MATRIX MEDIATORS OF WOUND HEALING

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DESCRIPTION: (Adapted from the applicant's abstract) Upon cutaneous trauma, a complex cascade of events is initiated within the wounded epidermis, "activating" resident keratinocytes (NHKs) and resulting in altered cellular growth and motility. Although the definitive signals that trigger commitment of basal keratinocytes to a pathway of migration and regenerative maturation remain largely unknown, the loss of adherence to the basement membrane is a critical aspect of epidermal migration and differentiation and likely involves regulated expression of "anti-adhesive" matrix proteins. One anti-adhesive protein that the investigators have identified as a potential regulator of the processes of re-epithelialization and regenerative maturation in NHKs is SPARC (also known as osteonectin and BM-40) SPARC is a widely distributed and highly conserved extracellular matrix (ECM)-associated glycoprotein that has been implicated in processes requiring tissue remodeling. Recent evidence in SPARC knockout mice suggests that loss of SPARC expression is associated with a defect in dermal wound repair. Inhibition of SPARC expression in stable anti-sense tranfectants severely inhibits the ability of basal NHKs to migrate in response to wounding thus supporting their hypothesis that expression of SPARC is a critical event in epidermal wound repair. Following wound closure, NHKs begin to differentiate and vertically migrate toward the surface of the skin. Anti-adhesive events are also associated with this process; the investigators have shown previously that SPARC is specifically induced prior to loss of adherence to the basement membrane and subsequent terminal differentiation of NHKs. Specific Aims for this project are: I. Determine the mechanisms underlying SPARC expression and the cell-type specificity of expression in subpopulations of NHKs undergoing: (A) Lateral migration in response to wounding and; (B) Vertical migration in response to regenerative maturation induced by NaBr. II. Ascertain the mechanism by which molecular perturbation of SPARC expression in NHKs alters: (A) NHK cell cycle kinetics: (B) NHK response to wounding; and (C) NHK differentiation. III. Determine how molecular perturbation of SPARC expression affects the regulation of wound-related changes in keratinocyte gene expression.