Lung development is a continuous process involving epithelial-mesenchymal interactions. The long term goal of our research is to understand the role of laminins in this process. Laminins are basement membrane-related glycoproteins produced by epithelial and mesenchymal cells and best characterized by their involvement in cell adhesion, migration and maintenance of the differentiated cell phenotype. Cells bind to laminins in part via the integrin family of extracellular matrix receptors. These are heterodimeric transmembrane glycoproteins with roles in signal transduction. During the current funding period we have found that different domains of laminins -1 and -2 are engaged in promoting lung morphogenesis by serving different functions; among them, the production of a polymer at the epithelial-mesenchymal interface seems critical for the maintenance of normal tissue structure. Furthermore, discontinuities in this laminin polymer result in direct epithelial-mesenchymal contact. Based on our recent studies we hypothesize that such heterotypic cell-cell contact induces the expression of laminins - 1 and -2 and their deposition at the epithelial-mesenchymal interface. The process is initiated by an integrin-mediated mechanism and results in basement membrane formation, differentiation of peribronchial mesenchyme into smooth muscle and budding of the bronchial tree.
The specific aims of this proposal are designed to test this hypothesis. During this investigation we shall: 1. characterize the mechanism involved in the secretion of laminin-2 to the extracellular compartment upon epithelial-mesenchymal contact and the role of integrins in this process; 2. determine the mechanism of regulation of laminin-1 expression in epithelial-mesenchymal cocultures; 3. elucidate the role of laminin-1 in bronchial smooth muscle cell differentiation and identify specific laminin-1 domains involved in the process; and 4. determine the role of laminin polymerization/depolymerization at the epithelial-mesenchymal interface in epithelial budding and in mesenchymal paracrine control over epithelium. We anticipate that each of the four aims proposed here will provide new insight in the process of organogenesis and contribute to the elucidation of pathological conditions that result or lead to defective lung development.
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