Corneal surgery, including refractive surgery, is one of the most frequent procedures used to correct vision (1). It is estimated that more than 17 million people worldwide have had some type of corneal surgery. The cornea is densely innervated with sensory nerves that exert a trophic influence on the corneal epithelium. Damage to these nerves leads to complications such as corneal hypoesthesia and dry eye as well as decreased wound healing (2-4), which results in loss of transparency and vision. Given the frequency and significance of this problem, this research project focuses on decreasing the incidence of postoperative complications by providing innovative understanding of the role lipid cell signaling mechanisms play after injury in enhancing the regeneration of corneal nerves damaged after these procedures. We will define the mechanism by which treatment with pigment epithelial derived factor (PEDF) and docosahexanoic acid (DHA) increase the regeneration of corneal nerves. Our central hypothesis is that PEDF activates a lipid cell signaling mechanism that stimulates 12/15 lipoxygeneases (12/15-LOX), increasing the synthesis of neuroprotectin D1 (NPD1) and arachidonic acid (AA) derived messengers involved in neuroprotection of corneal epithelial cells and nerve regeneration, and decreasing the incidence of dry eye. We predict that NPD1 modulates cell survival signaling after corneal injury and is the main mediator of nerve regeneration. We will test the hypothesis using an in vivo corneal surgery animal model including a genetic model (12/15-LOX knockout mice);in vivo esthesiometry and confocal microscopy;liquid chromatography-mass spectrometry lipidomic analysis;and cellular and molecular approaches.
Our specific aims are to test the hypothesis that: (1) PEDF increases after corneal surgery and stimulates the expression of 12/15-LOX, which in turn synthesizes NPD1 and AA derived mediators;(2) 12/15-LOX products selectively induce neurogenesis after corneal injury;(3) NPD1 acts as a neuroprotective agent in corneal epithelial cells, allowing for better wound healing and decreasing the incidence of dry eye after corneal surgery. Our studies target mechanisms of neuroregeneration relevant for the understanding and treatment of complications generated by corneal nerve damage. Our innovative approach defines potential therapeutic agents for neurotrophic keratitis and dry eye after refractive surgery.

Public Health Relevance

The research proposed in this project focuses on enhancing the regeneration of corneal nerves damaged after corneal surgery procedures to decrease the incidence of postoperative complications by providing innovative understanding of the role lipid cell signaling mechanisms play after injury. The proposed studies target mechanisms of neuroregeneration relevant to understanding and treating complications generated by corneal nerve damage. Our novel approach will define potential therapeutic agents for neurotrophic keratitis and dry eye after refractive surgery, yielding new insights into how injuries stemming from these procedures can be repaired or prevented.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY019465-03
Application #
8045366
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Mckie, George Ann
Project Start
2009-04-01
Project End
2013-03-31
Budget Start
2011-04-01
Budget End
2013-03-31
Support Year
3
Fiscal Year
2011
Total Cost
$337,392
Indirect Cost
Name
Louisiana State Univ Hsc New Orleans
Department
Neurosciences
Type
Schools of Medicine
DUNS #
782627814
City
New Orleans
State
LA
Country
United States
Zip Code
70112
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; 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; 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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