Age-related nuclear (ARN) cataract is a major cause of world blindness. There has been a revolution in our understanding of ARN cataract in the past 1-2 years. Up until that time, essentially all that was known was that ARN cataract is associated with profound oxidation and that this is accompanied by insolubilisation, coloration and cross-linking of lens proteins. It was unclear why such massive oxidative changes occurred in the nuclei of these lenses. Recent advances suggest that ARN cataract develops as a direct result of changes in the lens that occur with age. These include the discovery of the probable reason for lens coloration and the biochemical/physical basis that may allow oxidation in the centre of the lens to proceed; resulting ultimately in cataract. Briefly, a barrier to the movement of the antioxidant, glutathione (GSH) from its site of synthesis or reduction in the cortex, into the lens nucleus, forms in older individuals. Thus the nucleus of the older normal human lens becomes susceptible to oxidative stress. In addition, human lens UV filter compounds are intrinsically unstable and undergo deamination to form reactive ketones. Once the barrier forms, these have time to breakdown and then readily react with lens crystallins. This binding appears to be the basis for age-dependent human lens coloration and possibly ARN cataract. These findings suggest that most, if not all, of the features of ARN cataract may be explained on the basis of the onset of the lens bamer in middle age, and the subsequent oxidation and reaction of the nuclear proteins with UV filters. It is the aim of this grant application to investigate this proposal. If confirmed, this would have major implications for future cataract treatment, since it offers hope that drug intervention may be possible to prevent, or delay, ARN cataract.
The specific aims are to: 1. identify the sites of attachment of the UV filters, kynurenine, 3-hydroxykynurenine and 3-hydroxykynurenine glucoside to lens crystallins from older normal, as well as ARN cataract lenses and 2. establish a long-term culture facility for intact human lenses and to employ this to investigate: a) the bather to diffusion in older lenses, b) the binding of UV filters to crystallins in intact lenses as well as c) inhibition of the UV filter biosynthetic pathway as a pharmacological strategy to prevent nuclear cataract.
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