Retinal ganglion cell death is the final common pathway of almost all diseases of the optic nerve including glaucoma. Glaucoma is a leading cause of blindness and, although a number of risk factors have been identified, its causes remain unclear. Excitotoxins may be a major cause of cell death in glaucoma and the overall goal of this project is to determine the molecular mechanisms by which a variety of excitotoxic agents induce ganglion cell apoptosis. The proposal has four specific aims. In the first aim the hypothesis that glutamate induces apoptosis through a caspase-9 mediated pathway will be tested. In addition, other factors, including ischemia will be tested to determine whether they can act synergistically to exacerbate the effects of low concentrations of excitotoxins. In the second specific aim the hypothesis that mitochondrial uncoupling proteins can reduce excitotoxic ganglion cell death will be tested. The sensitivity of ganglion cells to excitotoxic and ischemic insults will be tested in culture and in the intact eye using genetically engineered mouse strains that overexpress or under express the protein UCP2.
The third aim will test the hypothesis that functional disorders of Muller glial cells may contribute to excitotoxic ganglion cell death. In particular, a variety of agents will be tested for their ability to inhibit Muller cell glutamate uptake.
The final aim will test the hypothesis that direct cell contact can protect ganglion cells from the toxic effects of nitric oxide. The specificity of this effect will be tested with a variety of cell types and the need for membrane contact by living cells will be tested using a variety of biochemical fractions. Overall, the experiments in this proposal will shed light on mechanisms of cell death of particular relevance to glaucoma. They will also further elucidate mechanisms of interaction between retinal ganglion cells and Muller glial cells. By identifying molecules that can alter responses to excitotoxins or ischemia, this proposal is likely to provide potential targets for novel therapeutic interventions to prevent or slow the progression of blindness resulting from glaucoma.
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