Transforming growth factors-? are secreted polypeptides that render both physiological and pathological functions. Two receptor tyrosine kinases, T?RI and T?RII mediate the impact of TGF-? signaling on the cell surface. Functional specificity and differences between the two receptors, subsequent to ligand binding have not been rigorously and mechanistically addressed in lung development and disease. We have found that TGF-? signaling through the T?RII plays a critical role in both morphogenesis and injury in the lung. In the mesenchyme, we found T?RII to be required for normal epithelial-mesenchymal communication through Shh. In the epithelium, signaling through T?RII regulates alveolar formation, and is required in Bleomycin-induced lung injury. Based on these concepts, we have formulated the following hypothesis: HYPOTHESIS: Normal lung development and Bleomycin-induced lung injury are dependent on TGF-? signaling through T?RII. The latter hypothesis is supported by the available data and some of its predictions are directly testable by the following four Specific Aims:
Specific aim 1. To Determine the Mechanism of Cross-Talk Between Shh &TGF-? Signaling Pathways.
Specific aim 2. To Identify Components of the TGF-? Pathway That Mediate the Cross-Talk With the Shh Pathway.
Specific aim 3. To Determine the Potential Role of Epithelial T?RII in Pathogenesis of Bleomycin-Induced Murine Model of Pulmonary Fibrosis. Health Relevance: TGF-? is implicated in many lung diseases including Pulmonary Fibrosis and Bronchopulmonary Dysplasia. To our knowledge, the studies proposed in this application are the first to address, cell-specifically (epithelial versus mesenchymal) the contributions of signaling through T?RII to pathogenesis of lung injury.
This project will use specific genetic tools to study the role of TGF-? during lung development and in pathogenesis of neonatal and adult chronic diseases.
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