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 Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL073014-01A1
Application #
6818003
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Berberich, Mary Anne
Project Start
2004-07-02
Project End
2005-03-31
Budget Start
2004-07-02
Budget End
2005-03-31
Support Year
1
Fiscal Year
2004
Total Cost
$279,000
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

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
De Langhe, Stijn P; Carraro, Gianni; Warburton, David et al. (2006) Levels of mesenchymal FGFR2 signaling modulate smooth muscle progenitor cell commitment in the lung. Dev Biol 299:52-62
del Moral, Pierre-Marie; De Langhe, Stijn P; Sala, Frederic G et al. (2006) Differential role of FGF9 on epithelium and mesenchyme in mouse embryonic lung. Dev Biol 293:77-89
Warburton, David; Bellusci, Saverio; De Langhe, Stijn et al. (2005) Molecular mechanisms of early lung specification and branching morphogenesis. Pediatr Res 57:26R-37R
Tefft, Denise; De Langhe, Stijn P; Del Moral, Pierre-Marie et al. (2005) A novel function for the protein tyrosine phosphatase Shp2 during lung branching morphogenesis. Dev Biol 282:422-31