The objective of our research is to elucidate the mechanisms methanol- induced retinal toxicity. Experiments will be conducted in a nonprimate animal model and in cultured retinal cells. These studies will test the hypothesis that formic acid, the toxic metabolite in methanol poisoning, inhibits retinal mitochondrial function resulting in retinal dysfunction and damage. They will also define the role of neuronal and glial elements in formate toxicity and determine if pharmacologic interventions which prevent mitochondrial dysfunction or blocks excitotoxicity will attenuate formate retinotoxicity. (1) Studies will be conducted to determine if formate-induced disruption of photoreceptor energy metabolism is an important component of formate-induced retinal toxicity. For these studies electroretinographic, biochemical and histological investigations will be conducted under conditions which physiologically modulate photoreceptor energy utilization. These studies will determine if photoreceptors are more susceptible to the cytotoxic actions of formate than other retinal cells due to their reliance on oxidative metabolism. (2) Studies will be conducted to determine the mechanisms by which formate compromises mitochondrial function and the cellular consequences of formate-induced mitochondrial dysfunction. These studies will determine the events that link cytochrome oxidase inhibition to mitochondrial failure and cell death in cultured retinal neurons and M?ller glia, thereby providing an understanding of the relationships between these biochemical events and the cytotoxicity produced by formate. Results from these studies will provide information on the mechanisms of formate toxicity which is necessary for the development of therapeutic strategies to counteract its damaging effects. (3) Experiments will be conducted to test the effectiveness of Pharmacologic interventions designed to prevent mitochondrial damage or block excitotoxicity. These studies will determine if pharmacologic interventions designed to improve mitochondrial energy production, restore mitochondrial glutathione, trap reactive oxygen species or attenuate the neurotoxic actions of excitatory amino acids will ameliorate formate toxicity in cultured retinal cells and in methanol-intoxicated rats. Results from these studies will provide the foundation for the development of effective therapy for methanol poisoning. Successful completion of these studies outlined in this proposal will improve our understanding of the pathogenesis of methanol poisoning and will provide valuable insight into the role of mitochondrial function in retinal disease.
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