季节性流感的间断暴发流行以及新型人感染禽流感的不断增加，对人类健康造成严重威胁。人感染流感病毒的主要靶器官为肺，课题组前期研究证实流感肺炎患者出院三个月后损伤肺泡依然未完全恢复，流感小鼠肺组织中TLR4表达明显上调。基于最新研究及本课题组对肺泡再生修复的研究结果。我们提出核心假说：II型肺泡上皮细胞（AT2）参与成年流感小鼠肺泡再生修复过程，不同类别流感病毒感染后，参与肺泡上皮细胞修复的细胞机制不完全一致；AT2参与成年流感小鼠肺泡再生修复具体活化机制为，流感病毒感染后AT2表面TLR4上调，进而通过TLR4-TRIF-p38/JNK-YAP途径调控肺泡的再生修复。本课题拟利用Sftpc-CreERT2, Rosa26-mTmG等系列小鼠模型研究流感肺损伤修复过程中参与上皮修复的主要细胞类型；明确YAP对肺泡再生的调控及其上游的主要信号分子，为未来重症流感肺损伤的救治提供新思路。

The intermittent outbreak of pandemic influenza and emerge of novel avian influenza A virus in human has caused great threat to people’s health worldwide. The main target organ was considered to be the lung during influenza virus infection. Our preliminary data revealed that the alveolar function following influenza pneumonia was still not fully recovered even three months after discharge. The expression of TLR4 in the lungs of influenza mice was significantly increased. Based on the recent researches and our preliminary data, we hypothesize that type II alveolar epithelial cells (AT2) are involved in the process of alveolar regeneration in adult influenza mice. AT2 cells are able to quickly undergo self-renewal and to subsequently differentiate into AT1 cells. The cellular mechanisms involved in the repair of alveolar epithelial cells after different types of influenza virus infection are not exactly the same. This process is mainly mediated via TLR4-TRIF-p38 / JNK-YAP pathway. In this study, we will use adult Sftpc-CreERT2, Rosa26-mTmG mice for lineage tracing of AT2 cells and to demonstrate their role as progenitor cells in the repair of the alveolar epithelium. Further, with YAP-/-、TLR4-/- mice, we planned to characterize the genetic program and pathway that regulate the AT2 cell proliferation by utilizing RNA-seq, immunostaining , and immunoblot. This finding will provide clue for the exploration of novel drugs to ameliorate the lung injury during severe influenza infection.