约有80%的类风湿性关节炎患者会并发间质性肺病，其治疗缺少理想的靶标和药物，亟需在炎症和纤维化机制及关联性上确立新的切入点。我们首次发现靶向Act1的新型DMARD药物艾拉莫德除抗炎作用外还可逆转TGFβ所致上皮间质转化并显著改善肺纤维化，提示Act1可能是纤维化进程中关联炎症与纤维化的关键分子。本项目拟深入探讨Act1调控TGFβ信号转导的分子机制，明确其在TGF-β信号中的功能和亚型及相互作用蛋白等；考察IL17-Act1和TGFβ-Act1通路在肺纤维化进展过程中的协同作用；并利用Act1敲除小鼠、TGFβ信号抑制剂、现有抗纤维化药物，确立Act1作为肺纤维化治疗的新靶标；以艾拉莫德为探针原型，合成系列类似物，发现具有抗炎抗肺纤维化活性的先导化合物或候选药物。本研究为合并间质性肺病的RA患者提供了新的治疗选择，还合理拓展了艾拉莫德的临床新用途，为难治性肺纤维化的治疗提供新的途径。

Studies suggested that about 80% of patients with rheumatoid arthritis (RA) always develop interstitial lung disease (ILD). However, it remains poorly understood, underappreciated, under recognized, underdiagnosed, of uncertain pathogenesis and without proven treatment. The wide-ranging prevalence and uncertain clinical outcomes have generated a clear need for more rigorous and thoughtful study. Our previous study has found that iguratimod, a novel DMARD which targets Act1, dose-dependently and potently diminished the severity of bleomycin-induced lung fibrosis not only by reducing inflammatory signals, but also through attenuating TGF-β signaling. These results indicates that Act1 may be the key connect point of inflammation and fibrosis in pulmonary diseases. The unique mechanism of Act1 in TGF-β signaling will be further elucidated in this proposal, including subcellular location, functional phosphorylation sides, novel isoform, and protein-protein interactions. The crosstalk of IL17-Act1 signaling and TGFβ-Act1 signaling in pulmonary fibrosis will be confirmed by varieties of methods. Then we will establish the key position of Act1 in fibrosis using Act1 knockout mice, inhibitors of TGF-β signaling, and clinical anti-fibrosis drugs. In addition, series of analogs of iguratimod will be synthesized. On the basis of their structures and isothermal titration calorimetry, lead compounds or candidates with anti-inflammation and anti-fibrosis activities will be found. In summary, this proposed research will add new insights into the treatment regiments for RA-ILD, and expand the clinic use of iguratimod.