脑源性神经营养因子调控腹泻型IBS肠粘膜屏障通透性的机制研究

项目名称： 脑源性神经营养因子调控腹泻型IBS肠粘膜屏障通透性的机制研究

项目编号： No.81200270

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学一处

项目作者： 于岩波

作者单位： 山东大学

项目金额： 23万元

中文摘要： 新近发现腹泻型肠易激综合征（IBS）肠粘膜上皮脑源性神经营养因子（BDNF）表达明显升高。本研究旨在从BDNF调控肠上皮细胞紧密连接蛋白表达的层面探讨腹泻型IBS肠粘膜屏障通透性异常的分子机制：①检测腹泻型IBS患者肠粘膜BDNF通路蛋白及紧密连接蛋白表达的改变，结合肠道通透性检测，揭示BDNF调控肠粘膜屏障功能的潜在机制；②建立肠功能紊乱小鼠模型，结合BDNF基因敲除小鼠，印证BDNF通路在调节肠上皮细胞紧密连接蛋白表达的作用及对小鼠肠道通透性的影响。③BDNF基因转染肠上皮细胞并体外培养，应用TrkB、Rho激酶、p-MLC通路蛋白拮抗剂进行干预，检测肠上皮细胞紧密连接蛋白的表达水平，结合跨上皮细胞电阻检测，进一步阐明BDNF调控肠粘膜屏障通透性的机制。本研究首次系统阐明神经因子BDNF调节腹泻型IBS肠粘膜上皮细胞紧密连接蛋白表达的潜在机制，对寻找腹泻型IBS治疗新靶点具有深远意义。

中文关键词： 脑源性神经营养因子；紧密连接蛋白；结肠屏障；IBS；

英文摘要： Recent evidence indicated that brain-derived neurotrophic factor (BDNF) was significantly increased in the colonic mucosa of patients with diarrhea-predominant irritable bowel syndrome (IBS-D). This study was designed to explore the mechanism of the abnormal intestinal mucosal permeability in IBS-D at the level of BDNF-mediated epithelial tight junction protein expression alterations. ① Detect the expression alterations of BDNF pathway proteins and tight junction proteins in the colonic mucosa of IBS-D patients, and combined with intestinal permeability evaluation, to reveal the underlying mechanisms of BDNF in the regulation of intestinal mucosal barrier function; ② Establish the mice model of bowel dysfunction, using BDNF-gene knockout mice as control, to confirm the role of BDNF pathway in the expression alterations of tight junction proteins and its effects on the intestinal permeability of mice; ③ Culture the BDNF-transfected epithelial cells in vitro, investigate the expressions of the tight junction proteins with intervention of TrkB, Rho kinase and p-MLC antagonists, and combine with transepithelial electrical resistance evaluation, to further clarify the mechanism of BDNF in the regulation of intestinal permeability. In short, this study is meaningful to elucidate the role of BDNF in the modulation of i

英文关键词： Brain-derived neurotrophic factor；Intestinal barrier；Tight junction proteins；IBS；