New models, new approaches, new horizons in corneal nerve regeneration

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PROJECT SUMMARY/ABSTRACT The cornea is the most highly innervated structure in the body, supplied by the ophthalmic branch of the trigeminal nerve. As part of the peripheral nervous system, corneal nerves respond to pain, temperature, mechanical and chemical stimuli. They also secrete various trophic and growth factors, which are essential to the health and function of the cornea. However, corneal nerves are highly susceptible to injury through various mechanisms that include trauma, infections, metabolic imbalances, and therapeutic interventions such as refractive surgeries. Once injured, they fail to reestablish their baseline density or morphology, contributing to corneal dysfunction. Currently, there are no targeted treatments specific for corneal nerve regeneration. The long-term goal of this proposal is to develop therapies for corneal nerve regeneration. The objective is to determine key molecular mechanisms involved in corneal nerve regeneration to help inform new experimental and therapeutic interventions. The central hypothesis is the N-Methyl-D-aspartate receptors (NMDAR), a type of glutamate receptor, help restore corneal nerve density and morphology, and therefore, corneal function. The rationale underlying this proposal is that NMDARs have been shown to enhance nerve regeneration in other analogous peripheral nervous systems. However, their role in corneal nerve regeneration remains unknown. Additional justification for investigating the role of NMDARs in corneal nerve regeneration is based on other published findings: 1) NMDARs are expressed throughout the nervous system, including the trigeminal nerves; 2) they have been shown to regulate neuronal maintenance and plasticity; 3) they regulate Schwann cell activity, which are supporting cells essential to nerve regeneration; and 4) NMDARs cooperate with other signaling molecules that have been shown to regulate corneal nerve regeneration such as LDL-receptor-related protein-1 and Ephrin type-B receptor 2. Therefore, we propose three aims to support our hypothesis. AIM 1 will determine the role of NMDAR in corneal nerve maintenance and regeneration by conditionally deleting NMDAR in sensory nerves and Schwann cells independently. AIM 2 will determine the effect of modulating NMDAR levels on corneal nerve regeneration. AIM 3 will determine key downstream effectors, including the EphB2-Sox2 axis, with spatial transcriptomics, correlated with protein levels and morphologic changes during corneal nerve regeneration. We will pursue these aims using innovative genetic mouse models, intravital imaging, and spatial genomics. The proposed aims are significant because they will define new molecular pathways that will inform the development of future therapies. The immediate expected outcome of this work is rigorous interrogation of key pathways in corneal nerve regeneration in vivo and contribution to our fundamental understanding of peripheral nerve regeneration. The results will have an important direct positive impact because they will interrogate new experimental approaches and inform the development of targeted therapies for corneal nerve regeneration.