Studies of the molecular embryology of the lung are likely to provide significant new mechanistic insights into the molecular processes of lung disease. During Years 01-03 of support, we have established that autocrine/paracrine signalling, specifically activation of EGF receptor (EGFR) by EGF, instructs embryonic mouse lung branching morphogenesis in chemically defined culture. New preliminary data indicate that EGF and TGF beta signalling pathways interact to instruct pulmonary morphogenesis. Hypothesis: TGF beta receptor mediated signalling instructs early mouse embryonic lung branching morphogenesis, modulates and is modulated by EGFR mediated signalling.
Specific Aims :
Aim 1. To define developmental and temporo-spatial expression of TGF beta I and IIR during embryonic pulmonary branching morphogenesis and cytodifferentiation in vivo and in serumless culture.
Aim 2. To determine the function of TGF beta signaling in regulating embryonic pulmonary branching morphogenesis and cytodifferentiation in serumless culture.
Aim 3. To define molecular mechanisms of crosstalk between EGF and TGF beta signalling: (i) in embryonic pulmonary branching morphogenesis and cytodifferentiation in serumless culture, (ii) in embryonic pulmonary mesenchymal cells in primary culture with comparisons to MvlLu cells.
Aim 4. To define protein-protein interactions between TGF beta I and II receptors as well as downstream signalling molecules. Future Aims: To define molecular mechanisms of growth factor receptor mediated interactive signalling and transcriptional activation of lung developmental genes. Clinical relevance: To provide a rationale for novel approaches to peptide growth factor based pulmonary therapeutic strategies to ameliorate lung injury and augment lung repair, particularly in very immature human infants in whom lung development is incomplete at birth.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL044977-07
Application #
2668680
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Project Start
1991-08-01
Project End
2000-02-29
Budget Start
1998-03-01
Budget End
1999-02-28
Support Year
7
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Southern California
Department
Pediatrics
Type
Schools of Medicine
DUNS #
041544081
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
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
El-Hashash, Ahmed H K; Turcatel, Gianluca; Varma, Saaket et al. (2012) Eya1 protein phosphatase regulates tight junction formation in lung distal epithelium. J Cell Sci 125:4036-48
El-Hashash, Ahmed H; Warburton, David (2011) Cell polarity and spindle orientation in the distal epithelium of embryonic lung. Dev Dyn 240:441-5
El-Hashash, Ahmed H K; Turcatel, Gianluca; Al Alam, Denise et al. (2011) Eya1 controls cell polarity, spindle orientation, cell fate and Notch signaling in distal embryonic lung epithelium. Development 138:1395-407
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
Jackson, Sha-Ron; Lee, Jooeun; Reddy, Raghava et al. (2011) Partial pneumonectomy of telomerase null mice carrying shortened telomeres initiates cell growth arrest resulting in a limited compensatory growth response. Am J Physiol Lung Cell Mol Physiol 300:L898-909
El-Hashash, Ahmed H K; Al Alam, Denise; Turcatel, Gianluca et al. (2011) Six1 transcription factor is critical for coordination of epithelial, mesenchymal and vascular morphogenesis in the mammalian lung. Dev Biol 353:242-58
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
Tarantal, A F; Chen, H; Shi, T T et al. (2010) Overexpression of transforming growth factor-beta1 in fetal monkey lung results in prenatal pulmonary fibrosis. Eur Respir J 36:907-14

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