The reversible modulation of both cell-cell and cell-substrate adhesive contacts if thought to play an important role during epithelial tissue remodeling. During the migratory phase of remodeling, a dramatic reduction in the number of cell-cell junctions known as desmosomes has been reported. However, the mechanisms governing desmosome disappearance or reassembly during this process are unknown. One example of remodeling that contributes to the progression of periodontal disease, which is a major health problem in the U.S., is the inward migration of junctional epithelium along the tooth surface that occurs following dissolution of gingival connective tissue. In order to understand how modulation of desmosomes may impact on oral epithelial cell migration, the molecular mechanisms that regulate desmosome assembly and dissolution must be elucidated using well-defined in vitro and cell culture models. In this project we will continue our efforts to define protein-protein interactions in the desmosome and t investigate how adhesive junctions are modulated in oral epithelial cell cultures. The specific aims are: 1) To determine the protein-protein interactions involved in establishing the structure of the desmosomal plaque and ensuring segregation of desmosomal and adherens junction components into distinct membrane domains, 2) To investigate intercellular junction dynamics and the role of the associated cytoskeleton and underlying extracellular matrix during migration of oral epithelial cells, using a combination of live cell observations and molecular genetic manipulation of oral epithelial ells, 3) To examine the contribution of proteinases present in the gingival microenvironment to junction dissolution and to define whether specific desmosomal cadherins are substrates for these proteinases. These studies will interface extensively with other project leaders who will provide reagents (i.e., IFAP300 from Dr. Goldman and laminin-5 peptides from Drs. Jones and Stack) and expertise (generation of fluorescently labeled probes for living cell observations, Dr. Goldman; zymographic analysis, Dr. Stack). This work will provide important insights into mechanisms by which cell-cell adhesive junctions are assembled and modulated in migrating oral epithelial cells, and will provide a basis for the design of therapeutic approached to curb the progression of periodontal disease.