基于FERM-SH2结构域二聚化调控的Seselin抗急性肺损伤作用及靶向抑制JAK2的分子机制研究

肺泡巨噬细胞大量激活是急性肺损伤病理进程的关键事件，但是调控机制尚未明确，潜在的药物靶标有待开发。我们通过数据库挖掘发现JAK2在肺脏巨噬细胞高表达，小分子化合物Seselin结合于FERM-SH2结构域抑制JAK2激活，改善小鼠急性肺损伤相关症状。本项目将在前期研究基础之上继续开展：1）探究Seselin与JAK2的结合界面，证实Seselin对JAK2的变构型抑制效应；2）借助Seselin的作用机制，解析FERM-SH2结构域二聚化对于JAK2信号通路的影响，揭示JAK2活性的调控方式；3）采用肺泡巨噬细胞JAK2敲除动物，体内确证Seselin的药理活性和作用机制，评估靶向抑制巨噬细胞JAK2的治疗策略对于急性肺损伤的改善作用。本项目将丰富JAK2小分子抑制剂的设计思路，为急性肺损伤相关重大疾病提供潜在的治疗靶标和候选小分子，具有一定的基础研究意义和潜在的实际应用价值。

The continued and violent activation of alveolar macrophages is an important pathological feature of acute lung injury (ALI). Despite decades of research, the mechanism of macrophage phenotype maintenance remains elusive and the treatment options for this disease are still limited. We have found that JAK2 is expressed at especially high levels in alveolar macrophages via database mining strategy, and small compound, seselin, targets FERM-SH2 domain of JAK2 to block the proinflammatory phenotype of macrophages, thus ameliorating ALI. In this project, we will focus on the role of seselin controlled JAK2 activity in ALI and try to clarify the mechnisms. 1) We will explore the binding interface between seselin and JAK2 to prove that seselin is an allosteric inhibitor for JAK2. 2) Based on the binding pattern of seselin, we will elucidate the role of FERM-SH2 domain dimerization in JAK2 signal transduction, subsequently reveal the molecular basis for JAK2 activation. 3) We will establish alveolar macrophages JAK2 knockout mice to further evaluate the bioactivity of seselin in vivo. More important, we will corroborate the therapeutic benefits of precisely controlled JAK2 activity for ALI. This project will indicate the underlying mechanism responsible for JAK2 activation, provide a new sight in developing novel JAK2 inhibitors, and provide potential therapeutic target and new drug candidate for the treatment of ALI.