日本血吸虫病的根本危害是虫卵沉积于肝脏引起的肉芽肿及随后发生的纤维化，故对肝纤维化免疫调节机制的研究一直是热点。TGF-β1、IL-13等细胞因子通过刺激肝星状细胞的活化在肝纤维化进程中发挥关键作用。KH型剪切调控蛋白（KSRP）属RNA 结合蛋白，在转录后水平调控细胞因子的表达，其是否调控肝纤维化相关的细胞因子及其在血吸虫病肝纤维化中的作用，尚未见报道。前期研究发现，日本血吸虫可溶性虫卵蛋白（SEA）可激活细胞KSRP的转录，KSRP的升高与Hippo信号通路失活相关，从而引起TGF-β1 mRNA的降解；小鼠体内过表达KSRP可明显缩小虫卵肉芽肿。为此，本项目将从细胞和动物两个层面揭示日本血吸虫感染通过Hippo信号通路激活KSRP转录，进而调控肝纤维化相关细胞因子的表达，影响星状细胞活化，从而抑制肝纤维化发生发展的分子机制，增添血吸虫感染免疫调节的新内容，为抗肝纤维化治疗提供新途径。

In hepatic schistosomiasis, egg-induced hepatic fibrosis can lead to portal hypertension, which causes much of the morbidity and mortality associated with this disease. Transforming growth factor beta1 (TGF-beta1), interleukin 13 (IL13) can activate hepatic stellate cells and play an important role in the occurrence and development of the liver fibrosis process. KH-type splicing regulatory protein is a RNA-binding protein, which can regulate several cytokines at post-transcriptional level. However, whether KSRP regulate the expression of fibrosis related factors and play a key role in pathogeneses associated with hepatic schistosomiasis are still largely unknown. Our preliminary data suggested that soluble egg antigens (SEA) from Schistosoma japonicum induces the upregulated expression of KSRP, which may dependent on the Hippo signal pathway. The upregulation of KSRP protein controlled the rates of degradation of TGF-beta1 mRNA. Overexpression of KSRP by hydrodynamic administration in mice significantly reduced the size of hepatic granulomas compared with controls. Based on preliminary data, this proposal tests the novel central hypothesis that Hippo signal pathway-mediated transcriptional mechanisms control the expression of KSRP, and upregulation of KSRP destabilizes TGF-beta1 mRNAs, providing negative regulation to inhibit the progress of liver fibrosis caused by S. japonicum. The project’s significance is that it may reveal a new mechanism by which liver cells maintain homeostasis in response to S. japonicum infection. The information resulting from these studies could identify new therapeutic strategies not only for liver fibrosis caused by S. japonicum, but also for other liver fibrosis in general.mRNAs, providing negative regulation to inhibit the progress of liver fibrosis caused by Schistosoma japonicum. The project’s significance is that it may reveal a new mechanism by which liver cells maintain homeostasis in response to Schistosoma japonicum infection. The information resulting from these studies could identify new therapeutic strategies not only for liver fibrosis caused by Schistosoma japonicum, but also for other liver fibrosis in general.