EPIDERMAL GROWTH FACTOR STIMULATES WOUND HEALING IN VIVO

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DESCRIPTION: (Adapted from the applicant's abstract) Maintenance of normal cutaneous function remains a daily challenge to humans since this barrier is under constant assault, both unplanned (trauma, burns, pathogenic organisms, UV exposure, ischemia, environmental toxins) and planned (surgery). This proposal is designed to examine cutaneous growth control mechanisms used by the skin in its attempt to maintain homeostasis. To define wound responses following trauma, key signal transduction responses along the epidermal growth factor receptor pathway will be examined in Aim I in an in vitro keratinocyte wound model with predictable migrating, proliferating, and differentiating keratinocytes that mimic the reepithelialization phase of wound repair. This model system should prove useful for dissecting signal transduction steps that are activated downstream from this prototype tyrosine kinase receptor (EGF-R). Keratinocytes will be transfected with mutant EGF-R forms to achieve dominant negative EGF-R keratinocytes. Possible alterations to the EGF-R mediated signal transduction pathway should yield valuable clues into growth control mechanisms activated in cutaneous wound healing. Significant findings along the EGF-R tyrosine kinase pathway will be further explored in human burns and chronic wounds. In Aim II, signal transduction responses will be defined using porcine in vivo wound models. EGF-R gene expression will be followed in the acute wound period using RT-PCR techniques. Possible differential effects following exogenous treatment from a variety of EGF like ligands will be explored in partial-thickness and grafted full-thickness injury models. Lastly, porcine wound repair parameters will be manipulated using gene therapy. Strategies will be employed to boost receptor levels with the goal of achieving facilitated repair. Growth factor/cytokine mechanisms controlling the transient growth and proliferation following cutaneous injury continue to be the central focus of this proposal. The prime goal of this proposal is to examine EGF-R associated signaling pathways to aid in the design of new therapies for wound repair.