Corneal surface injuries are painful and expose the eye to infectious microorganisms that can destroy vision. During our previous funding period, we developed and characterized a model for the study of recurrent corneal erosions in mice that uses a dulled blade to create debridement wounds. The erosions we study in the mouse cornea after dulled blade wounds serve as a model to understand the causes of the recurrent corneal erosions that occur in patients after superficial wounds such as fingernail injuries as well as secondary to inherited corneal dystrophies. We have shown that erosions form primarily in the inferior nasal quadrant and that MMP9 expression is elevated in the corneal epithelium before and after erosion formation. Furthermore, MMP9 associates with and cleaves hemidesmosomal a6b4 integrin. Despite slower wound healing and prolonged inflammation, mice lacking the heparan sulfate proteoglycan syndecan-1 (sdc1) have 50% fewer corneal erosions in vivo and cells isolated from sdc1 null mice have differences in integrin-mediated cell migration and TGFb1 signaling in vitro. The long-term goal of this project is to identify those factors that prevent the corneal epithelium from reforming an intact barrier after trauma to the ocular surface. Based on our past work and preliminary data, we hypothesize that recurrent erosions form after dulled blade wounds due to immune mediators released by damaged sensory nerves, apoptotic corneal stromal cells, and immune cells. This leads to poor reinnervation of sub-basal nerves and reduced activation of corneal stromal cells that combine to prevent formation of stable cell:matrix adhesions by corneal epithelial cells. To test this hypothesis we propose the following Aims: 1. Eliminate erosion formation after dulled blade wounds by altering immune cell recruitment. 2. Induce resolution of erosions after they form by manipulating the proliferation and activation of corneal stromal cells and reinnervation of sub-basal nerves. 3. Determine the role of TGFb1 signaling in the formation of erosions by treating mice with TGFb1 and TGFb1 neutralizing antibodies in vivo after dulled blade and rotating burr wounds and in vitro using corneal stromal cells and mouse keratinocytes. By understanding the molecular and cellular causes of chronic corneal inflammation and erosions, we will be better able to facilitate their resolution in mice and in people.
Corneal surface injuries are the major ophthalmic complaint. Recurrent erosions can develop after ocular trauma and chronic inflammation of the ocular surface interferes with the quality of life and productivity of millions of Americans;reduced innervation of the cornea by sensory nerves occurs after cornea surgery and with aging and plays a role in development of erosions. By characterizing the cytokines and immune cell types that prevent resolution of corneal wound healing as well as those that promote resolution, we will gain the insight needed to improve the quality of life for those suffering from ocular surface inflammatory conditions secondary to trauma.
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|Jurjus, Rosalyn A; Liu, Yueyuan; Pal-Ghosh, Sonali et al. (2008) Primary dermal fibroblasts derived from sdc-1 deficient mice migrate faster and have altered alphav integrin function. Wound Repair Regen 16:649-60|
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