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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY008512-23A1
Application #
8388623
Study Section
Special Emphasis Panel (DPVS)
Program Officer
Mckie, George Ann
Project Start
1992-07-01
Project End
2016-06-30
Budget Start
2012-08-01
Budget End
2013-06-30
Support Year
23
Fiscal Year
2012
Total Cost
$586,848
Indirect Cost
$196,292
Name
George Washington University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
043990498
City
Washington
State
DC
Country
United States
Zip Code
20052
Pal-Ghosh, Sonali; Pajoohesh-Ganji, Ahdeah; Tadvalkar, Gauri et al. (2016) Topical Mitomycin-C enhances subbasal nerve regeneration and reduces erosion frequency in the debridement wounded mouse cornea. Exp Eye Res 146:361-9
Stepp, Mary Ann; Tadvalkar, Gauri; Hakh, Raymond et al. (2016) Corneal epithelial cells function as surrogate schwann cells for their sensory nerves. Glia :
Pajoohesh-Ganji, Ahdeah; Pal-Ghosh, Sonali; Tadvalkar, Gauri et al. (2016) K14 + compound niches are present on the mouse cornea early after birth and expand after debridement wounds. Dev Dyn 245:132-43
Stepp, Mary Ann; Pal-Ghosh, Sonali; Tadvalkar, Gauri et al. (2015) Syndecan-1 and Its Expanding List of Contacts. Adv Wound Care (New Rochelle) 4:235-249
Pajoohesh-Ganji, Ahdeah; Pal-Ghosh, Sonali; Tadvalkar, Gauri et al. (2015) Partial denervation of sub-basal axons persists following debridement wounds to the mouse cornea. Lab Invest 95:1305-18
Menko, A S; Bleaken, B M; Libowitz, A A et al. (2014) A central role for vimentin in regulating repair function during healing of the lens epithelium. Mol Biol Cell 25:776-90
Stepp, Mary Ann; Zieske, James D; Trinkaus-Randall, Vickery et al. (2014) Wounding the cornea to learn how it heals. Exp Eye Res 121:178-93
Pal-Ghosh, Sonali; Pajoohesh-Ganji, Ahdeah; Menko, A Sue et al. (2014) Cytokine deposition alters leukocyte morphology and initial recruitment of monocytes and γδT cells after corneal injury. Invest Ophthalmol Vis Sci 55:2757-65
Pajoohesh-Ganji, Ahdeah; Pal-Ghosh, Sonali; Tadvalkar, Gauri et al. (2012) Corneal goblet cells and their niche: implications for corneal stem cell deficiency. Stem Cells 30:2032-43
Padmakumar, V C; Speer, Kelsey; Pal-Ghosh, Sonali et al. (2012) Spontaneous skin erosions and reduced skin and corneal wound healing characterize CLIC4(NULL) mice. Am J Pathol 181:74-84

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