Epithelial- mesenchymal (E-M) interactions play primary roles in development of epithelial organs. Most analyses of mechanisms mediating these E-M interactions have focused on components of the extracellular matrix (ECM). Recent advances in our understanding of cell adhesion molecules now afford an opportunity to examine the role of the actual epithelial cells in these interactions. Integrins constitute a class of cell surface proteins that serve as receptors for specific ECM components. The submandibular gland (SMG) of the fetal mouse presents a well characterized system to study epithelial-mesenchymal interactions both in vivo and in vitro. Published studies and preliminary data of the PI indicate that EGF and TGF alpha promote development of the SMG in culture, while an inhibitor of the EGF receptor (tyrphostin) diminishes SMG growth and development. The investigators hypothesize that these growth factors may be influencing SMG development by regulating expression of integrins on epithelial cells, which subsequently dictates the nature of their interactions with the mesenchyme during development.
Three Specific Aims are proposed to address this hypothesis: 1) To characterize the expression of integrins and ECM components during development of the SMG in vivo and in vitro and to establish if perturbations of these molecules interferes with normal SMG development. 2) To characterize the effects of EGF and TGF alpha on SMG development in vitro and to determine if these growth factors regulate expression of integrins and their ECM ligands. 3) To establish whether EGF and TGF alpha are physiologic regulators of SMG development and to determine whether they are produced by mesenchymal cells of the SMG. Results of these studies are expected to enhance the understanding of SMG developmental dynamics and potentially yield insight into the other processes impacted on by SMG epithelial mesenchymal interactions such as wound healing, metastasis and the genesis of congenital malformations.
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