ZT55选择性抑制JAK-STAT通路抗类风湿性关节炎作用及其分子机制

选择性和精确调控某一失衡的JAK-STAT信号通路对于自身免疫性疾病的机制探讨和新药发现至关重要。我们前期的研究发现来源于雷公藤的全新二萜类化合物ZT55具有很好的抗关节炎和免疫调控作用，进一步发现其可能是通过选择性抑制STAT1的磷酸化和阻断T细胞的增殖发挥作用，但确切机制尚不明确。本项目拟深入探讨ZT55作用于JAK-STAT通路的选择性和特点，通过对该通路上下游信号分子的作用方式、对T细胞分化为Th1、Th2和Th17的影响、及对FLS细胞活化的调控入手，明确其抑制JAK-STAT通路活化的作用位点和选择性调控特点；同时在关节炎动物模型进一步证实其药效和作用机理，从而阐明其选择性调控JAK-STAT通路发挥抗炎作用的确切机制。本研究对于认识JAK-STAT通路在类风湿性关节炎中的调控方式和选择性特点、以及发现药效肯定的选择性抑制JAK-STAT通路的小分子药物具有十分重要的意义。

Signaling pathways mediating the transduction of information between cells are essential for development, cellular differentiation and homeostasis. Their dysregulation is also frequently associated with human disease. The JAKs are cytoplasmic tyrosine kinases critical for intracellular signal transduction of many cytokines, growth factors, and hormones. The JAK-STAT pathway is critical for meeting the diverse challenges faced by the immune system. Small molecule inhibitors of JAK1 have been developed to target diseases with aberrant production of inflammatory cytokines. In particular, the use of a JAK-selective inhibitor has been shown to be effective in reducing symptoms in multiple rodent models of arthritis. Our previous studies had found that ZT55, isolated from Tripterygium wilfordii Hook.f, demonstrated significant activates on anti-arthritis and immune regulation. The exact mechanism of regulation remains unclear, despite its known function of the inhibition of STAT1 phosphorylation and the disruption of T cell differentiation. Thus, the work of clarification ZT55 systemic ways of action are of extreme important, including the characters of its selective manners on JAK-STAT pathways, the pattern of its action on upstream or downstream molecules, the influence of its modulatory activities on T cell directed differentiation and its regulatory activities on FLS cells. Furthermore, we’d like to further validate its therapeutic effects on various kinds of arthritis animal model. The research has great implications for understanding which JAK/STAT pathway is correlated under certain kind of autoimmune disease status and how JAK/STAT pathways work in rheumatoid arthritis，which may contribute a lot in discovering a new type of selective inhibitor of JAK-STAT pathways to cure autoimmune disease.