Ocular surface injury is second only to cataracts as the most common cause of visual impairment worldwide. Chemical exposure is a frequent route of ocular surface injury, and both acid and alkali burns of the cornea are considered ophthalmologic emergencies. However, alkali burns present more frequently and often pose a greater threat to sight due to the rapidity by which damage occurs after exposure. Healing of corneal epithelial injury occurs through cooperation between corneal stem cells, called limbal epithelial stem cells (LESCs), and the terminations of trigeminal neurons, called corneal nerves, that densely innervate the cornea. LESCs are responsible for generating new epithelial cells to replace those lost to injury while corneal nerves contribute to maintenance of corneal avascularity, number and function of LESCs, and differentiation of postmitotic corneal epithelial cells. When injury prevents rapid and efficient repair of the cornea, vision can be compromised or permanently lost due to abnormal epithelial growth and scarring. Standard clinical approaches to corneal injury focus on minimizing inflammation or restoring a stable tear film to promote corneal reepithelialization with less attention paid to corneal reinnervation. This project aims to ascertain the therapeutic efficacy and mechanism of a pair of novel pharmacologic agents in the cornea following alkali burn with the goal of informing improved strategies for managing corneal injury. Our agent (-)- P7C3-S243 has demonstrated potent neuroprotective effects in both peripheral and central nervous systems following injury, while P18C8 has demonstrated mitogenic efficacy. We hypothesize that (-)-P7C3-S243 and P18C8 will target the corneal nerves and epithelial cells, respectively, to accelerate recovery following alkali corneal injury. To test our hypothesis, we propose the following aims: 1) Determine whether coadministration of (-)-P7C3-S243 and P18C8 accelerates wound healing in a mouse model of chemical corneal injury. We will model alkali-induced corneal injury in mice through application of sodium hydroxide to the ocular surface, and evaluate both acute and chronic phases of corneal wound healing. 2) Determine the effects of (-)-P7C3-S243 and P18C8 on cultured corneal epithelial and trigeminal neurons. The focus of this aim will be on corneal nerves and corneal epithelial cells, the hypothesized targets of (-)- P7C3-S243 and P18C8, respectively. We will model axonal and epithelial injury in cultured mouse trigeminal neurons and corneal epithelial cells. At the conclusion of this project, we will have characterized the therapeutic efficacy of two novel pharmacologic agents in a model of alkali-induced corneal injury and established a foundation on which to advance mechanistic work for these agents. This research is thus positioned to advance current clinical practice paradigms by laying the groundwork for advancing new approaches to corneal injury, thereby supporting the mission of the National Eye Institute.
Covered by a thin film of protective cells, the cornea is a transparent, dome-shaped structure that focuses incoming light and maintains a physical barrier against infection and injury to the eye. Following traumatic corneal surface injury such as chemical exposure, vision can be compromised or permanently lost due to scarring and abnormal tissue growth. This project will determine the therapeutic efficacy and mechanism of a pair of novel drug-like compounds in the cornea with the unique strategy of targeting both the corneal epithelial cells and the nerves that endogenously support the health and integrity of these surface corneal cells.
