯片中发现初发型克罗恩病患者炎症部位TLE1基因表达量明显低于正常组人群，后在小样本病例中初步验证了芯片结果的可靠性。基于已有的大量研究证明该基因在肿瘤性疾病中抗凋亡方面的作用，我们推论并将全方位验证TLE1基因在克罗恩病患者的表达下降，令肠道粘膜抗凋亡作用下降而凋亡相关蛋白异常过度激活，致使肠道粘膜中自噬相关基因表达及功能异常，从而打破克罗恩病患者肠道粘膜先天免疫、粘膜屏障与肠道微生物群的稳态，最终确认这一致病假说。并通过干预TLE1基因表达，从而逆转凋亡异常介导的肠道粘膜自噬平衡紊乱，恢复克罗恩病患者正常肠道先天免疫功能，为该病的诊治拓宽新思路

中文关键词： 克罗恩病；TLE1；凋亡；自噬；粘膜屏障

英文摘要： Crohn’s disease is an multi-gene mediated autoimmune、chronic inflammatory disorder of the gastrointestinal tract. The pathogenesis of Crohn’s disease is complex with evidence to support both environmental and genetic factors. Currently the most in-depth research and analysis of Crohn’s disease pathogenesis involve in polymorphisms in NOD2、 autophagy variants and ER stress, which play the prominent role in the innate immune response towards intracellular bacteria. Our previous experiments through Whole-genome microarray found that the mRNA expression of TLE1 gene on the intestinal inflammatory mucosa of initial-onset Crohn’s disease patients was significantly lower than that of the normal people. After that, we preliminarily verified the reliability of microarray results in a small sample of Crohn’s disease cases. Based on existing numerous studies which have demonstrated the anti-apoptotic role of TLE1 gene in tumor diseases，We infer and will comprehensively verify that decreased expression of TLE1 gene in Crohn's disease cause decreased anti-apoptotic effects of intestinal epithelium through excessive activation of apoptosis-related proteins, resulting in aberrant intestinal mucosa autophagy-related gene expression and its dysfunction, thus upsetting the balance between the innate immunity, mucosal barrier homeostasis and intestinal microbiota in the intestinal mucosa of patients with Crohn’s disease. We will finally confirm this pathogenic hypothesis. Furthermore, through the intervention of TLE1 gene expression, it is possible for reversing the abnormal apoptosis mediated intestinal mucosa autophagy disorders. Thus patients with Crohn’s disease will possibly restore normal intestinal innate immune function. This study may expand new ideas for diagnosis and treatment of Crohn’s disease.

英文关键词： Crohn's disease;transducin-like enhancer of split 1;apoptosis;autophagy;mucosal barrier