Age-related nuclear (ARM) cataract is a major cause of world blindness. There has been a revolution in our understanding of ARN cataract in the past few years. Up until that time, essentially all that was known was that ARN cataract was associated with profound oxidation, insolubilization, coloration and cross-linking of lens proteins. It was unclear why such 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 a reason for lens coloration and also the biochemical/physical basis that allows oxidation in the centre of the lens to proceed; resulting ultimately in cataract.) Briefly, a barrier to the movement of the antioxidant, glutathione 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. 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 barrier in middle age and the subsequent oxidation and reaction of the nuclear proteins with reactive molecules, such as UV filters. We propose to investigate the reason for the onset of the barrier at middle age. In December 2004 we showed that the nucleus of normal lenses undergoes a massive increase in hardness with age. Could this be the reason for the development of the barrier? 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. Since the lens nucleus must undergo a major change in shape on accommodation, understanding the molecular basis of this enormous hardening may also impact on our understanding of presbyopia. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY013570-06
Application #
7498924
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Araj, Houmam H
Project Start
2001-09-30
Project End
2010-08-31
Budget Start
2008-09-01
Budget End
2010-08-31
Support Year
6
Fiscal Year
2008
Total Cost
$111,879
Indirect Cost
Name
University of Sydney
Department
Type
DUNS #
752389338
City
Sydney
State
Country
Australia
Zip Code
2006
Hooi, Michelle Yu Sung; Raftery, Mark J; Truscott, Roger John Willis (2012) Racemization of two proteins over our lifespan: deamidation of asparagine 76 in ýýS crystallin is greater in cataract than in normal lenses across the age range. Invest Ophthalmol Vis Sci 53:3554-61
Hooi, Michelle Yu Sung; Raftery, Mark J; Truscott, Roger John Willis (2012) Age-dependent deamidation of glutamine residues in human ýýS crystallin: deamidation and unstructured regions. Protein Sci 21:1074-9
Truscott, Roger J W; Mizdrak, Jasminka; Friedrich, Michael G et al. (2012) Is protein methylation in the human lens a result of non-enzymatic methylation by S-adenosylmethionine? Exp Eye Res 99:48-54
Nealon, Jessica R; Blanksby, Stephen J; Donaldson, Paul J et al. (2011) Fatty Acid uptake and incorporation into phospholipids in the rat lens. Invest Ophthalmol Vis Sci 52:804-9
Hooi, Michelle Yu Sung; Truscott, Roger J W (2011) Racemisation and human cataract. D-Ser, D-Asp/Asn and D-Thr are higher in the lifelong proteins of cataract lenses than in age-matched normal lenses. Age (Dordr) 33:131-41
Truscott, Roger J W; Comte-Walters, Susana; Ablonczy, Zsolt et al. (2011) Tight binding of proteins to membranes from older human cells. Age (Dordr) 33:543-54
Hains, Peter G; Truscott, Roger J W (2010) Age-dependent deamidation of lifelong proteins in the human lens. Invest Ophthalmol Vis Sci 51:3107-14
Beebe, David C; Truscott, Roger J W (2010) Counterpoint: The lens fluid circulation model--a critical appraisal. Invest Ophthalmol Vis Sci 51:2306-10; discussion 2310-2
Zhu, Xiangjia; Gaus, Katharina; Lu, Yi et al. (2010) ?- and ?-crystallins modulate the head group order of human lens membranes during aging. Invest Ophthalmol Vis Sci 51:5162-7
Friedrich, Michael G; Truscott, Roger J W (2010) Large-scale binding of *-crystallin to cell membranes of aged normal human lenses: a phenomenon that can be induced by mild thermal stress. Invest Ophthalmol Vis Sci 51:5145-52

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