Molecular and cellular mechanisms of mouse fetal lung maturation. (360G-Wellcome-093029_Z_10_Z)

Multipotent epithelial progenitors in the embryonic lung produce bronchiolar and then alveolar daughter cells. We will investigate the cellular and molecular mechanisms responsible for this bronchiolar to alveolar switch. The long-term aim of this research is to facilitate the development of therapeutic alveolargenesis. Key goals: 1. Cellular mechanism: determine if the bronchiolar to alveolar switch is intrinsic to the epithelium. We will transplant lineage-labelled multipotent epithelial progenitor cells into older, or younger, cultured lungs and quantitatively assess the fates of their daughters. 2. Molecular mechanism: define the minimal genes which are sufficient for the embryonic bronchiolar to alveolar switch. We will test which of the transcription factors expressed in the multipotent progenitors while they are producing alveolar descendents are sufficient to determine alveolar fate. The transcription factors will be ectopically expressed during the bronchiolar (pseud oglandular) phase of lung development in vitro. The molecular mechanisms of the phenotypes, in particular the transcription factor targets, will be determined in vivo. 3. Adult application: test the ability of the embryonic alveolar progenitor-specific transcription factors to convert postnatal progenitors from bronchiolar to alveolar fate. Transcription factors will be ectopically expressed in small numbers of postnatal bronchiolar progenitors in growing, steady-state, or injured animals.