ACTIVATION OF THE HEXOSE MONOPHOSPHATE SHUNT IN THE LENS

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It is now known that human senile cataracts have undergone extensive oxidative alteration. This is evidenced by the accumulation of disulfide-rich high molecular weight protein aggregates in the cataractous lenses. The source of oxidation has not yet been definitively identified. Elevated H2O2 levels, however, have been discovered in the aqueous humor and the lens of human cataract patients. This suggests that H2O2 and its derivatives may be involved in the cataractogenesis and that the cataracts are incapable of detoxifying H2O2 efficiently. We propose to investigate: (1) whether there is an inherent weakness in the lens's H2O2 detoxifying mechanism, (2) whether there is an age-related loss of H2O2 detoxification, particularly the hexose monophosphate shunt-coupled system, (3) whether H2O2-induced damage can be identified, and (4) whether it is possible to augment the lens's resistance to H2O2. Both biochemical assays and nuclear magnetic resonance spectroscopy will be employed in this proposal. Successful completion of the proposed studies and demonstration of feasibility will enable us to develop anti-cataract agent(s) for the treatment of human senile cataracts.