细胞因子TGF-β促进上皮组织衰老，但在衰老中产生的分子相互关系及关键下游基因尚有待阐明。我们在前期工作中首次发现，在小鼠肺上皮前体干细胞（肺上皮II型细胞）敲除TGF-β通路中抑制分子Smad7基因，引起肺上皮复制性衰老，肺泡融合成肺泡囊，并伴有FBW7抑癌基因表达降低；在细胞培养中，TGF-β1抑制FBW7基因表达，持续干扰FBW7基因表达引起细胞复制性衰老。本研究拟使用基因敲除小鼠模型与细胞生物学及生物化学相结合的方法，梳理FBW7基因被TGF-β信号调控的分子机制，解析FBW7蛋白在介导细胞衰老中的功能及其分子互作调控网络。从而阐明TGF-β信号分子与其下游FBW7基因在介导肺上皮衰老过程中的因果关系，揭示TGF-β/FBW7通路从有序调控到细胞衰老的无序转变中的关键节点并建立相关检测方法和干预手段。

TGF-β is a major family of cytokines important in epithelial aging, but the mechanism by which TGF-β induces cell aging remains unclear. In our early experiments, we found for the first time that knocking out the inhibitory Smad7 gene in the pulmonary type II alveolar epithelial cells induced lung epithelial aging, consistent with a significant role for TGF-β1 in aging. TGF-β1 treatment (or Smad7 KO) inhibited the tumor suppressor gene FBW7 expression, and silencing FBW7 caused cell replicative senescence. We aim to exploit the mouse models and cellular biochemical methods to characterize how FBW7 is negatively regulated by TGF-β signaling and how inhibition of FBW7 in turn mediates cell senescence in lung epithelium. We will elucidate the causal relationships among TGF-β, Smads proteins and FBW7 gene, the function and regulatory networks of FBW7 protein, and the deregulations that underpin lung epithelial aging for mechanisms of inquisition and intervention.