TGF BETA SIGNALING IN LUNG MORPHOGENESIS, INJURY AND REPAIR

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Hypothesis: (1) excess TGF-beta signaling disrupts the orderly temporo-spatial molecular cues that normally instruct lung morphogenesis and cytodifferentiation as seen following exposure of the developing lung to elevated ambient oxygen; therefore (2) modulationof excess TGF-beta signaling will ameliorate lung injury and augment repair of the developing lung. Speicifc Aims: 1. To determine the impact of increased ambient oxygen on TGF-beta production, activation and signaling in vivo in postnatal and adult murine lung. 2. To determine the spatial effects of over-expression of TGF-beta peptides ineither latent or active (mutated) forms using TGF-beta recombinant adenoviral vectors in embryonic mouse lung in ex vivo culture. 3. To detemine the effects of TGF-beta peptide over-expression on alveolarizationin neonatal mouse lung in vivo byintra-nasal or intratracheal administration of TGF-beta recombinant adenoviral vectors. 4. To determine the in vivo role of epithelial TGF-beta receptor signal transduction molecules onlung morphogenesis, injury and repair by transgenic expression of active versus C-terminally truncated negative Smads using the hSP-C lung epithelium specific promoter. 5. To determine whether strategies to down-modulate TGF-beta signaling including immunoperturbation, competing peptides and speicifc antisnse oligodeoxynucleotides can ameliorate the adverse impact of excess TGF-beta signaling. Significance to Human Health: the propsoed studies will determine whether excess TGF-beta signaling plays an adverse role in developing lung and will determine the feasibility of novel therapeutic strategies tomodulate TGF-beta signaling. Prevention andtreatment of chronic lung disease in premature infants may become possible.