Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL075773-02
Application #
6803559
Study Section
Special Emphasis Panel (ZHL1-CSR-K (S1))
Program Officer
Berberich, Mary Anne
Project Start
2003-09-30
Project End
2007-08-31
Budget Start
2004-09-01
Budget End
2005-08-31
Support Year
2
Fiscal Year
2004
Total Cost
$341,400
Indirect Cost

  Institution

Name
Children's Hospital of Los Angeles
Department
Type
DUNS #
052277936
City
Los Angeles
State
CA
Country
United States
Zip Code
90027

  Publications

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
Finney, Brenda A; del Moral, Pierre M; Wilkinson, William J et al. (2008) Regulation of mouse lung development by the extracellular calcium-sensing receptor, CaR. J Physiol 586:6007-19
Chen, H; Zhuang, F; Liu, Y-H et al. (2008) TGF-beta receptor II in epithelia versus mesenchyme plays distinct roles in the developing lung. Eur Respir J 32:285-95
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

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