Glaucoma is the world's leading cause of irreversible vision loss. The only modifiable risk factor for glaucoma is intraocular pressure (IOP) and thus all existing medical and surgical approaches target the IOP. Unfortunately, many patients continue to lose vision despite IOP management. Glaucoma involves progressive degeneration of retinal ganglion cells (RGCs), whose axons form the optic projection from retina to brain. Thus, our long-term goal is to develop new treatments to abate this neurodegeneration directly in an IOP- independent manner, based on identification and targeting of critical mechanisms of disease progression. We previously reported that erythropoietin or a mutated version of it, EPO-R76E, are able to preserve the RGCs in models of glaucoma. Our data shows that it modulates neuroinflammation and increases expression of antioxidant proteins. In our parent R01, we propose to use gene therapy strategies in the microbead occlusion model to determine the role of NRF2 and the antioxidant response element in EPO-R76E-mediated neuroprotection in glia and RGCs, separately, in glaucoma. In this supplement application, we propose to expand the scope of investigation to explore the endogenous response of the retina and RGCs to hypertension-induced oxidative stress. The anticipated significant accomplishment of this proposal is identification of new druggable targets early in glaucoma pathogenesis and clarity on the cell types to target, which will increase the safety and efficacy of treatments. It also provides an unique opportunity for Sarah Naguib to be mentored into an independent vision researcher poised for a successful post-doctoral fellowship.
In this diversity supplement application, we will test the hypothesis that EPO-R76E reduces neurodegeneration in glaucoma by increasing an endogenous anti-oxidative response of RGCs, thereby reducing overall reactive oxygen species (ROS). The success of this project will direct the development of targeted and efficacious therapeutics for glaucoma patients that target the neurodegeneration. It will also further the development of Sarah Naguib into an independent vision scientist.
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