The primary goal of research on the mechanism of senile cataract formation is to discover treatments which can inhibit, or at least delay, the progression of cataract formation. If this pathology could be delayed by only 10 years, this would eliminate most of the cataract operations performed each year. Analysis of aged human lenses show increased aggregation and crosslinking of proteins, which are thought to be fundamental in cataract formation. The chemistry of these processes, however, remains largely unknown. We have been investigating the modification of lens proteins by ascorbic acid glycation, and have discovered a great number of similarities between in vitro glycated proteins and the proteins isolated from aged human lenses. The formation of advanced glycation endproducts may be responsible for the yellowing or brunescence of the lens, the generation of active oxygen species and the formation of protein crosslinks. This work has been hampered because so little is known about either the chemistry of ascorbic acid glycation in particular or the structure of advanced glycation endproducts and crosslinks in general. In the work proposed here we will measure the glycation of lens proteins by various ascorbic acid breakdown products under """"""""physiological"""""""" conditions in order to determine the activity of each compound in glycation and crosslinking. Crosslinks between specific amino acid pairs will be prepared and their stability measured and compared to the stability of the crosslinks present in the water-insoluble fraction from aged human lens. The chemical nature of several ascorbate-derived crosslinks will be determined using a new isolation method with a model peptide. Finally, the nature of the sensitizers produced by ascorbate glycation will be compared to those in aged human lens for the specific active oxygen species produced.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY007070-13
Application #
2888298
Study Section
Visual Sciences A Study Section (VISA)
Project Start
1987-08-01
Project End
2000-07-31
Budget Start
1999-08-01
Budget End
2000-07-31
Support Year
13
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Missouri-Columbia
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
112205955
City
Columbia
State
MO
Country
United States
Zip Code
65211
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