Project Summary/Abstract Diabetes mellitus is recognized as a leading cause of new cases of blindness among Americans between the ages of 20 and 74. The prevalence of diabetic eye disease is expected to continue to increase in the American population and worldwide as a result of the dramatic increase in the number of people with diabetes. At present, there is no medical treatment to delay or prevent the onset and progression of cataract or retinopathy, the most common causes of vision loss in diabetics. We propose a study organized around two specific aims to develop novel therapeutic compounds identified from extracts of the Indian gooseberry plant Emblica officinalis. These natural compounds have activity as aldose reductase inhibitors and show promise as agents to suppress metabolic abnormalities associated with the onset and progression of diabetic cataract and retinopathy. In aim 1, we will purify sufficient quantities of the lead compounds to conduct toxicity studies using lens and retinal pigment epithelium tissue culture systems. We will examine the efficacy of lead compounds against cataract formation in our human aldose reductase transgenic mouse model. Studies will also be carried out to evaluate the ability of lead compounds to suppress markers of inflammation in a diabetic mouse model. In specific aim 2, we will use molecular modeling to design novel derivatives to enhance binding affinity and specificity. Derivatives will be synthesized and evaluated for efficacy in tissue culture and animal model systems. We will examine interactions between optimized compounds and human aldose reductase by steady- state kinetics. Binding specificity will be examined using several members of the aldo-keto reductase gene superfamily.