Bronchopulmonary Dysplasia or BPD is a chronic lung disease that results from interruption of normal in utero lung development by premature birth. We have shown that bioactive TGFBeta in the lungs of human preterm infants predicts severity of BPD, suggesting a possible role in its pathogenesis and arrested lung development. Another key signaling molecule with suggested role in pathogenesis of BPD is FGF10 which was recently found to be decreased significantly in BPD lungs. Our preliminary studies establish an operational link between FGF10 &TGFBeta through the Pten/PI3k/Akt/Erk pathway. We have further shown that FGF10 can protect lungs from TGFBeta?induced fibrosis in mice. This project will use simple genetic and molecular approaches to address the role of TGFBeta &FGF10 in pathogenesis of BPD. The logical basis for the current proposal rests on a number of preliminary, but important data that collectively, support the following overall hypothesis: HYPOTHESIS: We hypothesize that TGFBeta signaling via T?RII derails lung morphogenesis by inhibiting epithelial progenitor cell proliferation, mediated thru increased Pten, which leads to inhibition of PI3k/Akt/Erk pathway. We further hypothesize that FGF10 can protect the neonatal lung from hyperoxia/TGFBeta-mediated injury &BPD at least in part by countering the inhibitory effect of TGFBeta on the PI3k/Akt/Erk pathway. The following specific aims will test the validity of the above hypothesis Specific Aim 1. To Determine the Precise Pathway via Which TGFBeta Inhibits Epithelial Progenitor Cell Proliferation and Morphogenesis in both in vitro &in vivo Models. The availability of genetically engineered mice offers an unprecedented opportunity to elucidate the precise role of a key target of TGFBeta, Pten, &its signaling target, the PI3k/Akt/Erk pathway in both in vitro &in vivo settings.
Specific Aim 2. To determine the Potential Role of TBetaRII in Epithelial &Mesenchymal Compartments of the Lung in Pathogenesis of Hyperoxia-?Induced Hypoalveolization in Neonatal Mice (The mouse BPD Model). Mice carrying either Epithelial-?or Mesenchymal-specific deletion of TBetaRII will be exposed to hyperoxia and the process of alveolization will be measured by state-of-the-art technical approaches.
Specific Aim 3. To Determine the Role of FGF10 in a Murine Model of Hyperoxia-?Induced Hypoalveolization. We have shown that mesenchymal deletion of TBetaRII leads to increaseded FGF10. Remarkably regulated ectopic expression of Fgf10 in transgenic mice protects from bleomycin-induced adult lung injury. In this aim, we will test the hypothesis that ectopic Fgf10 also protects from hyperoxia-induced lung injury in neonatal transgenic mice. As in Specific Aim 1, the focus of the mechanisms in this aim will be the PI3k/Akt/Erk pathway.

Public Health Relevance

This research project uses experimental models to elucidate how excess TGF?beta, a growth factor, implicated in chronic lung disease in prematurely born infants causes abnormal behavior of lung cells and hence lung injury.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL107307-03
Application #
8588348
Study Section
Special Emphasis Panel (ZRG1-CVRS-G (03))
Program Officer
Lin, Sara
Project Start
2012-01-01
Project End
2015-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
3
Fiscal Year
2014
Total Cost
$368,552
Indirect Cost
$130,641
Name
University of Southern California
Department
Pediatrics
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Volckaert, Thomas; Yuan, Tingting; Chao, Cho-Ming et al. (2017) Fgf10-Hippo Epithelial-Mesenchymal Crosstalk Maintains and Recruits Lung Basal Stem Cells. Dev Cell 43:48-59.e5
Chao, Cho-Ming; Yahya, Faady; Moiseenko, Alena et al. (2017) Fgf10 deficiency is causative for lethality in a mouse model of bronchopulmonary dysplasia. J Pathol 241:91-103
El Agha, Elie; Moiseenko, Alena; Kheirollahi, Vahid et al. (2017) Two-Way Conversion between Lipogenic and Myogenic Fibroblastic Phenotypes Marks the Progression and Resolution of Lung Fibrosis. Cell Stem Cell 20:261-273.e3
Chao, Cho-Ming; Moiseenko, Alena; Zimmer, Klaus-Peter et al. (2016) Alveologenesis: key cellular players and fibroblast growth factor 10 signaling. Mol Cell Pediatr 3:17
Chao, Cho-Ming; El Agha, Elie; Tiozzo, Caterina et al. (2015) A breath of fresh air on the mesenchyme: impact of impaired mesenchymal development on the pathogenesis of bronchopulmonary dysplasia. Front Med (Lausanne) 2:27
Sureshbabu, Angara; Syed, Mansoor A; Boddupalli, Chandra Sekhar et al. (2015) Conditional overexpression of TGF?1 promotes pulmonary inflammation, apoptosis and mortality via TGF?R2 in the developing mouse lung. Respir Res 16:4
Al Alam, Denise; El Agha, Elie; Sakurai, Reiko et al. (2015) Evidence for the involvement of fibroblast growth factor 10 in lipofibroblast formation during embryonic lung development. Development 142:4139-50
Li, Changgong; Li, Min; Li, Sha et al. (2015) Progenitors of secondary crest myofibroblasts are developmentally committed in early lung mesoderm. Stem Cells 33:999-1012
Carraro, Gianni; Shrestha, Amit; Rostkovius, Jana et al. (2014) miR-142-3p balances proliferation and differentiation of mesenchymal cells during lung development. Development 141:1272-81
El Agha, Elie; Herold, Susanne; Al Alam, Denise et al. (2014) Fgf10-positive cells represent a progenitor cell population during lung development and postnatally. Development 141:296-306

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