肠黏膜CD8+CD39+T细胞源GZMA-PIEZO1轴调控黏液屏障在食物过敏中的作用机制

肠道微环境改变致肠黏液屏障功能受损是食物过敏（FA）重要致病因素。前期研究证实结肠炎患儿肠黏膜CD8+CD39+T细胞丰度降低导致肠屏障损伤。预实验发现：FA中CD8+CD39+T细胞促进肠黏液屏障功能依赖于颗粒酶A（GZMA）；抑制肠上皮细胞机械敏感离子通道蛋白1（PIEZO1）活性则逆转GZMA对黏液屏障功能的促进作用；反之，激活PIEZO1活性可拮抗GZMA减少导致的黏液屏障功能降低，其机制尚不清楚。本项目首次探讨在FA中，肠黏膜CD8+CD39+T细胞源GZMA-PIEZO1信号轴诱导肠上皮黏液屏障功能及调控机理。内容包括：①临床分析CD8+CD39+T细胞丰度与肠黏液屏障损伤的相关性；②阐明肠黏膜CD8+CD39+T细胞源GZMA-PIEZO1促进肠黏液屏障功能及分子机制；③动物模型验证靶向促进GZMA-PIEZO1轴可改善FA症状。本项目的完成将为FA诊治提供新靶标。

Impaired intestinal mucosal barrier function caused by changes in intestinal microenvironment is an important pathogenic factor for food allergy (FA). It was previously confirmed that decreased frequency of CD8 + CD39 + T cells in the intestinal mucosa of children with colitis led to mucosal barrier damage. The preliminary experiment found that CD8 + CD39 + T cells promoted colonic mucosal barrier function in granzyme A (GZMA) dependent pathway in FA; inhibition of mechanosensitive ion channel protein 1 (PIEZO1) activity in colonic epithelial cells reversed the effect of GZMA on mucosal barrier function. Conversely, activation of PIEZO1 in colonic epithelial cells antagonized the loss of GZMA-induced mucosal barrier damage. However, the mechanism remains unclear. This proposal is the first time to explore the function and mechanism of mucosal CD8 + CD39 + T cells-derived GZMA-PIEZO1 axis in regulating mucosal barrier function in colonic mucosal microenvironment in FA. To test this hypothesis, the proposed study will use the following AIMs: (1) To analyze the relationship between CD8 + CD39 + T cell abundance and colonic mucosal barrier damage in a clinic setting; (2) To explain the role and mechanism underlying colonic mucosal CD8 + CD39 + T cell-derived GZMA-PIEZO1 axis in regulating of colonic mucosal barrier function in vivo and in vitro ; (3) To confirm that promotion of GZMA-PIEZO1 axis-mediated mucosal barrier function can improve FA symptoms in the animal model. The project would provide a new target for the diagnosis and treatment of FA.