The Rex Laboratory

3. Erythropoietin

Erythropoietin (EPO) was first identified as a cytokine that blocks cell death of red blood cell precursors resulting in an increased hematocrit. More recently it was found to be able to block neuronal cell death in multiple models. In addition, it can decrease oxidative stress and neuroinflammation as described in our recent review (Figure X). Since all of these processes occur in both glaucoma and ocular trauma we are investigating the efficacy of EPO therapy in models of these degenerations. To avoid the increase in red blood cell production while maintaining neuroprotection we use a mutant form of EPO that we identified, EPO-R76E.

We have achieved good success with recombinant adeno-associated (rAAV)-mediated delivery of EPO or EPO-R76E in the DBA/2J model of glaucoma (Sullivan 2011). In that study we initiated treatment prior to onset of degeneration. We are now actively investigating if delayed therapy (at onset of elevated intraocular pressure) will still be effective. To test therapeutic efficacy we measure axon transport, optic nerve histology, and visual function. To assess how EPO is working to block pathogenesis, we perform confocal microscopy and quantify alterations in micro and macro glial reactivity.

Research in the Rex Laboratory is split into three main areas of interest.

1. Ocular Trauma

An estimated 300,000 service members were exposed to improvised explosive devices in the recent wars in Iraq, resulting in traumatic brain injury (http://veterans.rand.org). Recently, a group of Veterans with mild traumatic brain injury due to blast exposure, who retained closed globes, were shown to have ocular pathologies including corneal abrasions, hyphemas, cataracts, corneal edema, angle recession, hemorrhage, retinal tears or detachments, macular holes, choroidal rupture, commotio retinae, and optic neuropathy (Blanch and Scott, 2009; Cockerham et al., 2011). Unfortunately, most service members and Veterans do not receive this level of examination so the prevalence of vision impairing damage is unknown. Further, since the realization that blast exposure without the presence of perforating or penetrating injury may cause permanent vision loss due to damage to the retina is new, there is a lack of animal models.

We have developed and characterized a system that directs an over-pressure air-wave to the eye. This system induces similar injuries as those described in patients with ocular trauma due to blast or blunt force trauma. Shortly after blast we detect outer retina damage including vacuolization of the retinal pigment epithelium, photoreceptor outer segment disruption, and retinal detachments. These injuries decrease over time illustrating the resilience of the tissue. In contrast, in the inner retina we detect oxidative stress and glial reactivity early after blast, followed by visual dyfunction and degeneration of the optic nerve. The damage caused by blast is mitigated by decreased neuroinflammation. We are now investigating the efficacy of anti-oxidant and neuroprotective strategies.

2. Glaucoma

Glaucoma is a neurodegenerative disease of complex etiology. The underlying mechanisms leading to retinal ganglion cell death and permanent vision loss are being actively elucidated. We now know that Glaucoma is an axonopathy - the cell death is secondary to the axon degeneration.  In addition, several studies show that there is increased neuroinflammation, including glial reactivity, early in the pathogenesis in models of glaucoma. Our laboratory uses two mouse models of glaucoma to investigate the cellular and molecular mechanisms that underlie vision loss and degeneration in glaucoma.

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