The long-term goals of this component seek to 1) elucidate the hierarchy of transcriptional controls that determine the commitment of progenitor cells that produce the differentiated cells of the developing and mature respiratory epithelium and 2) utilize transcriptional control elements governing lung epithelial cell gene expression to determine the pathogenesis of acute and chronic lung disorders such as respiratory distress syndrome, pulmonary fibrosis, bronchopulmonary dysplasia and other disorders of surfactant homeostasis. Our analysis of the transcriptional controls of surfactant proteins A, B, C and CC10 provided critical insight into the role of thyroid transcription factor 1 (TTF-1), a 38 kilosdalton homeodomain, containing protein of the NK-2 family, and the HNF-3 family of nuclear transcription proteins in lung-specific gene expression. We hypothesize that these proteins bind to and activate promoter elements that control the temporal, spatial and humoral influences on lung epithelial cell gene expression. The present application will now determine the role of TTF-1 and HNF-3alpha in lung development, differentiation and gene expression using gene ablation and gene addition experiments in vitro and in vivo. The mechanisms controlling TTF-1 gene expression in the developing lung epithelium will be discerned. Downstream targets activated by TTF-1 will be identified by differential display to determine their roles in gene expression and surfactant homeostasis in developing and mature lung.
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