SHH Mediates Reciprocal Tissue Interactions During Formation of the Peripheral Lung Formation and maintenance of the peripheral lung requires precise reciprocal interactions between multiple cell types and distinct tissue compartments. Lung formation is dependent upon the concerted actions of complex transcriptional and signaling pathways that include TTF-1, beta-catenin, FGF-R2IIIb, VEGF-A, and sonic hedgehog (SHH) (expressed in the endodermally-derived lung buds) that, in turn, interact with Wnt, FGF family members, VEGF receptors, and transcriptional pathways (for example FoxF1, POD-1, Gli' s) that mediate vasculogenesis and smooth muscle development, in the mesenchyme and stroma. This application seeks to test the hypothesis that SHH signaling plays instructive roles during the formation of acinar/alveolar compartment of the lung, initiating and modulating tissue interactions between the epithelium and the developing vascular system via these various transcriptional and signaling pathways. We will utilize transgenic mice in which SHH is conditionally deleted via timed epithelial expression of cre to delete floxed SHH alleles. SHH will be replaced under conditional control in the developing embryonic lung in both SHH-/- and SHH replete (wild type) mice. Effects of SHH deletion, addition, and mutation on alveolar-vascular formation will be assessed during the embryonic, perinatal, and postnatal periods. The temporal-spatial requirements and effects of SHH on lung alveologenesis, vasculogenesis, and gene expression will be discerned. SHH will be expressed in the perinatal period to determine the potential role for SHH in reinitiating events involved in formation of the alveoli and pulmonary vasculature. Effects of regulated expression of SHH will be assessed in the neonatal mouse during exposure to hyperoxia. Cell lineage and marker analysis will be utilized to test whether SHH plays roles in commitment, differentiation, and migration of epithelial, endothelial, and smooth muscle cells during branching morphogenesis and alveologenesis. This application seeks to understand and test the utility of the SHH pathway for protection and repair of the neonatal lung -- processes relevant to our understanding of the pathogenesis and treatment of bronchopulmonary dysplasia in preterm infants.
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