Aging is a major risk factor for human cataract development. The cumulative effects of oxidative stress result in detrimental changes that occur with aging in all tissues. A feature of human lens aging is a 14- fold loss of the key cellular anti-oxidant, glutathione. Low levels of glutathione are invariably associated with cataract formation, and low levels by themselves have been shown to cause cataracts. Thus, glutathione deficiency in lens is a risk factor for human cataractogenesis. Age-associated reduction of the lens' ability to synthesize glutathione may be caused by a 4-fold loss in the uptake of L-cysteine (a biochemical precursor of glutathione) and a 16-fold activity loss of the first enzyme required for its biosynthesis. We propose to apply knowledge gained during the past years of this research grant toward development of biochemical and pharmacological methods for maintaining high levels of glutathione in the aging and diabetic human lens. The program couples the efforts of a biochemist with long-term interests in glutathione metabolism of the lens in synergistic concert with those of a medicinal chemist with long term interests in the design and synthesis of L-cysteine prod rugs and gamma-glutamyl and other peptidyl drug delivery systems. The proposal consists of two parts. The first part explores possible causes of the considerable decline in glutathione content in the human lens with age. These include exposure to ultraviolet light and reactive phosphorylated metabolites of polyols, which may in activate the L-cysteine uptake system and/or the glutathione biosynthesis enzymes. The second, and significant part with regard to potential clinical application, is to increase the glutathione content in lens by pharmacological intervention. This will be done by (a) increasing the uptake of L-cysteine and (b) developing prodrugs to augment glutathione. The prodrugs will be evaluated in vitro with human lens and corneal preparations and in vivo, using selected prodrugs administered parenterally or topically to corneas of galactose-fed rats. The results of this research could lead to the elimination of a significant risk factor in human cataractogenesis associated with aging and diabetes. In addition, there is the persistent question of whether maintenance of adequate glutathione levels will delay/prevent galactose- induced cataract formation. This unique collaboration appears to position the investigators favorably to supply the long-desired answer.
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