DESCRIPTION (provided by applicant): 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.

PROJECT NARRATIVE 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.