Changes in transient receptor potential melastatin 8 expression and function after corneal nerve regeneration

The National Eye Institute awarded the University of Illinois $110,228 on February 8, 2027, to investigate changes in transient receptor potential melastatin 8 (TRPM8) expression and function during corneal nerve regeneration, under the Vision Research program (CFDA 93.867).

The research examines how TRPM8, a cold thermoreceptor critical to corneal sensory function and homeostasis, is affected by corneal nerve injury and how it contributes to nerve recovery. Corneal nerve injuries from trauma, surgery, or disease often result in incomplete or maladaptive regeneration, leading to neuropathic pain, impaired sensation, poor wound healing, and diminished vision and quality of life. The project uses corneal epithelial debridement in rodent models to mimic clinical contexts including corneal abrasion and laser-assisted in situ keratomileusis (LASIK). The first objective investigates anatomical and molecular recovery of TRPM8-expressing nerves using immunohistochemistry and three-dimensional light sheet microscopy to visualize TRPM8 protein expression and spatial transcriptomics of the trigeminal ganglion, with the goal of identifying TRPM8's potential as a therapeutic target.

Work is performed in Illinois. The period of performance runs through August 15, 2030. This is a project grant, an assistance type supporting individual research projects.

Abstract

Corneal nerves consist of the densest network of innervation in the body, branching from the trigeminal ganglion (TG) and terminating at the corneal epithelial surface. These nerve endings express ION channel receptors that regulate essential sensory functions such as cooling, hydration, nociception, and mechanosensation. The transient receptor potential melastatin 8 (TRPM8), known as the cold thermoreceptor, is a crucial ION channel that maintains corneal homeostasis via blink reflex, tear response, and supply of trophic factors upon cold stimulus. Thus, intact corneal nerve innervation is crucial for sensory functions and overall corneal health. However, corneal nerve injuries resulting from trauma, surgery, or disease often lead to incomplete or maladaptive nerve regeneration, which subsequently affects the function of sensory modalities such as TRPM8. Dysfunction of sensory modalities can lead to neuropathic pain, impaired sensation, and poor wound healing, significantly impacting vision and quality of life. Although TRPM8 has a known role in corneal epithelial and nerve health, changes in overall corneal nerve structure, TRPM8 expression, and TRPM8 function during and after nerve regeneration remain poorly understood. This project aims to determine how TRPM8 is affected by injury, how IT contributes to corneal nerve recovery, and its potential as a therapeutic target. The injury model for this project is corneal epithelial debridement (CED) in rodent models. IT will mimic clinical contexts like corneal abrasion, laser-assisted in situ keratomileusis (LASIK), and other refractive surgeries. The first objective of this proposal will investigate the anatomical and molecular recovery of TRPM8-expressing nerves using immunohistochemistry and 3-D light sheet microscopy (LSM) of TRPM8 protein expression. Spatial transcriptomics of TGS will also be employed to correlate potential regulatory changes at the transcriptional level with changes in TRPM8 protein expression. The second objective will assess the effect of TRPM8 deletion on corneal nerve regeneration and how TRPM8 modulates nerve repair and epithelial integrity. The final objective of this proposal will utilize in vivo electrophysiology and functional behavioral assays to evaluate TRPM8 functional activity following CED and the application of TRPM8 agonists, menthol and icilin, at acute and chronic time points. Overall, this research addresses a critical GAP in understanding the mechanisms that direct corneal nerve recovery and provides insight into developing targeted therapies that could improve outcomes for patients suffering from nerve-related ocular pathologies.