Endophilin A2 调控炎症性肠病发生及机制研究

So far, the curative effect of clinical treatment to inflammatory bowel diseases is still not satisfactory because its pathogenesis is still not clear. Our previous study using gene chip has shown that the expression of endophilin A2 in colon tissue from inflammatory bowel diseases patients is decreased. Moreover, DSS-induced colitis was significantly alleviated in endophilin A2 transgenic mice, but the mechanisms are not clear. Basis on these findings, the aim of our present study is to verify the protective role of endophilin A2 against inflammatory bowel diseases using endophilin A2 transgenic mice and endophilin A2 knockout mice. Next, we will investigate the effect of endophilin A2 on the function of intestinal immune system and the integrity of intestinal barrier(including the number of paneth cells、the secretion of antibacterial explore peptide and the permeability of intestinal mucosa) to the possible mechanisms underlying the beneficial effects of endophilin A2 on intestinal homeostasis. This work will answer whether downregulation of endophilin A2 is an critical contributor to inflammatory bowel diseases and how endophilin A2 regulates intestinal homeostasis. These findings will provide the evidence that modulation of endophilin A2 expression may be a nove therapeutic stratage for inflammatory bowel diseases.

目前临床治疗炎症性肠病的效果仍不满意，主要与该类疾病发病机制不清有关。我们前期利用基因芯片技术筛查发现 炎症性肠病患者结肠粘膜endophilin A2蛋白表达降低，而且endophilin A2 转基因小鼠可对抗葡聚糖硫酸钠诱导的肠道炎症反应，但机制不清。本研究拟在前期工作基础上，首先采用endophilin A2基因敲除鼠和endophilin A2转基因鼠明确其在炎症性肠病发病过程中的作用，并进一步探讨endophilin A2对肠道免疫系统功能和肠道屏障功能（包括肠道潘氏细胞的数量，抗菌肽的分泌和肠道粘膜的通透性等）的影响以分析其可能的作用机制。本课题将较系统的阐明endophilin A2对炎症性肠病产生的影响及其调控机制，为评估其是否可作为炎症性肠病新的防治靶点提供科学依据。

目前临床治疗炎症性肠病的效果仍不满意，主要与该类疾病发病机制不清有关。我们采用endophilin A2肠上皮特异性敲除小鼠和endophilin A2转基因鼠明确其在炎症性肠病发病过程中的作用，并进一步探讨endophilin A2对肠道免疫系统功能和肠道屏障功能的影响以分析其可能的作用机制。首先，我们采用westernblot 、免疫组化及免疫荧光技术观察了endophilin A2 在UC 患者病变结肠黏膜及正常人的结肠黏膜上的表达情况；同时还观察了endophilin A2 在DSS 诱导的小鼠肠炎模型及正常小鼠结肠上的表达。第二，用DSS 诱导endophilin A2 转基因小鼠和肠上皮特异性敲除小鼠建立急性肠炎模型，从动物整体水平探讨endophilin A2对肠道粘膜的影响并探究其在炎症性肠病中可能的作用机制。