Damage to the cornea compromises its important optical and protective functions; rapid repair is therefore critical. However, the mechanisms and factors orchestrating wound healing are unclear. A better understanding of the process is essential to our ability to improve and regulate corneal repair after accidental or surgical injury and in diseases such as recurrent erosion syndrome and diabetes where the integrity of the cornea is compromised. The overall goal of this project is to determine if and how defensins participate in corneal wound healing. Defensins are peptides best known for their antimicrobial activity but whose functional repertoire also includes mitogenic, chemoattractant and signaling properties. Two types of defensin are available to the cornea, alpha-defensins are present in tears and neutrophils recruited after injury and beta-defensins are produced in situ by corneal epithelial cells. Our overlying hypothesis is that alpha and beta defensins promote corneal wound healing. We hypothesize that they do so by stimulating corneal epithelial cell and fibroblast migration, proliferation and production of cytokines/growth factors. Furthermore, we hypothesize that cytokines produced after epithelial injury upregulate the expression of endogenous epithelial defensins which are then available in sufficient quantities to exert a physiological effect. Human corneal epithelial cells and fibroblasts and human corneas in organ culture will be utilized to address the following hypotheses:
Specific Aim 1 : Hypothesis: alpha and beta defensins stimulate human corneal epithelial cell and fibroblast migration and proliferation.
Specific Aim 2 : Hypothesis: alpha and beta defensins upregulate the production of cytokines and growth factors by human corneal epithelial cells and fibroblasts.
Specific Aim 3 : Hypothesis: Expression of endogenous beta-defensin 2 is upregulated after injury in response to an increase in cytokines.
Specific Aim 4 : Hypothesis: alpha and beta defensins stimulate re-epithelialization in wounded human corneas. The results of these studies will help delineate the as yet unidentified role of defensins in corneal wound healing and restoration of normal corneal function.
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