环境应激引起肺上皮细胞衰老，驱动肺组织过早老化、纤维化，但应激因子如何引起肺上皮组织衰老的机制一直未知。我们前期工作发现，应激引起肺泡上皮干（祖）细胞明显减少，肺泡干细胞发生复制性衰老、并向成纤维细胞及平滑肌纤维细胞异常分化。我们还首次发现，E3泛素连接酶FBW7是引起肺泡干细胞衰老及转分化的中介；在小鼠肺泡干细胞中敲除FBW7基因，肺泡干细胞数量增加，呼吸功能改善，肺早衰和纤维化被阻断。我们将进一步梳理FBW7介导干细胞衰老和异常分化的原因；解析肺泡干细胞异常分化、导致肺纤维化的分子基础，聚焦转录因子FOXO3和肺泡干细胞表明活性蛋白C的调控机制；探索小分子化合物和多肽对FBW7的干预作用和路径。从而阐明应激引起肺泡干细胞损伤、肺组织衰老及纤维化的内在联系，揭示环境因子与遗传要素互作网络的关键节点，为建立靶向分子预警和干预策略及手段奠定基础。

Both environmental stress and genetic factors have been linked to the development of lung senescence and fibrosis. However, it remains unknown how stress induces early pulmonary senescence, fibrogenesis and accelerates episodic onsets of fibrotic development and respiratory failure. Our preliminary work showed that stress such as radiation and oxidative stress accelerated pulmonary alveolar stem cell replicative senescence and aberrant transdifferentiation. Further studies revealed that the E3 ubiquitin ligase FBW7 mediated the cell cycle arrest and myofibrogenic differentiation. Targeted disruption of the Fbw7 gene in the pulmonary alveolar stem cells improved respiratory function, and prevented the stress-induced pulmonary aging and fibrosis. Thus, we will exploit human cells, mouse models and molecular biochemical approaches to characterize the processes of FBW7-mediated stress-induced pulmonary alveolar stem cell replicative senescence and transdifferentiation, and explore the ways of preserving pulmonary stem cells and thereby preventing lung senescence and fibrosis. We will elucidate the functional and regulatory networks of FBW7 deregulation underpinning pulmonary premature senescence and fibrosis in response to stress, focusing on transcription factor FOXO3 and pulmonary alveolar stem cell surfactant protein C. Our work will therefore elucidate the causal relationships between environmental cues, FBW7, and the consequences of pulmonary senescence and fibrosis, and provide further strategies for intervention.