METALLOPROTEINASES AND FAILURE TO RE-EPITHELIALIZE

许多慢性皮肤创伤的一个突出特征，特别是 静脉淤积性溃疡，是表皮不能再浮出水面 床很好听。延迟的再上皮化和持久性上皮 缺陷也是角膜创伤的一个特征，这些伤口会继续 溃疡，或不能愈合的溃疡。重新启动失败- 在这两种情况下，上皮化似乎都是由于，而不是不充分。 细胞增殖，但细胞迁移能力受损 并在真皮/基质上形成稳定的附着 组织的一层。因为在机制上有明显的相似性， 考虑这两种疾病的慢性愈合方面似乎是有用的。 组织类型试图发展对失败的理解 治愈。在初步工作中，对可能的 在这种疾病中的酶参与使用大鼠角膜模型 由热损伤引起的溃疡。这些研究支持了 再上皮化失败是由于过度的假说 基质金属蛋白酶的酶介导的蛋白水解性 家族，特别是明胶酶B，正常的修复似乎是 被这种酶破坏，因为它能降解基底物 上皮细胞在其上迁移以使损伤重新浮出水面并 它随后必须形成稳定的附着物。的表达 上皮细胞的明胶酶B是遗传程序的正常部分 用于损伤的角膜的再上皮化。然而，在角膜中 不能重新上皮化的损伤，这种酶在很多情况下都有表达 更高的水平。这项提案的目标是使用转录 以明胶酶B基因启动子为探针鉴定调控基因 控制再上皮化的分子，或参与其上皮化的分子 皮肤和角膜都失败了。此外，还计划进一步 关于明胶溶解作用的假说探讨 金属蛋白水解酶与上皮化失败的关系 皮肤和角膜，由于这些酶在表皮和角膜中过度表达 转基因小鼠角膜上皮细胞。

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.