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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR042981-04
Application #
2457977
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Project Start
1994-08-01
Project End
1998-07-31
Budget Start
1997-08-01
Budget End
1998-07-31
Support Year
4
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Tufts University
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02111
Bargagna-Mohan, Paola; Mohan, Royce; Russo, Laoti et al. (2007) Cell lines and transgenic mice expressing a matrix metalloproteinase-9 promoter-driven reporter gene: potential for assay of ultraviolet light effects and light-inhibiting compounds. Cutan Ocul Toxicol 26:383-97
Jung, Jae-Chang; Leco, Kevin J; Edwards, Dylan R et al. (2002) Matrix metalloproteinases mediate the dismantling of mesenchymal structures in the tadpole tail during thyroid hormone-induced tail resorption. Dev Dyn 223:402-13
Mohan, Royce; Chintala, Shravan K; Jung, Jae Chang et al. (2002) Matrix metalloproteinase gelatinase B (MMP-9) coordinates and effects epithelial regeneration. J Biol Chem 277:2065-72
Mohan, R; Sivak, J; Ashton, P et al. (2000) Curcuminoids inhibit the angiogenic response stimulated by fibroblast growth factor-2, including expression of matrix metalloproteinase gelatinase B. J Biol Chem 275:10405-12
Sivak, J M; Mohan, R; Rinehart, W B et al. (2000) Pax-6 expression and activity are induced in the reepithelializing cornea and control activity of the transcriptional promoter for matrix metalloproteinase gelatinase B. Dev Biol 222:41-54
Bargagna-Mohan, P; Strissel, K J; Fini, M E (1999) Regulation of gelatinase B production in corneal cells is independent of autocrine IL-1alpha. Invest Ophthalmol Vis Sci 40:784-9
Fini, M E (1999) Keratocyte and fibroblast phenotypes in the repairing cornea. Prog Retin Eye Res 18:529-51
Mohan, R; Rinehart, W B; Bargagna-Mohan, P et al. (1998) Gelatinase B/lacZ transgenic mice, a model for mapping gelatinase B expression during developmental and injury-related tissue remodeling. J Biol Chem 273:25903-14
Fini, M E; Cook, J R; Mohan, R (1998) Proteolytic mechanisms in corneal ulceration and repair. Arch Dermatol Res 290 Suppl:S12-23
Fitch, J; Fini, M E; Beebe, D C et al. (1998) Collagen type IX and developmentally regulated swelling of the avian primary corneal stroma. Dev Dyn 212:27-37

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