亮氨酸对热休克转录因子2促进溃疡性结肠炎粘膜愈合的调控机制研究

粘膜愈合是溃疡性结肠炎（UC）的治疗目标，氨基酸在肠粘膜修复中发挥重要作用。既往文献报道活动期UC患者血清中亮氨酸水平增加；作为原料及内源性活性物质，亮氨酸可以调控合成热休克蛋白参与组织修复。本小组前期研究及预实验发现：①热休克转录因子2（HSF2）能抑制肠粘膜炎症反应并上调修复因子表达，促进UC肠粘膜修复；②亮氨酸能上调培养细胞中HSF2转录；③亮氨酸能促进DSS结肠炎小鼠粘膜修复。提示亮氨酸可能调控并激活HSF2进而促进UC肠粘膜修复，但机制不清，故本项目拟通过：①临床水平：研究UC粘膜愈合前后亮氨酸、HSF2及促粘膜修复因子的相关性；②细胞水平：在培养细胞中探索亮氨酸调控HSF2的信号通路及关键蛋白；③动物水平：在DSS肠炎模型中探讨亮氨酸对HSF2基因敲除和过表达小鼠肠粘膜愈合进程及能力的影响。为明确亮氨酸对HSF2促进UC肠粘膜愈合的调控机制及研发UC新的治疗靶点提供理论依据。

Mucosal healing is the treatment target of ulcerative colitis (UC). Amino acids play an important role in intestinal mucosal repair. Leucine levels are increased in serum of active UC patients, which can regulate the synthesis of heat shock protein and participate in tissue repair and renewal as raw materials and endogenous active substances. Our previous study and preliminary experiments found that: (1) HSF2 can promote mucosal repair by inhibiting intestinal mucosal inflammation and up-regulating the expression of repair factors; (2) leucine can increase the expression of HSF2 in intestinal epithelial cells; (3) leucine can promote colon mucosal repair in DSS colitis model. These were suggested that leucine may regulate and activate HSF2 to participate in UC intestinal mucosal repair, but the detailed mechanism was unclear, so this project was conducted through: (1) in the clinical level : to study the changes and correlation between leucine and HSF2 before and after mucosal healing; (2) in the cell level: to explore the signaling pathway and key proteins of HSF2 regulated and activated by leucine; (3) in the animal level: to investigate the effect of leucine on the healing process and ability of intestinal mucosa in mice with HSF2 gene knockout and overexpression in DSS colitis model. In order to clarify the mechanisms of leucine regulating HSF2 in UC mucosal healing, and to provide theoretical basis for developing new therapeutic targets for UC.