TGF BETA3 IN LUNG MORPHOGENESIS, INJURY AND REPAIR

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Members of the transforming growth factor (TGF) family are key cytokines involved in tissue morphogenesis and repair. Todefine key functions specific to TGF-beta3, we generated TGF-beta3 null mutant mice. These shoul unique phenotypic features restricted to delayed pulmonary development and a cleft palate and die shortly after birth. Lungs appeared primitive with decreased alveolarization. The risk for developing neonatal lung disease. These data indicate an important role for TGF-beta in perinatal lung deelopment and we hypothesize that TGF-beta3 is involved in the pathobiology of lung disease. We propose to further determine whether the temporo-spatial influence of TGF-beta on lung development evident from the null mutant occurs primarily during the early embryonic versus late fetalstages and whether the primary effects are on gene expression in the epithelium or mesenchyme. Candidate genes will be identified in the molecular signaling pathways through which TGF-beta3 regulates lung development and repair of lung injury, using representational difference analysis for cocmparing our TGF-beta3 null mutants and overexpressors to wild type. Effects of TGF-beta3 overexpression on lung organogenesis and repair will be investigated, as compared to the known deleterious effects of TGF-beta1, using transgenic mice overexpressing TGF-beta3 froma tightly regulatable TGF-beta3 promoter. The consequences of TGF-beta3 absence on postnatal lung development and lung repair in response to experimentally elicited pulmonary injury will be assessed in TGF-beta3 null mutants, in which the production of TGF-beta3 can be switched on and off as required. Our experiments will identify specific roles of TGF-beta3 in both lung development and repair including the development of neonatal chronic lung disease using unique in vivo mouse models. The data generated will be of importance towards the realization of the long-termgoals of this Program Project of developing rational therapeutics against neonatal pulmonary disease.