Abstract
Epithelial wound healing is a common occurrence in many organisms. In spite of a long history of study in this field, we do not have a complete understanding of the molecular and cellular mechanisms of wound healing, which is a key element to appreciate in order to modulate this process for better clinical outcomes. Optimal outcomes are especially critical in the cornea as a failure to regenerate can result in blindness and a huge decline in quality of life. Matrix Metalloproteinases (MMPs) are a family of zinc dependent proteases that have been shown to be both regulators and effectors of the corneal wound healing process. Strict regulation of MMP-9, the most extensively studied member of the MMP family, has been shown to be critical for efficient wound regeneration. While we now know that MMP-9 is important, and we even have evidence defining some of the roles it plays in the corneal wound healing process, the mechanism by which MMP-9 is regulated is still under debate. Possible extracellular regulatory mechanisms range from cell-cell interactions to cell-matrix interactions to secreted factors. However, the detailed mechanism of events that takes place on the extracellular surface and the downstream signals that mediate MMP-9 are unknown. Therefore, one of the objectives of the presented work is to define the external mechanisms which mediate MMP-9 expression in resurfacing epithelial cells and to link these external signals to internal signaling pathways in vitro. Furthermore, while MMP-9 acts to slow the resurfacing phase of wound healing, other MMPs seem to cause opposing effects. The second objective of the presented work is to provide the first global spatial and temporal MMP expression profile for an in vivo epithelial wound healing scenario and to define possible macroscopic roles of these heretofore unknown MMPs. Finally, this thesis will look at the expression of many MMP family members in a penetrating model which is an increasingly more common wound scenario due to the increase in corrective surgery. The final objective is to examine human post-LASIK corneas and correlate MMP expression with age, post-operative time, or histopathological abnormalities. The knowledge obtained from all aspects of these studies will contribute to the current understanding and knowledge about the roles and regulatory mechanisms of MMPs in the corneal wound healing process.