Excess TGF beta in neonatal lung injury and repair

Summary

Principal Investigator: D Warburton
Abstract: Hypothesis: The TGFbeta signaling pathway may function as a final common pathway to mediate the negative impact of neonatal lung injury on alveolar formation and gas exchange. Aim 1. Candidate gene induction: to determine the impact of neonatal hyperoxia and/or LP5 endotoxin, on time and space-specific expression and activity of TGFbeta ligand, cognate receptor and cognate Smad (2,3 and 4) expression in neonatal mouse lung. Aim 2. Candidate gene function: to compare the impact of neonatal hyperoxia and/or LP5 endotoxin, versus local overexpression of IL1-beta, or TNF-alpha, with that of TGF-beta1 using recombinant adenoviral vectors to determine which of them also phenocopies BPD by abrogation of alveolarization. Aim 3. Smad3 as a common downstream gene: to discover which effects of neonatal hyperoxia and/or LPS endotoxin injury, IL1beta, TNFalpha, and/or TGFbeta1 signaling in neonatal lung are transduced through a common TGF-alpha/Smad3 signaling pathway, using the Smad3 null mouse as a test model. Aim 4. Protection: to determine whether the negative sequelae of neonatal hyperoxia and/or LP5 endotoxin injury on alveolar formation can be blocked or ameliorated, either upstream or downstream within the TGF-beta pathway using recombinant viruses expressing Decorin or Smad7. Health Significance: we postulate that blocking key upstream inducers of TGFabeta signaling, correctly modulating TGFbeta signaling and/or inhibiting the downstream effects of TGFbeta could prevent or ameliorate alveolar hypoplasia/BPD.
Funding Period: 2004-07-02 - 2005-03-31
more information: NIH RePORT

Top Publications

  1. pmc miR-17 family of microRNAs controls FGF10-mediated embryonic lung epithelial branching morphogenesis through MAPK14 and STAT3 regulation of E-Cadherin distribution
    Gianni Carraro
    Developmental Biology, Regenerative Medicine and Surgery Program, Saban Research Institute, Children s Hospital Los Angeles, Keck School of Medicine and School of Dentistry, Los Angeles, CA 90027, USA
    Dev Biol 333:238-50. 2009
  2. pmc 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
    Pierre Marie del Moral
    Saban Research Institute, Childrens Hospital Los Angeles, Los Angeles, CA 90027, USA
    Methods Mol Biol 633:71-9. 2010
  3. ncbi Molecular mechanisms of early lung specification and branching morphogenesis
    David Warburton
    Developmental Biology Program, The Saban Research Institute of Childrens Hospital Los Angeles, CA 90027, USA
    Pediatr Res 57:26R-37R. 2005
  4. ncbi A novel function for the protein tyrosine phosphatase Shp2 during lung branching morphogenesis
    Denise Tefft
    Developmental Biology Program, Department of Surgery, USC Keck School of Medicine and the Saban Research Institute of Children s Hospital Los Angeles, Los Angeles, CA 90027, USA
    Dev Biol 282:422-31. 2005
  5. ncbi Differential role of FGF9 on epithelium and mesenchyme in mouse embryonic lung
    Pierre Marie del Moral
    Developmental Biology Program, Saban Research Institute of Children s Hospital Los Angeles, Los Angeles, CA 90027, USA
    Dev Biol 293:77-89. 2006
  6. ncbi Levels of mesenchymal FGFR2 signaling modulate smooth muscle progenitor cell commitment in the lung
    Stijn P De Langhe
    Developmental Biology Program, Department of Surgery, Saban Research Institute of Childrens Hospital Los Angeles, CA 90027, USA
    Dev Biol 299:52-62. 2006

Scientific Experts

  • D Warburton
  • Pierre Marie del Moral
  • Stijn P De Langhe
  • Saverio Bellusci
  • Gianni Carraro
  • Denise Tefft
  • Wei Shi
  • Gianluca Turcatel
  • Diego Guidolin
  • Pier Paolo Parnigotto
  • Caterina Tiozzo
  • Brittany M Young
  • Ahmed El-Hashash
  • Kasper Wang
  • Jacqueline M Veltmaat
  • Frederic G Sala
  • Mohammad K Hajihosseini
  • Frederic Sala

Detail Information

Publications6

  1. pmc miR-17 family of microRNAs controls FGF10-mediated embryonic lung epithelial branching morphogenesis through MAPK14 and STAT3 regulation of E-Cadherin distribution
    Gianni Carraro
    Developmental Biology, Regenerative Medicine and Surgery Program, Saban Research Institute, Children s Hospital Los Angeles, Keck School of Medicine and School of Dentistry, Los Angeles, CA 90027, USA
    Dev Biol 333:238-50. 2009
    ....
  2. pmc 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
    Pierre Marie del Moral
    Saban Research Institute, Childrens Hospital Los Angeles, Los Angeles, CA 90027, USA
    Methods Mol Biol 633:71-9. 2010
    ..g., epithelial and mesenchymal separation) and microbead studies...
  3. ncbi Molecular mechanisms of early lung specification and branching morphogenesis
    David Warburton
    Developmental Biology Program, The Saban Research Institute of Childrens Hospital Los Angeles, CA 90027, USA
    Pediatr Res 57:26R-37R. 2005
    ....
  4. ncbi A novel function for the protein tyrosine phosphatase Shp2 during lung branching morphogenesis
    Denise Tefft
    Developmental Biology Program, Department of Surgery, USC Keck School of Medicine and the Saban Research Institute of Children s Hospital Los Angeles, Los Angeles, CA 90027, USA
    Dev Biol 282:422-31. 2005
    ..Our results show that the protein tyrosine phosphatase Shp2 plays an essential role in modulating growth factor mediated tyrosine kinase receptor activation in early embryonic lung branching morphogenesis...
  5. ncbi Differential role of FGF9 on epithelium and mesenchyme in mouse embryonic lung
    Pierre Marie del Moral
    Developmental Biology Program, Saban Research Institute of Children s Hospital Los Angeles, Los Angeles, CA 90027, USA
    Dev Biol 293:77-89. 2006
    ..Our work shows for the first time that FGF9 acts on the epithelium involving FGFR2b to control its proliferation but not its differentiation and contributes to the regulation of canonical Wnt signaling in the epithelium...
  6. ncbi Levels of mesenchymal FGFR2 signaling modulate smooth muscle progenitor cell commitment in the lung
    Stijn P De Langhe
    Developmental Biology Program, Department of Surgery, Saban Research Institute of Childrens Hospital Los Angeles, CA 90027, USA
    Dev Biol 299:52-62. 2006
    ..Our work unravels part of the complex interactions that govern normal lung development and may be pertinent to understanding the basis of respiratory defects in Apert syndrome...