The focus of effort in our laboratory has been to identify cellular and molecular responses to corneal epithelial wounding that initiate, enhance or retard cell migration, proliferation and formation of hemidesmosomes. An improved understanding of these factors could provide modalities for improved treatment of debilitating epithelial problems including recurrent corneal erosions and neurotrophic keratitis, among others. Our recent exciting studies in live cell imaging have led us to evaluate the molecular mechanisms underlying the immediate and long term responses that are induced by injury and to evaluate how the release of growth factors and nucleotides from epithelial cells alters the cellular environment and induces signal transduction mediated events that regulate wound repair. When an injury to the corneal epithelium occurs a soluble factor is released that causes the rapid release of Ca2+ that propagates from the wound to neighboring cells in seconds and does not require gap junctions. We have demonstrated that the active component active component is less than 5 kDa, activates ERK1/2 and is inhibited by an enzyme that cleaves terminal phosphate groups off nucleotides, indicating that it is an extracellular nucleotide which initiates signaling events through the activation of a P2Y purinergic receptor on the cell surface. This is the first time that purinergic signaling pathways have been implicated in epithelial injury and repair. In addition, EGF receptors (ErbB1) are activated at the wound margin and mediate the expression of the integrin subunit, beta4, a critical component of hemidesmosomes. We have also demonstrated that stimulating both EGF and purinergic signaling pathways results in unparalled enhancement of epithelial cell migration leading us to examine how the two systems communicate.
The aims are to: I. Identify which ErbB receptor subtypes regulate Ca2+ wave propagation, cell migration and activation of adhesion proteins. II. Evaluate the role of purinergic receptors in wound repair and III. Examine cross-talk between ErbB and purinergic signaling systems to further understand the response to injury and disease.

National Institute of Health (NIH)
National Eye Institute (NEI)
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Special Emphasis Panel (ZRG1-VISA (01))
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Fisher, Richard S
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Boston University
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Lee, Albert; Karamichos, Dimitrios; Onochie, Obianamma E et al. (2018) Hypoxia modulates the development of a corneal stromal matrix model. Exp Eye Res 170:127-137
Kneer, Krisandra; Green, Michael B; Meyer, Jenna et al. (2018) High fat diet induces pre-type 2 diabetes with regional changes in corneal sensory nerves and altered P2X7 expression and localization. Exp Eye Res 175:44-55
Minns, Martin S; Trinkaus-Randall, Vickery (2016) Purinergic Signaling in Corneal Wound Healing: A Tale of 2 Receptors. J Ocul Pharmacol Ther 32:498-503
Minns, Martin S; Teicher, Gregory; Rich, Celeste B et al. (2016) Purinoreceptor P2X7 Regulation of Ca(2+) Mobilization and Cytoskeletal Rearrangement Is Required for Corneal Reepithelialization after Injury. Am J Pathol 186:285-96
Derricks, Kelsey E; Trinkaus-Randall, Vickery; Nugent, Matthew A (2015) Extracellular matrix stiffness modulates VEGF calcium signaling in endothelial cells: individual cell and population analysis. Integr Biol (Camb) 7:1011-25
Sanderson, Julie; Dartt, Darlene A; Trinkaus-Randall, Vickery et al. (2014) Purines in the eye: recent evidence for the physiological and pathological role of purines in the RPE, retinal neurons, astrocytes, Müller cells, lens, trabecular meshwork, cornea and lacrimal gland. Exp Eye Res 127:270-9
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
Karamichos, D; Hutcheon, A E K; Rich, C B et al. (2014) In vitro model suggests oxidative stress involved in keratoconus disease. Sci Rep 4:4608
Lee, Albert; Derricks, Kelsey; Minns, Martin et al. (2014) Hypoxia-induced changes in Ca(2+) mobilization and protein phosphorylation implicated in impaired wound healing. Am J Physiol Cell Physiol 306:C972-85
Chi, Cheryl; Trinkaus-Randall, Vickery (2013) New insights in wound response and repair of epithelium. J Cell Physiol 228:925-9

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