ACTIVATION OF THE HEXOSEMONOPHOSPHATE SHUNT IN THE LENS

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The broad, long-term objective of this application is to apply findings generated from the proposed studies to the non-surgical treatment of human cataracts of osmotic-oxidative origin. The specific aims include the examination of four different aspects of hexose monophosphate shunt (HMPS) activation in the lens: (A) to quantify the HMPS and associated metabolic activities; (B) to investigate the recovery process in metabolically stressed lenses with regard to HMPS activity, glucose and phosphorus metabolism, and ionic transport; (C) to test mannose replacing glucose as the substrate of glycolysis and its effect on polyol pathway activation and oxidative resistance; and (D) to study the indirect effect of growth factors on the HMPS activity. Experimental models include (1) in-vivo models such as streptozotocin-diabetic rats (treated with insulin, aldose reductase inhibitors, or fed a mannose diet) and rats/rabbits fed 50% galactose, and (2) lens incubation under osmotic-oxidative stress using animal (rat, rabbit and Guinea pig) lenses and adult/infant human lenses. These lenses are examined with in-vitro nuclear magnetic resonance (NMR) spectroscopy supplemented with biochemical assays. To achieve the objective, first the basal lens metabolism and its response to and recovery from metabolic stresses are elucidated. The possibility of relieving these stresses is then examined, for example, with metabolic modulations such as the use of mannose to replace glucose. Similarly, the effect of growth factors on HMPS activation is first evaluated, after which, it will be possible to modify lens HMPS activation to maintain the availability of NADPH and ribose-Phosphate for biosynthesis and oxidative resistance.