IL-17C-IL-17RE信号通路在炎症性疾病中的作用机制

IL-17A参与多种炎症性疾病如自身免疫病的病理，已成为相关疾病的治疗靶标。我们最近首次发现了IL-17C的功能，它通过结合特异性受体IL-17RE及该家族中共享受体IL-17RA，诱导炎症性基因的表达，参与宿主肠道抗感染免疫。我们的预实验结果也显示该通路参与调控炎症性自身免疫病的病理。由于IL-17C-IL-17RE的配对及其功能才刚刚被揭开，这条信号通路中的转导机制还是研究空白，并且其参与炎症性疾病病理的机制还不清楚。本申请拟研究IL-17C-IL-17RE通路的信号转导机制，筛选新的信号分子，阐明其在炎症性自身免疫病中的功能与作用机制，并通过可溶性受体靶向该通路探讨其在自身免疫病中的治疗作用。同时与IL-17A的功能与作用机制做对比，阐明IL-17C与IL-17A在信号转导及炎症性疾病病理机制中的异同。这些原创性研究将为相关炎症性疾病的治疗提供重要的理论基础、新靶标与新策略。

IL-17A has been shown to play a critical role in the pathogenesis of variety of inflammatory disorders including autoimmune diseases. Targeting IL-17A or its receptor holds great promising in the therapy of autoimmune diseases. We recently discovered the function of IL-17C, a previously uncharacterized member of IL-17 cytokine family. IL-17C associates with IL-17RE (an orphan receptor) and IL-17RA (a shared receptor) to activate down-stream signaling and induce production of pro-inflammatory genes, and plays an important role in host mucosal immunity against infections. Our preliminary results also showed that IL-17C critically regulated the pathogenesis of autoimmune diseases. As the pairing of IL-17C and its receptor IL-17RE has just recently been discovered, the signaling and functional mechanism of this IL-17C-IL-17RE pathway in the pathogenesis of inflammatory autoimmune diseases is largely unknown. This grant is proposed to investigate the signaling mechanism of the new pathway, screen for new signaling molecules, and demonstrate the functional mechanisms of this pathway in the pathogenesis of autoimmune diseases. The grant also plans to target the IL-17C-IL-17RE pathway through the soluble receptor of IL-17RE to study its therapeutic effect on the pathogenesis of autoimmune diseases. Furthermore, the grant plans to compare the function and signaling of IL-17C with those of IL-17A in the pathogenesis of autoimmune diseases for similarity and difference. The aims of the proposal are to find new therapeutic targets and provide new information for targeting strategies for inflammatory autoimmune diseases.