Studies on the hexose monophosphate shunt (HMPS) and its associated pathways are proposed in this application. We will examine the following five topics: 1) Control of the HMPS; 2) Activity of the HMPS and its associated pathways; 3) Re-examination of the polyol pathway and previously unrecognized rate-limiting steps; 4) The significance of disturbance to membrane metabolism; and 5) The effect of oxidation on basal HMPS activity and oxidative resistance. These studies are based on data obtained over the past two years. We have found evidence of: 1) competition for NADPH between aldose reductase and glutathione reductase and 2) prominent changes in membrane metabolites in the diabetic rats. We will employ biochemical procedures as well as biophysical methods such as nuclear magnetic resonance spectroscopy to examine the interaction of various NADPH-requiring pathways and electron paramagnetic resonance spectroscopy to probe membrane structural change. These studies are crucial to the understanding of diabetic cataractogenesis. Studies on oxidative resistance can pave the groundwork for the design of non-surgical anti-senile cataract therapy.
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