Recessive dystrophic epidermolysis bullosa (RDEB) is an inherited disease characterized by skin fragility and blistering which results in chronic erosions. Anchoring fibrils which contain collagen type VII are reduced or absent in RDEB. Recently, it has been found that collagen type VII is hydrolyzed by skin collagenase. Cultured explants of involved and uninvolved skin from RDEB patients have increased collagenolytic activity. This points towards a dysregulation of collagenase activity which could be caused by errors of transcription, collagenase activation or inhibition. Collagenase activity is low in normal unwounded skin but is increased during wound repair. The high baseline expression of collagenase in unwounded RDEB skin and the additional upregulation of collagenase during repeated wounding and healing seem to be the stimulus for blistering. To the extent that regulation of collagenase is unknown, rational therapy for skin fragility, and scarring in RDEB is unfounded. The theme of project IV is """"""""Regulation of expression and activation of collagenase type I in normal and RDEB fibroblasts and keratinocytes using reconstituted skin as a model"""""""". We have recently developed models which allow the study of fibroblasts and keratinocytes in a three dimensional model of reconstituted skin and in collagen gels. This model can be studied in vitro and in vivo in the athymic or SCID mouse. The production of and response to cytokines and growth factors will be examined in these models.
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