肺上皮管腔分支的形成和管腔大小的调控是肺发育的关键之一。研究表明在发育过程中，肺上皮祖细胞通过SHH，FGF和RA(retinoid acid)等旁分泌信号与周边间质细胞相互作用，决定肺管腔形成，但这些关键信号调控上皮的细胞生物学行为从而影响管腔成熟的机制不明。我们的研究发现KLF5是受SHH影响的重要肺上皮转录因子。肺上皮特异性高表达KLF5可导致肺管腔扩大和分支减少，肺上皮特异性KLF5敲除导致肺上皮管腔扩张障碍，提示KLF5在肺上皮管腔的形成中起关键的调控作用。进一步的研究显示KLF5的表达显著抑制了极性调控蛋白CDC42的活性，同时介导了细胞形状的变化。因此，该研究将通过利用肺上皮特异性基因敲除和高表达动物模型研究KLF5通过调控CDC42相关的细胞极性调控肺上皮管腔形成和成熟的机制,为进一步理解和治疗早产儿呼吸窘迫综合症、支气管肺发育不良等肺上皮管腔发育不良相关疾病提供理论依据.

Precise regulation of epithelial tubulogenesis is critical for lung development. Studies showed signals that mediate reciprocal interactions between the epithelium and the mesenchyme, including SHH, FGF, RA and WNT, are critical for respiratory tubulogenesis. But the underlying cellular mechanism which mediated the morphological changes of the respiratory tubulogenesis is unclear. We found induced expression of KLF5 was identified in the abnormal branched respiratory tubules after deletion of SHH. Pulmonary epithelial cell specific overexpression or deletion of KLF5 caused abnormal formation and maturation of respiratory tubules, indicating that KLF5 mediated SHH signaling in regulation of pulmonary tubulogenesis. Our recent evidence reveals that induced expression of KLF5 inhibited activation of CDC42, a critical regulator of cell polarity, associating with significant changes of cell shape. In this application, mouse models in which Klf5 is deleted or induced in developing pulmonary epithelial cells will be used to test the general hypothesis that KLF5 mediates lung tubulogenesis through regulation of CDC42 related epithelial cell polarity. These studies will finally provide a basis for understanding the pathogenesis of pulmonary diseases of immaturity, including neonates respiratory distress syndrome, bronchial pulmonary dysplasia (BPD) and asthma.