TGF-β信号新调控蛋白Act1的药物靶标属性及RA-ILD新型药物研究

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.

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。

TGF-β信号在间质性肺病甚至肺纤维化的发生发展过程中起重要作用。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TGF-β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。本项目验证了Act1在间质性肺病病人及博来霉素诱导的急性肺纤维化模型小鼠的肺组织中高表达；证实这种高表达是在TGF-β诱导下发生的，与去泛素化酶活性密切相关；深入阐明Act1调控TGF-β信号转导的分子机制及Act1的新功能；明确艾拉莫德通过与Act1结合抑制TGF-β诱导的Act1蛋白表达水平；确证了艾拉莫德抑制EMT改善肺纤维化的疗效。本研究将合理地扩大艾拉莫德的临床应用，并对肺纤维化的发病机制和临床治疗带来新的启示。