The primary and long-term objective of the proposed investigation is to study the mechanism(s) of cataractogenesis and develop approaches to delay, eventually inhibit cataract development and regress opacities in progression. For the proposed studies two experimental rat models, galactose cataract and cataracts associated with hypertension will be used to fulfill our objectives. These models will provide significant and relevant information towards understanding cataract development in humans associated with two risk factors, diabetes and hypertension. The proposed study on galactose cataract is a logical extension of our current ongoing investigations. For hypertension model, salt-sensitive hypertensive Dahl rats with a significant incidence of cataract development will be used. Potent aldose reductase inhibitors and antioxidants will be used to study their effect on delaying, inhibiting and reversing galactose-induced alterations int he lens and cataract. Moreover, allopurinol, a drug used for gout therapy and postulated to promote galactose cataract development will be used to investigate its role as a co-factor in sugar cataractogenesis. Chronic and acute salt restriction approach will be used to study delay, inhibition and reversal of cataracts in salt-sensitive hypertensive rats. Morphological techniques involving light, transmission and scanning electron microscopy, ultrastructural cytochemistry and immunocytochemistry, and biochemical and molecular biology techniques will be used for this study. Using these approaches alterations in lens morphology, sites and level of enzyme activities (Na+-K+-ATPase, Ca2+-ATPase, acid phosphatase and arylsulfatase) will be evaluated in both models. In addition, for galactose model changes in the plasma membrane protein MP26, hexoses and polyo1 levels and gene expression for several proteins in the lens will be investigated. this study will contribute information of clinical significance towards understanding of cataractogenesis in human and potentially lead toward development of means to delay, inhibit and reverse opacities associated with diabetes and hypertension.
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