This grant proposal is from a highly experienced investigator to examine whether a mutant form of alphaA-crystallin (R116 C), associated with autosomal dominant cataract in human, has altered property of elevated plasma membrane binding and therefore, causes cataract. Preliminary results shows a change in the property of the mutant alpha-crystallin compared wild type alpha, and according to the P.I., this may be a causative factor in the human autosomal dominant cataract. To investigate this causative factor in the autosomal dominant cataract, three specific aims are proposed. These will determine the specificities of lens membrane proteins and lipids during binding with alpha-crystallin, the effect of post-translational modifications of alpha-crystallin on its membrane-binding capability and finally the role of the mutant protein in cataract development by producing a transgenic mouse strain for lens expression of R116C mutant form of alphaA-crystallin. Together, the studies will provide insight regarding the role of alphaA R116C mutant in potential mechanism of the human autosomal dominant cataract.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
1R01EY013897-01
Application #
6444525
Study Section
Special Emphasis Panel (ZRG1-SSS-R (02))
Program Officer
Liberman, Ellen S
Project Start
2002-05-01
Project End
2006-04-30
Budget Start
2002-05-01
Budget End
2003-04-30
Support Year
1
Fiscal Year
2002
Total Cost
$374,625
Indirect Cost
Name
Washington University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Srinivas, Pasumarthi; Narahari, Akkaladevi; Petrash, J Mark et al. (2010) Importance of eye lens ?-crystallin heteropolymer with 3:1 ?A to ?B ratio: stability, aggregation, and modifications. IUBMB Life 62:693-702
Barton, Kelly A; Hsu, Cheng-Da; Petrash, J Mark (2009) Interactions between small heat shock protein alpha-crystallin and galectin-related interfiber protein (GRIFIN) in the ocular lens. Biochemistry 48:3956-66
Bhagyalaxmi, S G; Srinivas, Pnbs; Barton, Kelly A et al. (2009) A novel mutation (F71L) in alphaA-crystallin with defective chaperone-like function associated with age-related cataract. Biochim Biophys Acta 1792:974-81
Shi, Yanrong; Barton, Kelly; De Maria, Alicia et al. (2009) The stratified syncytium of the vertebrate lens. J Cell Sci 122:1607-15
Hsu, Cheng-Da; Kymes, Steven; Petrash, J Mark (2006) A transgenic mouse model for human autosomal dominant cataract. Invest Ophthalmol Vis Sci 47:2036-44