靶细胞中IL-17信号转导途径具有多样性，在其介导的免疫炎症性疾病的病理过程中发挥着关键的作用，但作为药物靶标尚缺少合适的切入点。我们的前期研究发现SHP-2在IL-17的靶细胞中高表达，并介导特定的分子事件。本项目拟通过分子、细胞和动物模型多层面确证SHP-2是IL-17信号的重要产物和核心调控分子；探讨其在病理状态下介导IL-17信号转导的分子机制；进一步寻找SHP-2的降解机制，明确直接促进其降解的E3泛素连接酶，阐明分子基础，从而发现药物调控的切入点；并探讨降解缺失与IL-17促进SHP-2高表达的关系；在此基础上设计靶向特定功能域或位点的肽段或化合物，确立能够介导SHP-2降解从而降低其蛋白表达水平的抑制剂，并用于治疗IL-17介导的免疫炎症性疾病，为从改变SHP-2蛋白表达水平角度调控IL-17信号，研制新型免疫抑制剂打下坚实基础。

IL-17 signaling transduction pathway is diverse in target cells, which plays a key role in the pathological processes of immunoinflammatory diseases. However, strategies to target IL-17 signaling have not been investigated. Our previous studies have found that SHP-2 is highly expressed in IL-17 target cells and mediates specific molecular events. In this study, we will make an effort to confirm that SHP-2 is an important product and core regulatory molecule of IL-17 signaling through molecular, cellular and animal models. Then we will investigate the molecular mechanism of IL-17 signaling transduction pathway under pathological conditions. We will further explore the degradation mechanism of SHP-2 and identify the E3 ubiquitin ligase which directly promotes the degradation. The structure basis will help for providing a new method for drug targeting. Based on these findings, we will design and synthesize peptides or compounds targeting the specific domain or amino acid residue. Finally, we will examine the effect of the chosen peptide or compound which decreasing the expression of SHP-2 on the IL-17 mediated signaling and diseases. This study will lay the foundation for the new drug development against IL-17 signaling.