Corneal epithelial cells have acquired the ability to rapidly change their cell:cell and cell:substrate adhesion junctions to permit mobilization after injury. Integrins on the epithelial cells are used as signaling and cell:substrate adhesion molecules and laminins and collagens in the basement membrane and stroma act as substrates to support metaloproteinase-dependent cell migration. The signaling and adhesive functions of integrins can be regulated by their lateral association with other integral membrane molecules including proteoglycans of the syndecan family. Data show that a mouse strain genetically deficient in syndecan-1 exhibits delayed corneal and skin wound healing due in part to slower epithelial cell migration. We hypothesize that the activity of integrins in epithelial cells is regulated in part by syndecan:integrin associations and that the loss of syndecan-1 in epithelia results in a reduction in cell signaling via integrins and growth factor receptors. The following specific aims are proposed to further our understanding of the molecules regulating reepithelialization in the cornea:
Aim 1. To determine the roles played by cell proliferation, differentiation and protein synthetic rates in the impaired wound response observed in the syndecan-1 knock-out (synd1ko) mouse in vivo.
Aim 2. To determine if it is possible to restore the normal phenotype to synd1ko corneal cpithelial cells by providing exogenous synd1 and/or growth factors that stimulate the EGF-receptor.
and Aim 3. To determine in cultured epidermal keratinocytes derived from the syn1ko mouse and in mouse and human corneal epithelial cell lines, the roles played by synd1-mediated signaling in regulating cell proliferation, apoptosis, cell adhesion, and endocytosis. By examining the mechanism of delayed corneal wound healing in genetically engineered mice, basic concepts regulating healing will be revealed and better treatments for those suffering from poor healing can be developed.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Visual Sciences A Study Section (VISA)
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Fisher, Richard S
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George Washington University
Anatomy/Cell Biology
Schools of Medicine
United States
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Kaplan, Nihal; Ventrella, Rosa; Peng, Han et al. (2018) EphA2/Ephrin-A1 Mediate Corneal Epithelial Cell Compartmentalization via ADAM10 Regulation of EGFR Signaling. Invest Ophthalmol Vis Sci 59:393-406
Stepp, Mary Ann; Pal-Ghosh, Sonali; Tadvalkar, Gauri et al. (2018) Reduced intraepithelial corneal nerve density and sensitivity accompany desiccating stress and aging in C57BL/6 mice. Exp Eye Res 169:91-98
Stepp, Mary Ann; Pal-Ghosh, Sonali; Tadvalkar, Gauri et al. (2018) Reduced Corneal Innervation in the CD25 Null Model of Sjögren Syndrome. Int J Mol Sci 19:
Gjika, Eda; Pal-Ghosh, Sonali; Tang, Anna et al. (2018) Adaptation of Operational Parameters of Cold Atmospheric Plasma for in Vitro Treatment of Cancer Cells. ACS Appl Mater Interfaces 10:9269-9279
Pal-Ghosh, Sonali; Tadvalkar, Gauri; Stepp, Mary Ann (2017) Alterations in Corneal Sensory Nerves During Homeostasis, Aging, and After Injury in Mice Lacking the Heparan Sulfate Proteoglycan Syndecan-1. Invest Ophthalmol Vis Sci 58:4959-4975
Stepp, Mary Ann; Tadvalkar, Gauri; Hakh, Raymond et al. (2017) Corneal epithelial cells function as surrogate Schwann cells for their sensory nerves. Glia 65:851-863
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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; Pal-Ghosh, Sonali; Tadvalkar, Gauri et al. (2015) Syndecan-1 and Its Expanding List of Contacts. Adv Wound Care (New Rochelle) 4:235-249
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