EphB2下调促进肠黏膜CHAT神经修复参与肠炎反应调控的作用机制研究

研究发现肠神经元过表达小鼠的肠炎反应较肠神经元低表达小鼠的肠炎反应明显加重，提示肠神经系统与炎症反应相关。UC病变主要发生在肠黏膜层和黏膜下层，UC时肠黏膜神经纤维的变化与炎症反应的关系如何尚不明确。我们的前期研究发现肠炎严重程度与肠黏膜总的神经纤维活化互呈正相关，但同时伴有肠黏膜CHAT神经的表达减少；引起CHAT神经表达减少的机制未明。进一步研究发现肠炎时，EphB2高表达于肠黏膜神经纤维膜上，抑制EphB2的表达可以显著抑制肠炎反应和上调CHAT神经的表达，而抑制CHAT下游通路时，肠炎反应又再次加重。因此我们提出：抑制EphB2可以介导肠黏膜CHAT神经修复从而参与肠炎反应调控这一科学假说。本项目将以模式动物、临床样本为对象，在组织、细胞和分子水平验证上述假说，重点探讨EphB2介导肠黏膜CHAT神经表达变化的作用机制，以从肠黏膜神经纤维改变的新视角来探寻UC治疗的新思路。

It was found that the intestinal inflammatory response of mice with overexpression of enteric neurons was significantly worse than that of mice with low expression of enteric neurons, suggesting that the enteric nervous system was related to the intestinal inflammation. The lesions of ulcerative colitis (UC) were mainly occurred in the intestinal mucosa and submucosa, and the relationship between the changes of intestinal mucosa nerve fibers and the inflammatory response in UC was still unclear. Our previous study found that the severity of colitis was positively correlated with the activation of total nerve fibers in intestinal mucosa, however, the expression of CHAT nerve in intestinal mucosa was also decreased, which the mechanism remains unclear. Further study showed that EphB2 was highly expressed on the nerve fiber membrane of intestinal mucosa in colitis. Inhibition of EphB2 expression could significantly reduce the intestinal inflammatory response and up-regulate the expression of CHAT nerve. However, when the downstream CHAT pathway was inhibited, the colitis reaction was aggravated again. Therefore, we proposed the scientific hypothesis that inhibition of EphB2 mediated the intestinal mucosal CHAT nerve repair and thus participated in the regulation of the enteritis response. In this study, we will use model animals and clinical samples as research objects, and verify the above hypothesis at the tissue, cellular and molecular levels. We will mainly focus on the mechanism of EphB2 mediate the changes in intestinal mucosal CHAT nerve expression, so as to explore new ideas for UC treatment from a new perspective of changes in intestinal mucosal nerve fibers.