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 (a-MSH) in both human and
murine CEnC, (2) significant suppression of CEnC death induced by inflammatory cytokines or the oxidant
hydrogen peroxide by a-MSH. and 3) decrease in eye banked CEnC loss when donor tissues are kept in
medium supplemented with a-MSH. Based on these preliminary data, we hypothesize that a-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 a-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 a-
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 a-MSH protects
and regenerates CEnC in response to injuries and degeneration. In Aim 1 we test the hypothesis that a-MSH
promotes CEnC regeneration following acute corneal injury by reducing CEnC apoptosis and improving
proliferation and migration; in Aim 2 we hypothesize that a-MSH prevents pathogenesis of Fuchs-like chronic
endothelial degeneration by reducing oxidative stress and we will determine the therapeutic potential of
delayed a-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.
