In the processes of lung development and wound healing following injury, the architecture of the lung is determined by programmed cellular migration and differentiation that depends on the interaction of cells with each other and their extracellular environment. The integrins are a family of heterodimeric adhesion receptors that mediate many of the interactions of cells within the lung with their extracellular matrix. They have been implicated in many biologic processes, including morphogenesis, inflammation, healing and metastasis, and are likely of central importance in the regulation of lung development. Although the structures of many of the integrin alpha and beta subunits have been well characterized and their presence has been documented in various tissues throughout the body, there are many important questions that remain. The work proposed in this application addresses two important issues concerning integrins and the normal lung. The first goal of this proposal is to map the structure/function relationships of the integrin beta1 subunit by determining the epitopes of four anti-avian beta1 monoclonal antibodies that interfere with known integrin functions. This will be accomplished by the construction and analysis of chimeric avian-mouse pi subunits. The second goal of this proposal is to characterize the pattern and timing of integrin a subunit expression in the developing mouse embryonic lung. This will be accomplished by determining the presence of a subunit messenger RNA utilizing polymerase chain reaction amplification of isolated murine lung MRNA throughout development, and by in situ hybridization of embryonic lungs to localize the specific cell types in which integrin subunit message is expressed. The dissection of structure/function relationships may allow us to identify specific domains of the heterodimer that could be the targets of blocking agents such as antibodies, peptides, or pharmaceuticals. Thus, coupled with a knowledge of the pattern of integrin expression, these agents could be potentially useful in a wide range of therapeutic applications for the diseases of the lung in which integrins are involved.
