Corneal nerves are important for the health of the cornea, as well as for protecting the eye from outside elements. These nerves are predominantly nociceptive, coding discomfort and pain in response to mechanical stimulation, temperature change and/or chemical stimulation. Disease, infection and ocular surgery can all damage corneal nerves, with long-term consequences in terms of pain, dry eye, recurrent erosions, opacity and even blindness. Yet, there are no effective therapies in clinical practice fo treating nerve dysfunction in the will use our cat model of corneal wound healing after photorefractive keratectomy (PRK) and a combination of in vivo and in vitro approaches to study the basic mechanisms controlling adult, corneal nerve regeneration post-injury. Our preliminary data show clear abnormalities of re-innervation in different nerve layers (stroma, sub-basal plexus, epithelium) and major modulation of nerve regeneration by topical anti-fibrotics. These data suggest an inhibitory influence of myofibroblasts on regenerating nerves and/or their associated glia (non-myelinating Schwann cells - NMSCs), leading us to propose the following central hypothesis for this renewal application: myofibroblast transformation that occurs in response to large corneal wounds directly inhibits nerve regeneration. Thus, blocking myofibroblast differentiation during the early wound healing response is critical for restoring normal corneal innervation to the epithelium and stroma. We will test this hypothesis by:
Aim 1 - assessing the impact of myofibroblast differentiation on corneal nerve regeneration and NMSCs after PRK;
Aim 2 - assessing the effect of blocking myofibroblast differentiation on corneal nerve regeneration and NMSCs after PRK;
Aim 3 - context of corneal wounds. The proposed experiments assessing the long-term impact of abnormal corneal re-innervation on corneal optics;
and Aim 4 - characterizing the interactions between corneal fibroblasts, myofibroblasts and sensory neurons in vitro and testing the hypothesis that myofibroblasts inhibit neurite outgrowth via Sema3A. The proposed, systematic characterization of nerve regeneration, nerve-myofibroblast interactions and their molecular mechanisms during wound healing are critical for the development of new therapeutic strategies to treat corneal wounds with an eye to promoting optimal nerve regeneration and ensuring long-term health of the ocular surface.

Public Health Relevance

Despite its clinical relevance, our knowledge about corneal nerve regeneration after injury remains sub- optimal. The proposed experiments will systematically study nerve regeneration in the cat cornea following photorefractive keratectomy to test our central hypothesis that corneal myofibroblasts are directly inhibitory to nerve regeneration. Our findings will provide direction for how corneal wounds should be treated to ensure correct re-innervation and avoid long-term health consequences (vision loss, pain, dry eye and other chronic ocular surface problems), which plague patients today.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Diseases and Pathophysiology of the Visual System Study Section (DPVS)
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Mckie, George Ann
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University of Rochester
School of Medicine & Dentistry
United States
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Jeon, Kye-Im; Hindman, Holly B; Bubel, Tracy et al. (2018) Corneal myofibroblasts inhibit regenerating nerves during wound healing. Sci Rep 8:12945
Wozniak, Kaitlin T; Gearhart, Sara M; Savage, Daniel E et al. (2017) Comparable change in stromal refractive index of cat and human corneas following blue-IRIS. J Biomed Opt 22:55007
Wozniak, Kaitlin T; Elkins, Noah; Brooks, Daniel R et al. (2017) Contrasting cellular damage after Blue-IRIS and Femto-LASIK in cat cornea. Exp Eye Res 165:20-28
Jeon, Kye-Im; Phipps, Richard P; Sime, Patricia J et al. (2017) Antifibrotic Actions of Peroxisome Proliferator-Activated Receptor ? Ligands in Corneal Fibroblasts Are Mediated by ?-Catenin-Regulated Pathways. Am J Pathol 187:1660-1669
Jeon, Kye-Im; Phipps, Richard P; Sime, Patricia J et al. (2015) Inhibitory effects of PPAR? ligands on TGF-?1-induced CTGF expression in cat corneal fibroblasts. Exp Eye Res 138:52-8
Savage, Daniel E; Brooks, Daniel R; DeMagistris, Margaret et al. (2014) First demonstration of ocular refractive change using blue-IRIS in live cats. Invest Ophthalmol Vis Sci 55:4603-12
Jeon, Kye-Im; Kulkarni, Ajit; Woeller, Collynn F et al. (2014) Inhibitory effects of PPAR? ligands on TGF-?1-induced corneal myofibroblast transformation. Am J Pathol 184:1429-45
Weis, Adam J; Huxlin, Krystel R; Callan, Christine L et al. (2013) Keratocyte apoptosis and not myofibroblast differentiation mark the graft/host interface at early time-points post-DSAEK in a cat model. PLoS One 8:e75623
Hindman, Holly B; Huxlin, Krystel R; Pantanelli, Seth M et al. (2013) Post-DSAEK optical changes: a comprehensive prospective analysis on the role of ocular wavefront aberrations, haze, and corneal thickness. Cornea 32:1567-77
Huxlin, Krystel R; Hindman, Holly B; Jeon, Kye-Im et al. (2013) Topical rosiglitazone is an effective anti-scarring agent in the cornea. PLoS One 8:e70785

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