Normal lung development requires spatially and temporally correct interactions between embryonic epithelium and mesenchyme. While it is apparent that lung morphogenesis and differentiation are highly complex processes requiring a number of different signaling molecules, previous studies have established a primary role for the fibroblast growth factor (FGF) family. Of the twenty-one currently identified FGFs, six are present in the developing, lung. This project seeks to define the role of these ligands in lung morphogenesis, differentiation, and repair in four Specific Aims. In the first Specific Aim the investigators will culture purified lung epithelium from transgenic embryos conditionally expressing FGF10 to compare the effects of FGF10 on morphogenetic patterning vs epithelial cytodifferentiation. The role of BMP-4 as a downstream effector of FGF10 will also be determined. The investigators have previously shown that FGF7 can reprogram embryonic tracheal epithelium to express a distal lung phenotype. In the second Specific Aim they will determine which other FGF(s) can specify the distal lung epithelial phenotype. The investigators will first determine the temporal and spatial expression of the six lung-expressed FGFs, then systematically evaluate them for their ability to reprogram tracheal epithelium in mesenchyme-free culture. They will use antisense strategies to determine how inhibiting specific FGFs affects lung morphogenesis and differentiation. In the third Specific Aim the investigators will use two transgenic mouse models to determine how blockade of FGF signaling affects lung growth and differentiation in late-gestation, during postnatal alveolarization, and in the adult. The first model will use a conditionally expressed dominant-negative FGF receptor targeted to the lung, which should affect all FGF signaling. The second model will allow them to block only FGF signaling that is mediated by the FGFR2IIIb splice variant, which has been shown to be critical for lung development. These same two transgenic models will be used in Specific Aim 4 to define how inhibition of FGF signaling affects the response of the neonatal lung to chronic hyperoxia. At the end of this project the investigators will have a much better understanding of the role of the FGF family in lung development. These data should have an important impact on the development of strategies for the prevention and treatment of diseases resulting from fetal lung immaturity.
