Therapeutic Function of alpha-Melanocyte Stimulating Hormone (α-MSH) in Acute Injury and Chronic Degeneration of Corneal Endothelium

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Corneal endothelial cells (CEnC) are critical for maintaining corneal transparency. Many factors, including aging, oxidative stress, and inflammation have been implicated in CEnC damage. CEnC loss is an integral and important contributor to many pathologies: it complicates eye banking where prolonged storage leads to progressive decline in CEnC density, and is the proximal cause of corneal edema after a variety of ocular surgeries including complex or prolonged cataract extraction, vitrectomy, or glaucoma procedures. CEnC loss is also the chief proximate cause of graft failure, whether immune-driven or not. Thus, cytoprotective strategies that enhance CEnC viability could have a major impact on a wide number of settings that would otherwise lead to CEnC decompensation and corneal edema. Clinical data from a number of clinical and experimental studies have demonstrated a strong correlation between nerve density and CEnC numbers; numerous conditions, including diabetes, dry eye, and herpetic keratitis, which induce nerve damage, are also associated with measurable CEnC loss. Our preliminary in vitro and ex vivo data show (1) high constitutive expression of melanocortin receptor for the neuropeptide alpha-melanocyte stimulating hormone (α-MSH) in both human and murine CEnC, (2) significant suppression of CEnC death induced by inflammatory cytokines or the oxidant hydrogen peroxide by α-MSH. and 3) decrease in eye banked CEnC loss when donor tissues are kept in medium supplemented with α-MSH. Based on these preliminary data, we hypothesize that α-MSH provides therapeutic protection for CEnC in response to both acute and chronic stressors associated with corneal endotheliopathy. Specifically, we will explore the role of α-MSH in maintaining CEnC viability, integrity, and function in acute endothelial injury (Aim 1) and Fuchs-like chronic endothelial degeneration (Aim 2). Our proposed aims are grounded on our extensive preliminary data showing the regenerative effect of α- MSH on murine CEnC wound healing and its cytoprotective effect against cytokines and oxidative stress- induced CEnC apoptosis in mice and human. Our overarching hypothesis is that neuropeptide α-MSH protects and regenerates CEnC in response to injuries and degeneration. In Aim 1 we test the hypothesis that α-MSH promotes CEnC regeneration following acute corneal injury by reducing CEnC apoptosis and improving proliferation and migration; in Aim 2 we hypothesize that α-MSH prevents pathogenesis of Fuchs-like chronic endothelial degeneration by reducing oxidative stress and we will determine the therapeutic potential of delayed α-MSH treatment in protecting CEnC and halting/slowing disease progression. This grant brings together synergy between our lab, which has an extensive expertise in transplantation and corneal pathobiology, with an investigative group that includes experts on chronic CEnC disorders such as Fuchs dystrophy (Dr. Jurkunas) and neuropeptide biology (Dr. Taylor). Data from this project could very well lead to innovations in the therapy of corneal endothelial pathologies.