ICOSL/ICOS调控IL-21活化日本血吸虫感染小鼠HSCs介导肝纤维化的分子机制

血吸虫虫卵肉芽肿反应及继发纤维化是导致血吸虫致病的主要原因，而肝星状细胞（HSCs）的活化和增殖是肝纤维化的关键环节。本课组在前期系列研究中证明ICOSL/ICOS信号可介导血吸虫慢性致病期T细胞亚群(Th1/Th2/Th17/Tfh)的极化并调节疾病进程，特别是近期研究发现HSCs表面具有IL-21受体，ICOSL/ICOS信号可介导Tfh细胞因子IL-21上调表达活化HSCs导致肝纤维化。据此，提出“ICOSL/ICOS信号调控Tfh细胞因子IL-21介导HSCs活化可能是控制血吸虫病肝纤维化进程的潜在新途径”的科学假设。本项目拟应用本课题组特定的ICOSL敲基因和ICOS转基因小鼠疾病模型验证该假设，拟探讨IL-21介导HSCs活化与经典信号通路TGF-β1/Smad等的相关性及潜在新的信号通路等重要科学问题，深入阐明血吸虫病肝纤维化的分子机制，为血吸虫病肝纤维化的防治提供新的思路。

Granuloma formation and subsequent hepatic fibrosis induced by Schistosoma japonicum is the main reason leading to shistosomiasis, and the activation and proliferation of hepatic stellate cells(HSCs)is the key link leading to the occurrence of liver fibrosis. Based on previous studies, it has been found ICOSL/ICOS signal can mediate T cell subgroups (Th1/Th2/Th17/Tfh) polarization and regulate the disease process of chronic schistosomiasis, In recently,we have found that IL-2R is expressed on HSCs and up-regulation of IL-21 contributing liver fibrosis of chistosomiasis by activating HSCs in Mice. Accordingly, we proposed a hypothesis“It is a new perspective of controling progress of liver fibrosis by Tfh cytokine IL-21 activating HSCs regulated by ICOSL/ICOS signal in schistosomiasis”. In this program, we intend to application specific ICOSL gene knock-out and ICOS transgenic mouse models of disease to test this hypothesis, and investigate that the important scientific idea of the effects of IL-21 on the important signal pathway which the TGF-β1/Smad etc. mediate the activation of HSCs and may be potential new pathway, and further elucidating the molecular mechanisms of hepatic fibrosis in shcistosomiasis, the results of this study will provide a new perspective to prevent and control the liver fibrosis in schistosomiasis.