Mechanisms of Lung Development and Injury

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DESCRIPTION (provided by applicant): The significance of TGF¿ as a signaling molecule during development & disease can be hardly over-stated. Given the complexity of the signaling pathway, it is not surprising that there is a wide spectrum of versatility and selectivity in TGF¿ biological activity. Along the pathway, selective utilization of receptors is a potential mechanism for generating versatility. The in vivo role of the individual receptors in the lung mesoderm and epithelium has been a major interest in our group. In separate studies, we have used epithelial- or mesodermal-specific cre mice to inactivate Alk5 or T¿R2, and examined the consequences in a highly systematic fashion. As a consequence, we now have an insight, however limited, into the role of each receptor in TGF¿ function. In the last cycle of this project, in addition to completing the original specific aims, we also collected preliminary data on the specific role of Alk5 in the lung mesoderm by genetic & molecular approaches. The preliminary findings collectively point to a unified underlying theme; that Alk5-mediated TGF¿ signaling is critical to progenitor/stem cell biology in various lung compartments. The simplified observed changes in the absence of mesodermal Alk5 function are, 1) reduced basal cell population in the trachea, 2) profoundly abnormal cartilage formation in the trachea, and 3) a major shift in the balance between lipofibroblasts versus myofibroblasts in the lung parenchyma. The phenotypes are fully penetrant, but the underlying mechanisms remain unknown. Elucidating these mechanisms is the goal of this application. Hypothesis: Mesodermal Alk5-mediated TGF¿ signaling controls the emergence/maintenance or differentiation of progenitor/stem cells in the lung. We will test the validity of this hypothesis by the following specific aims: Specific Aim 1: To Determine The Mechanisms by Which Inactivation of Alk5 in The Pulmonary Mesoderm Depletes Basal Cells. Specific Aim 2: To Determine The Role of Alk5 in Tracheal Morphogenesis. Specific Aim 3: To Determine Potential Phenotype Plasticity in Alk5-Regulated Lipofibroblast versus Myofibroblast Differentiation. Specific Aim 4: To Determine Whether Pulmonary Fibrosis Can be Rescued or Contained (i.e., Limited) by Inactivation of Alk5 & Trans-Differentiation of Activated Myofibroblasts to Lipofibroblasts. By completion of this work, we hope to have unraveled the specific role played by Alk5-mediated TGF¿ signaling in the ontogeny of key epithelial and mesenchymal progenitor/stem cell populations in the trachea and the lung parenchyma. The studies proposed here also offer the unique opportunity of examining, from a novel perspective the specific role of Alk5 in pathogenesis of pulmonary fibrosis in a mouse model.