GRK2介导JAK1-STAT3信号转导的抑制改善类风湿关节炎成纤维样滑膜细胞异常增殖的机制

成纤维样滑膜细胞（FLS）中异常活化的信号调控至生理状态是类风湿关节炎（RA）治疗的新策略。前期发现恢复G蛋白偶联受体激酶2（GRK2）对胞内蛋白活性的抑制改善FLS异常增殖。预实验发现GRK2结合JAK1调控FLS增殖，但具体机制不明。本课题假设：恢复GRK2对JAK1-STAT3信号抑制改善FLS异常增殖。分离RA患者、胶原性关节炎大鼠和GRK2+/-小鼠FLS，通过免疫共沉淀等方法，观察GRK2对JAK1活性的抑制，阐明恢复GRK2对JAK1-STAT3的抑制改善FLS异常增殖。利用分子对接等分子生物学方法，研究GRK2与JAK1的结合作用及位点，阐明GRK2的C端与JAK1的SH2区结合，介导JAK1-STAT3信号抑制改善FLS异常增殖的分子机制。本课题揭示恢复GRK2对JAK1-STAT3信号抑制调控FLS生理和病理平衡的新机制，为创制安全有效的新型治疗RA药物提供实验依据。

Regulating the abnormally activated signals in fibroblast-like synovial cells (FLS) to physiological state is a new strategy for the treatment of rheumatoid arthritis (RA). Previous studies found that the restoration of the inhibition of intracellular proteins activity by G protein-coupled receptor kinase 2 (GRK2) improved the abnormal proliferation of FLS. Preliminary experiments showed that GRK2 might regulate the proliferation of FLS by binding to JAK1, but the specific mechanism remains unclear. The hypothesis of this study was that the restoration of the inhibition of JAK1-STAT3 signal transduction by GRK2 improves abnormal proliferation of FLS. The FLS of RA patients, collagen-induced arthritis rats and GRK2+/- mice were separated, and methods such as immunoprecipitation were used to observe the inhibition of GRK2 on the activity of JAK1, and to clarify that GRK2 mediates the inhibition of JAK1-STAT3 signaling to improve the abnormal proliferation of FLS. Using molecular docking and other molecular biology methods were used to observe the binding and binding sites of GRK2 and JAK1, and to clarify the molecular mechanism by which the C-terminus of GRK2 binds to the SH2 domain of JAK1. This project reveals the new mechanism that the restoration of the inhibition of JAK1-STAT3 signal transduction by GRK2 regulates the physiological and pathological balance of FLS, which will provide experimental evidence for the creation of safe and effective new therapeutic drugs for treating RA.