Alterations in corneal innervation result in impaired corneal sensation, severe dry eye and damage to the epithelium that may in turn lead to corneal ulcers, melting and perforation. These alterations frequently occur after refractive surgery, corneal transplant, herpetic infection, chemical burns, keratoconus, multiple sclerosis, Sjogren's syndrome and diabetes mellitus. Although there are treatments to alleviate severe dry eye, there are no therapies to compensate for the loss of innervation. This research project builds upon our finding that pigment epithelium-derived factor (PEDF) plus docosahexaenoic acid (DHA) or the docosanoid derivative neuroprotectin D1 (NPD1) induces nerve regeneration after corneal surgery that damages stromal nerves. We now focus on defining the molecular mechanism by which PEDF plus DHA or NPD1 regenerates corneal nerves after experimental refractive surgery. We additionally investigate the bioactivity of these mediators in an animal model of herpes simplex virus type-1 (HSV-1), focusing on compromised sensitivity, nerve regeneration and inflammation. Our central hypothesis is that PEDF acts through a mediated mechanism that activates cytosolic phospholipase A2/extracellular-regulated kinase (cPLA2/ERK1/2) signaling to release DHA for the synthesis of NPD1, which stimulates nerve growth factor (NGF) expression that, in turn, modulates corneal nerve regeneration. In addition to corneal surgery, HSV-1 infections cause lost sensitivity, dry eye and corneal lesions that could lead to stromal and epithelial damage. We propose to test the hypothesis that NPD1 induces recovery of sensitivity and regenerates corneal nerves after herpes viral infection. We will employ: 1) in vivo models of refractive surgery and HSV-1 infection relevant to the clinical setting;2) primary and cell line cultures and co-cultures of trigeminal ganglion neurons with corneal epithelial cells and stromal fibroblasts to uncover the molecular mechanisms of neurite outgrowth;3) LC-tandem mass- spectrometry lipidomic analysis to characterize and quantify DHA and its derivative, NPD1;4) gas esthesiometry to assess corneal sensitivity to different modalities of stimulus after nerve regeneration;and 5) molecular biology techniques and our immunostaining method to quantify the epithelial, sub-basal and stromal corneal nerves. The proposed studies target new mechanisms to understand and treat complications due to corneal nerve damage. Our innovative approach will define potential agents for neurotrophic keratitis and dry eye after refractive surgery and HSV-1 infection.

Public Health Relevance

The research proposed in this project focuses on understanding the molecular mechanisms of enhancing the regeneration of nerves damaged after corneal surgery procedures and after herpes simplex virus (HSV)-1 infection, and decreasing the incidence of complications by providing innovative understanding of the role played by the novel omega-3-derived lipid mediator, neuroprotectin D1. Our innovative approach will define potential therapeutic agents for neurotrophic keratitis and dry eye, yielding new insights into how nerve injury stemming from surgical procedures and HSV-1 infection can be ameliorated or prevented.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Special Emphasis Panel (DPVS)
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Mckie, George Ann
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Louisiana State Univ Hsc New Orleans
Schools of Medicine
New Orleans
United States
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He, Jiucheng; Cosby, Richard; Hill, James M et al. (2017) Changes in Corneal Innervation after HSV-1 Latency Established with Different Reactivation Phenotypes. Curr Eye Res 42:181-186
He, Jiucheng; Neumann, Donna; Kakazu, Azucena et al. (2017) PEDF plus DHA modulate inflammation and stimulate nerve regeneration after HSV-1 infection. Exp Eye Res 161:153-162
Pham, Thang Luong; He, Jiucheng; Kakazu, Azucena H et al. (2017) Defining a mechanistic link between pigment epithelium-derived factor, docosahexaenoic acid, and corneal nerve regeneration. J Biol Chem 292:18486-18499
He, Jiucheng; Pham, Thang Luong; Kakazu, Azucena et al. (2017) Recovery of Corneal Sensitivity and Increase in Nerve Density and Wound Healing in Diabetic Mice After PEDF Plus DHA Treatment. Diabetes 66:2511-2520
He, Jiucheng; Bazan, Haydee E P (2016) Neuroanatomy and Neurochemistry of Mouse Cornea. Invest Ophthalmol Vis Sci 57:664-74
He, Jiucheng; Cortina, M Soledad; Kakazu, Azucena et al. (2015) The PEDF Neuroprotective Domain Plus DHA Induces Corneal Nerve Regeneration After Experimental Surgery. Invest Ophthalmol Vis Sci 56:3505-13
He, Jiucheng; Bazan, Haydee E P (2015) Morphology and neurochemistry of rabbit iris innervation. Exp Eye Res 135:182-91
Cortina, Maria Soledad; He, Jiucheng; Russ, Tiffany et al. (2013) Neuroprotectin D1 restores corneal nerve integrity and function after damage from experimental surgery. Invest Ophthalmol Vis Sci 54:4109-16
Kenchegowda, S; He, J; Bazan, H E P (2013) Involvement of pigment epithelium-derived factor, docosahexaenoic acid and neuroprotectin D1 in corneal inflammation and nerve integrity after refractive surgery. Prostaglandins Leukot Essent Fatty Acids 88:27-31
He, Jiucheng; Bazan, Haydee E P (2013) Corneal nerve architecture in a donor with unilateral epithelial basement membrane dystrophy. Ophthalmic Res 49:185-91

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