An outstanding feature of many chronic skin wounds, in particular the venous stasis ulcer, is the failure of the epidermis to resurface the sound bed. Delayed re-epithelialization and persistent epithelial defects are also a characteristic of corneal wounds which go on to ulcerate, or of ulcers which do not heal. Failure of re- epithelialization, in both cases, appears to be due, not to inadequate cell proliferation, but to the impaired capacity of cells to migrate across the wound bed and to form stable attachments to the dermal/stromal layer of the tissue. Because of the apparent similarity in mechanism, it seems useful to consider aspects of chronic would healing in both tissue types in attempting to develop an understanding of failure to heal. In preliminary work, an investigation was made into possible enzymatic involvement in this disorder using a rat corneal model of ulceration induced by thermal injury. These studies have supported the hypothesis that failure of re-epithelialization is due to excessive proteolytic activity mediated by enzymes of the Matrix Metalloproteinase family, in particular, gelatinase B. Normal repair appears to be disrupted by this enzyme due to its capacity to degrade the basement membrane on which the epithelium migrates to resurface an injury and to which it subsequently must form stable attachments. Expression of gelatinase B by the epithelium is a normal part of the genetic program for re-epithelialization of an injured cornea. However, in corneal injuries that fail to re-epithelialize, the enzyme is expressed at much higher levels. The goal of this proposal is to use the transcriptional promotor of the gelatinase B gene as a probe to identify regulatory molecules that control re-epithelialization, or contribute to its failure, in both skin and cornea. In addition, it is further planned to explore the hypothesis about the role of gelatinolytic metalloproteinases, with regard to failure to re-epithelialize in both skin and cornea, by over-expression of these enzymes in the epidermis and the corneal epithelium of transgenic mice.
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