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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZHL1-CSR-K (S1))
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Berberich, Mary Anne
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Children's Hospital of Los Angeles
Los Angeles
United States
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Sala, Frederic G; Del Moral, Pierre-Marie; Tiozzo, Caterina et al. (2011) FGF10 controls the patterning of the tracheal cartilage rings via Shh. Development 138:273-82
Lazarus, Alon; Del-Moral, Pierre Marie; Ilovich, Ohad et al. (2011) A perfusion-independent role of blood vessels in determining branching stereotypy of lung airways. Development 138:2359-68
El-Hashash, Ahmed H K; Al Alam, Denise; Turcatel, Gianluca et al. (2011) Eyes absent 1 (Eya1) is a critical coordinator of epithelial, mesenchymal and vascular morphogenesis in the mammalian lung. Dev Biol 350:112-26
Del Moral, Pierre-Marie; Warburton, David (2010) Explant culture of mouse embryonic whole lung, isolated epithelium, or mesenchyme under chemically defined conditions as a system to evaluate the molecular mechanism of branching morphogenesis and cellular differentiation. Methods Mol Biol 633:71-9
Carraro, Gianni; del Moral, Pierre-Marie; Warburton, David (2010) Mouse embryonic lung culture, a system to evaluate the molecular mechanisms of branching. J Vis Exp :
Carraro, Gianni; El-Hashash, Ahmed; Guidolin, Diego et al. (2009) miR-17 family of microRNAs controls FGF10-mediated embryonic lung epithelial branching morphogenesis through MAPK14 and STAT3 regulation of E-Cadherin distribution. Dev Biol 333:238-50
Shi, Wei; Xu, Jun; Warburton, David (2009) Development, repair and fibrosis: what is common and why it matters. Respirology 14:656-65
Moeller, Antje; Ask, Kjetil; Warburton, David et al. (2008) The bleomycin animal model: a useful tool to investigate treatment options for idiopathic pulmonary fibrosis? Int J Biochem Cell Biol 40:362-82
Sun, Jianping; Chen, Hui; Chen, Cheng et al. (2008) Prenatal lung epithelial cell-specific abrogation of Alk3-bone morphogenetic protein signaling causes neonatal respiratory distress by disrupting distal airway formation. Am J Pathol 172:571-82
Warburton, David; Perin, Laura; Defilippo, Roger et al. (2008) Stem/progenitor cells in lung development, injury repair, and regeneration. Proc Am Thorac Soc 5:703-6

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