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.
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