Cytoprotective and Pro-regenerative Neuropeptide as Countermeasure to Mustard Gas Ocular Damage - PROJECT SUMMARY / ABSTRACT Mustard agents, in particular sulfur mustard and nitrogen mustard, can pose potent threats to both Service Members and civilians by penetrating exposed tissues and resulting in devastating effects on myriad organs, among which the ocular surface is the most vulnerable. Around 40% of exposed victims who survive attacks of mustard suffer from ocular problems, with severe corneal sequelae termed mustard gas keratopathy (MGK) that impairs corneal transparency and visual function. The current post-exposure management is very limited and largely ineffective in preventing the development of MGK. We have recently established a mouse model of nitrogen mustard gas ocular damage and show significant loss of corneal nerves as reported in human patients, indicating that impaired neurotrophic support contributes to development of MGK. Among various nerve-derived factors, alpha- melanocyte-stimulating hormone (α-MSH) is critical to ocular homeostasis through exerting anti-inflammatory, cytoprotective, and pro-regenerative function. Our pilot study has demonstrated the effectiveness of α-MSH treatment in preventing the development of persistent corneal epitheliopathy, edema, and opacity, as well as reducing corneal nerve and endothelial loss, in mice exposed to nitrogen mustard. Mechanistically, we demonstrate predominant expression of melanocortin receptor-1 (MC1R), among various α-MSH receptors, in corneal epithelium, suggesting a link of therapeutic effects of topical α-MSH to MC1R signaling pathway. In the current proposal, we thus hypothesize that topical α-MSH treatment mitigates mustard gas corneal damage by primarily activating MC1R-mediated protein kinase A (PKA) pathway at the ocular surface that leads to reduced apoptosis, enhanced regeneration, and suppressed inflammation. The principal objectives of this project are to (i) assess the therapeutic efficacy of α-MSH in preventing the development of MGK; and (ii) determine mechanisms by which α-MSH prevents MGK. To achieve these objectives, two specific aims have been developed: Aim 1: We will test our hypothesis that topical treatment with α-MSH after mustard exposure prevents persistent corneal epitheliopathy and endothelial damage, reduces nerve degeneration, and suppresses corneal inflammation and scarring; and Aim 2: We will test our hypothesis that topically applied α-MSH binds to MC1R in the cornea and activates the PKA pathway to exert its therapeutic function. Successful completion of this project will help validate a potential molecule capable of mitigating mustard- induced ocular damage, and thus lay a foundation for our next steps, involving translational studies to further investigate the function of α-MSH in mitigating sulfur mustard-induced ocular damage.
