The integrin alphavbeta6 is a receptor for the extracellular matrix proteins fibronectin and tenascin. This receptor is highly expressed in the epithelium of the respiratory tract and the skin during development, after injury or inflammation, and in malignant tumors, but is not expressed at either site in normal, healthy adults. In vitro, heterologous expression of alphavbeta6 in tumor cells increases cell adhesion to fibronectin and tenascin and also increases the capacity of these cells to proliferate. However, nothing is known about what role, if any, this receptor plays in vivo. To examine the in vivo function of alphavbeta6, we are producing mice that are deficient in receptor expression using standard homologous recombination in embryonic stem cells. In parallel, we are producing mice that overexpress either functional receptor, or a mutant version engineered to be incapable of binding ligand, under the control of highly active promoters that target expression to the airway epithelium (CC10), to alveolar type II cells and bronchiolar epithelium (SPC), or to basal keratinocytes (K14). Examination of the growth and development of mice deficient in beta6 protein should provide important clues to what role, if any, this receptor plays in epithelial differentiation and organogenesis. In addition, we propose to produce cutaneous wounds and respiratory epithelial injuries in these mice to determine the role of alphavbeta6 in epithelial repair in the lungs and skin. We also propose to examine the effects of overexpression of intact or mutant beta6, and of knockout of the beta6 gene, on the development of spontaneous and chemically-induced lung tumors. These studies should provide important information about the in vivo function of this integrin in lung (and cutaneous) development, in the repair of lung (and cutaneous) injury, and in the development, growth and/or progression of lung tumors.
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