Periodontal disease is characterized by degradation of the basement membrane between the junctional epithelium and the tooth, resulting in detachment of the epithelium from the tooth surface followed by apical migration and proliferation of epithelial cells. Formation of this long junctional epithelium precludes attachment of periodontal ligament cells to the root surface, thereby preventing successful healing. Stable attachment of epithelia cells to the internal basal lamina prevents this ling junctional epithelium formation and facilitates repair of damaged periodontal tissue. Ultrastructural data indicate that hemidesmosomes are present at the dento-epithelial junction and contribute to maintenance of normal tissue architecture. A newly described laminin isoform, laminin-5, is involved in an unique integrin-mediated interaction with epithelial cells which can induce hemidesmosome assembly, resulting in the formation of a stable cell:matrix attachment and loss of migratory capacity. However, laminin-5 has also been associated with migrating cells, suggesting a role in mediating cellular motility. To address the differential role of laminin-5 in promoting both gingival epithelial cell adhesion and migration, it is the working hypothesis of this proposal that proteolytic processing of laminin-5 by enzymes present in the gingival microenvironment alters laminin-5 structure and thereby modulates its function. To address this hypothesis, experiments are proposed to analyze the normal processing of laminin-5 which accompanies incorporation into the insoluble extracellular matrix; to identify the subunit and site of cleavage of laminin-5 by a variety of proteinases, and to analyze the effect of these proteolytic modifications on cellular functions related to adhesion and migration. A more detailed understanding of the factors which regulate gingival epithelial cell migration may lead to the development of novel therapeutic approaches by which the formation of long junctional epithelium may be inhibited.
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