Recent interest in the use of surgical procedure to correct vision has resulted in renewed interest in mechanisms of stromal wound healing and remodelling. The lab goal is to elucidate molecular mechanisms activating quiescent stromal cells to initiate the deposition of repair tissue and to mediate subsequent repair tissue remodelling. Previous work indicates that stromal cell activation is controlled by an epithelial/stromal interaction. The matrix metalloproteinases, collagenase (CL) and stromelysin (SL) are expressed by stromal cells concomitant with their activation following corneal injury. Expression of these enzymes thus serves as a marker of the activation process and can be monitored to assay for controlling substances produced by the epithelium. Once activated, stromal cells develop competence to express CL/SL under autocrine control, and in response to agents which mimic aspects of signaling between cells and their extracellular matrix. Thus an investigation of the mechanisms that lead to development of competence for CL/SL expression can serve as a useful focus for defining the molecular changes that control the switch to the activated phenotype. Moreover, since CL/SL act as important mediators of repair tissue remodelling, studies along these lines would be expect to shed new light on regulation of the remodelling process. In preliminary studies a corneal epithelial stimulator of CL/SL expression was identified as the cytokine, IL-1alpha. In the current proposal, aspects of the molecular structure and expression of the corneal epithelial cytokine(s) inhibiting release of CL/SL by cultured stromal cells will also be characterized. The hypothesis that release of stimulatory cytokines, such as IL-1alpha, may be a common autocrine mechanism by which stromal interact reciprocally with their extracellular matrix to modulate expression of CL/SL will be tested. Steps in the molecular pathway leading to CL/SL stimulatory cytokine (I1-1alpha) expression and bioactivity will be examined. Finally, and most importantly, the role of I1-1alpha in controlling stromal cell activation and CL/Sl expression and modulation during corneal repair will be explored. This will be accomplished by measuring expression of I1-1alpha expression in repair tissue and correlating these results with those attempting to interfere with IL-1 activity in healing wounds by direct application, or transgenic expression, of an IL-1 antagonist.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY009828-06
Application #
2608648
Study Section
Visual Sciences A Study Section (VISA)
Project Start
1993-12-01
Project End
1999-11-30
Budget Start
1997-12-01
Budget End
1998-11-30
Support Year
6
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Tufts University
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02111
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