Hypothesis: Therapies aimed at negatively modulating specific targets upstream of, within or downstream of the TGF13 signaling pathway may prevent neonatal lung injury, augment neonatal lung repair and hence optimize alveolar formation.
Aim 1. Candidate gene induction in the upstream cascade: to determine the impact of neonatal hyperoxia and/or LPS endotoxin on time and space-specific expression and activity of ILll3 and TNFo_, their cognate receptors, Toll family LPS endotoxin receptors and TGF13 expression and signaling in neonatal lung.
Aim 2. Candidate upstream target gene function: to compare the impact of neonatal hyperoxi_ and/or LPS endotoxin, versus local overexpression of IL1-13, or TNF-_, or TGF-(_ using recombinanl viral vectors to determine which of them most closely phenocopies BPD by abrogation ol alveolarization.
Aim 3. Synergy between candidate upstream target genes: to determine whether synergy tc abrogate formation of alveoli exists between neonatal hyperoxia, LPS endotoxin, ILl13, TNFo_, and/or TGF-13 in our neonatal rat model.
Aim 4. Smad3 as a common downstream target mechanism: to discover whether the effects ol neonatal hyperoxia, and/or LPS endotoxin injury as well as of ILll3, TNF(_, and/or TGF13 signaling ir neonatal lung are transduced through a common TGF-odSmad3 signaling pathway, using the Smad,_ null mouse as a test model.
Aim 5. 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 downstrearr within the TGF-13 pathway using recombinant viruses expressing Decorin or Smad7.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL060231-09
Application #
7615585
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
9
Fiscal Year
2008
Total Cost
$403,045
Indirect Cost
Name
Children's Hospital of Los Angeles
Department
Type
DUNS #
052277936
City
Los Angeles
State
CA
Country
United States
Zip Code
90027
Buckley, Susan; Shi, Wei; Xu, Wei et al. (2015) Increased alveolar soluble annexin V promotes lung inflammation and fibrosis. Eur Respir J 46:1417-29
Xing, Yiming; Wang, Runming; Li, Changgong et al. (2015) PTEN regulates lung endodermal morphogenesis through MEK/ERK pathway. Dev Biol 408:56-65
Li, Changgong; Li, Aimin; Xing, Yiming et al. (2013) Apc deficiency alters pulmonary epithelial cell fate and inhibits Nkx2.1 via triggering TGF-beta signaling. Dev Biol 378:13-24
Gong, Dapeng; Fei, Fei; Lim, Min et al. (2013) Abr, a negative regulator of Rac, attenuates cockroach allergen-induced asthma in a mouse model. J Immunol 191:4514-20
Xu, Pinglong; Liu, Jianming; Derynck, Rik (2012) Post-translational regulation of TGF-* receptor and Smad signaling. FEBS Lett 586:1871-84
Tiozzo, Caterina; Danopoulos, Soula; Lavarreda-Pearce, Maria et al. (2012) Embryonic epithelial Pten deletion through Nkx2.1-cre leads to thyroid tumorigenesis in a strain-dependent manner. Endocr Relat Cancer 19:111-122
Lamouille, Samy; Connolly, Erin; Smyth, James W et al. (2012) TGF-?-induced activation of mTOR complex 2 drives epithelial-mesenchymal transition and cell invasion. J Cell Sci 125:1259-73
Xu, Pinglong; Liu, Jianming; Sakaki-Yumoto, Masayo et al. (2012) TACE activation by MAPK-mediated regulation of cell surface dimerization and TIMP3 association. Sci Signal 5:ra34
Turcatel, Gianluca; Rubin, Nicole; El-Hashash, Ahmed et al. (2012) MIR-99a and MIR-99b modulate TGF-* induced epithelial to mesenchymal plasticity in normal murine mammary gland cells. PLoS One 7:e31032
El-Hashash, Ahmed H K; Warburton, David (2012) Numb expression and asymmetric versus symmetric cell division in distal embryonic lung epithelium. J Histochem Cytochem 60:675-82

Showing the most recent 10 out of 126 publications