基于我们前期研究发现的IL-17信号新分子事件—SHP-2/Act1相互作用，本项目拟用SPR、ITC、FRET等多种方法验证SHP-2/Act1间的结合，探讨该相互作用在IL-17信号介导的免疫炎症中的作用及其作用方式，并在关节炎患者组织样本及细胞上验证；用蛋白截短法、关键氨基酸突变、计算机模拟等方法阐明其相互作用的分子基础，确定相互作用界面的结构；进一步探讨IL-17R、IKKi、TRAF5、TRAF6、TRAF3及其它胞内分子对SHP-2/Act1相互作用的调控，探讨SHP-2抑制剂、促进剂及影响Act1的化合物对SHP-2/Act1相互作用的调控，以发现药物调控该相互作用的切入点；在此基础上基于阻断相互作用界面设计并合成系列化合物，确立阻断界面结合的化合物并用于治疗小鼠实验性脑脊髓炎或胶原性关节炎等免疫炎症。本研究可为发现针对IL-17信号的免疫炎症新调控方法打下基础。

This study is based on our previous findings on the novel molecular event, SHP-2/Act1 interaction in IL-17 signaling. We will elucidate the binding of SHP-2 with Act1 by various methods including SPR, ITC and FRET, examine the role of the interaction in the immunoinflammation mediated by IL-17 and the effective patterns, and confirm the interaction by using joint tissues and cells isolated from patients with arthritis. We also want to clarify the molecular basis for the binding by protein truncation, amino acid mutation and molecular docking to find the structure of interaction interface of SHP-2/Act1. Then the role of IL-17R、IKKi、TRAF5、TRAF6、TRAF3 and other molecules in the regulation and the effects of SHP-2 inhibitors and activators and those targeting Act1 on the interaction will be investigated to provide a new method for drug targeting. On the basis of these efforts, we will design and synthesize a series of compounds targeting the interaction interface of SHP-2/Act1. Finally we will examine the effect of the chosen compound on the immunoinflammations including experimental autoimmune encephalomyelitis and collagen-induced arthritis in mice. This study will be useful for the discovery of a novel approach to the regulation of immunoinflammation.