Lung epithelial and vascular morphogenesis

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DESCRIPTION (provided by applicant): Co-morphogenesis of the lung vasculature in correct apposition to the epithelium is essential for the eventual transition to air breathing and is adversely impacted in lethal forms of human lung hypoplasia and neonatal lung injury. As yet the mechanisms that drive this coordinated process are incompletely understood. Null mutation reveals that FGF10 signaling is absolutely required for epithelial morphogenesis in the lung. Now our published and preliminary results show that VEGF signaling enhances both vascular and epithelial morphogenesis. However VEGFR2 is expressed in the embryonic mesenchyme and not the epithelium, suggesting indirect stimulation of the epithelium. Hypothesis: FGF and VEGF signaling functionally co-regulate lung epithelial and vascular morphogenesis. Aim 1. To determine the precise temporospatial relationship between the key elements in the FGF10 and VEGF signaling pathways during embryonic lung morphogenesis. Aim 2. To determine the functional impact of VEGF signaling on lung epithelial and vascular morphogenesis in vivo using novel inducible and reversible gain and loss of function in mice. Aim 3. To determine the function of FGF10 signaling to regulate VEGF signaling during lung epithelial and vascular morphogenesis in vivo. Aim 4. To determine and compare the functional role of key FGF10 and VEGF signaling elements and to determine whether the effects of VEGF on the epithelium are direct or indirect in serumless, chemically defined embryonic lung organ culture system.