ASM信号调节炎性肠病异常Th免疫反应的机制研究

Excessive T helper cell (Th) type 1 (Th1) and Th17 immune responses contribute to pathogenesis of inflammatory bowel disease (IBD). In the previous NSFC-funded project, we have found that mTOR signaling regulates Th1 and Th17 responses in vitro. Further preliminary studies show that acid sphingomyelinase (ASM)/ceramide pathway mediates CD3/28 signal cascades including PI3K-Akt-mTOR signaling, and reguates Th1 and Th17 responses. So far, the expression and function of ASM pathway in IBD remains unclear, and the molecular mechanisms how ASM pathway controls Th responses in IBD, including Th1, Th2, Th17, and Treg, are still to be elucidated. We hypothesize that ASM pathway regualtes Th responses of IBD through mediating PI3K-Akt-mTOR signaling, and possibly cytokine receptor-STATs/SMADs signaling. We propose to address the function of ASM pathway in two specific aims. First, to investigate the downstream signals of ASM pathway during the differentiation process of Th cells including Th1, Th2, Th17, and Treg. Second, to explore the pivotal role of ASM pathway in the development of aberrant Th responses of animal colitis models and human IBD. The project will be performed with CD4+ T cells in vitro, experimental models of colitis and human IBD, to discuss the mechanisms of ASM pathway in regulation of different Th responses and related signals, and aberrant Th immune responses of IBD and murine colitis. In summary, the proposed project will provide novel information about the mechanisms and molecular signals of ASM pathway, and may offer a promising alternative to our current approaches of managing immune diseases including IBD.

异常Th1及Th17免疫反应在IBD发病中发挥重要作用，前一课题提示mTOR通路调节Th1、Th17功能。前期进一步发现，ASM信号介导CD4+ T细胞激活及相关mTOR通路，并调节Th1、Th17分化。而ASM信号在IBD肠粘膜Th细胞表达情况、ASM是否参与调节IBD异常Th免疫反应等直接关系其病理机制的问题尚亟待研究。本研究以ASM信号调节Th分化相关信号通路为切入点，进一步研究ASM信号在IBD、结肠炎小鼠肠粘膜Th细胞的表达，及该信号对这些Th细胞功能的调节及信号机制；同时利用小鼠结肠炎模型，探讨体内ASM信号对肠道异常Th反应的调节和机制。本项目从细胞、动物、人体多方面来探讨ASM信号对炎性肠病炎症肠粘膜不同Th细胞功能的调节作用，以阐明ASM信号调节肠道异常Th免疫反应的机制，为将来利用ASM信号治疗IBD、深入ASM信号的药理研发打下理论研究基础。

异常辅助性T细胞（Th）1型（Th1）及Th17免疫反应在炎性肠病（IBD）发病中发挥重要作用。课题发现酸性鞘磷脂酶（ASM）信号能调节Th1、Th17相关关键信号通路，并调节Th1、Th17分化，提示ASM信号可通过调节Th1、Th17分化调控IBD肠道Th1、Th17免疫反应和功能；研究进一步体外研究ASM信号对IBD及实验性结肠炎肠粘膜Th细胞的调节，及该信号调节这些Th细胞的信号机制；同时利用小鼠结肠炎模型，发现体内ASM信号对Th1、Th17免疫反应的调节作用、ASM信号对肠道炎症反应抑制作用的机制。研究从细胞、动物、人体多方面探讨了Th1、Th17免疫反应在IBD发病中作用，及ASM信号调节炎症肠粘膜Th1、Th17免疫反应、抑制肠道炎症反应的机制。项目探讨了ASM信号调节肠道异常Th免疫反应的机制，为将来利用ASM信号治疗IBD、深入ASM信号的药理研发打下理论研究基础。