Correlations of structure and function in regenerating corneal nerves

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ABSTRACT/PROJECT SUMMARY Corneal nerves create the densest sensory network in the body and provide trophic support to the corneal epithelium. Three types of modalities constitute the overall corneal nerve population and convey discrete sensations by responding to various stimulations of the corneal surface. Damage to the cornea is common and can be the consequence of diverse causes, ranging from surgical interventions to metabolic disorders. Although corneal nerves are able to regrow after injury, their structural integrity is frequently disrupted and associated with prolonged changes in sensation, pain, and poor epithelial healing. The specific functional recovery of the three nerve subtypes after injury is still largely unknown, thus limiting both predictions of patient treatment outcomes and design of effective therapeutics. The first objective of this proposal is to investigate the structural and functional changes in the corneal nerve modalities after regeneration from acute corneal injury. This will be achieved by combining in vivo extracellular electrophysiology, a highly sensitive technique that records the electrical activity of a single neuron, with nerve imaging, immunohistochemical, and molecular techniques. Proposed therapeutics for corneal nerve injuries have been shown to promote faster and more extensive growth of nerves both in vitro and in vivo. However, little is known about these treatments’ functional consequences on neuronal activity. Effective therapeutics for nerve injury must ensure regeneration of full neural functionality, maintaining proper thresholds for irritant detection while avoiding painful misfiring. VEGF, an endogenous molecule expressed in the cornea post injury, is a candidate therapeutic for corneal injuries. Although it has been shown to have pro-neural effects when supplemented in animal models after corneal damage, the functional outcomes of VEGF application have not been characterized. The second objective of this proposal will use electrophysiological, immunohistochemical, imaging, and molecular techniques to investigate the structural and functional consequences of treatment with VEGF on the recovery of corneal nerves subtypes. Overall, this study will elucidate the functionality of the regenerated corneal nerve subtypes and will be the first to test the functional impacts of VEGF as a potential therapy for corneal nerve repair. This project will be conducted by an MD/PhD student at the University of Illinois-Chicago (UIC), Chicago’s major public research university, within the top-ranked Department of Ophthalmology and Visual Sciences. It will be unique in its assessment of both structural and functional consequences of neuronal regeneration by combining classical molecular methods with a sensitive technique for corneal nerve activity. The training objectives of this project are designed to develop the career of a budding physician-scientist interested in the topic of neural regeneration in ophthalmology. This fellowship project will be guided by expert mentorship of a team that includes a leading corneal physician-scientist and electrophysiologists from both UIC and Weill Cornell.