Studies in our laboratories have centered on basic and clinical aspects of epidermal biology. The clinical areas of investigation have focused on developing an understanding of the intrinsic factors within the would bed that can either enhance or inhibit normal wound healing. We have also shown that cultured epidermal allografts (CEAs) can be successfully cryopreserved for long term storage, subsequently retrieved and used to enhance the would healing. Our basic efforts focused on defining the role of epidermal plasminogen activator inhibitor type-1 (PAI-1), a regulator of matrix integrity and cell-to-matrix adhesion, in directed migration of normal human keratinocytes (NHKs) post-wounding and during regenerative maturation. We showed that during regenerative maturation PAI-1 expression is confined to participate subpopulations of distinct epidermal cells, is upregulated via a secondary response pathways and that this induction is growth factor and substrate-dependent. It is hypothesized that growth factor-mediated reprogramming of PAI-1 gene expression is critical to the normal process of would repair. The ultimate aim of our combined studies is to develop an understanding of the mechanisms governing human keratinocyte migration and differentiation in response to wounding and to utilize our knowledge to design more optimal biological would dressings to further enhance the healing of both partial and full thickness burn wounds. To do this, we will address the following aims: I. To assess both the kinetics and molecular mechanisms underlying induced PAI-1 gene transcription in human keratinocytes in response to specific growth factors upon experimental monolayer wounding. II. To specifically perturb the kinetics and extent of PAI-1 synthesis in human keratinocytes via molecular genetic manipulations in order to assess the relevance of PAI-1 expression to defined epidermal cell growth state transitions associated with 'healing' in vitro and in vivo; III. To conduct a randomized clinical study on the use of CEAs to accelerate the healing of 3:1 meshed graft interstices in full thickness injuries, IV. To optimize composite skin grafting techniques in a pre-clinical porcine model to further enhance the utility of CEAs in the context of full thickness would healing.
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