A normal long-lived, dark-eyes mouse strain, the (C57BL/6xDBA/2) F1 hybrid mouse has been studied for late life incidence of cataracts. This incidence approaches 100% in very late life and, in preliminary studies, appears to accumulate progressively during old age in mice. The time of cataract occurrence and its non-association with other eye or general systemic pathologies differentiate this mouse model from others now in use. These particulars indicate that it promises to be an ideal model for the human aging cataract. It is the intent of the applicants to complete the model studies involving time of occurrence, the genetic background involved, the histopathology of the lens and adjoining eyes, and the possible importance of oxidative DNA damage in its causation. It will be determined whether this mouse strain is unique in its very high late incidence of cataracts or whether other strains will provide similar findings. Of particular importance is the fact that life long caloric restriction (CR) at 60% of ad libitum (AL) diet significantly reduces the incidence and delays the appearance of the cataracts. CR has been shown to reduce oxidative damage to cells and their DNA and to preserve the replicative capacity of cells both in vivo and in vitro. The amount of DNA damage present, measured as either or single or double stranded DNA breaks, as well as telomeric shortening, will be determined in the lens epithelial cells of chronologically spaced groups of mice. This will be done both in untreated lens cells and in those that have received an in vitro oxidative challenge. Any effects of lifetime light exposure will be accounted for. All of these measurements will be matched to the ability of the lens cells from the same donors to form large clones in culture, a reliable measurement of physiological cellular aging. This study will define a mouse model for human age-related cataract formation and will use it to provide information on the harmful role of oxidative damage to lens epithelial cell DNA, correlating this with cataract development.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY011733-04
Application #
6363146
Study Section
Visual Sciences A Study Section (VISA)
Program Officer
Liberman, Ellen S
Project Start
1998-03-01
Project End
2002-06-30
Budget Start
2001-03-01
Budget End
2002-06-30
Support Year
4
Fiscal Year
2001
Total Cost
$278,151
Indirect Cost
Name
University of Washington
Department
Pathology
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Urfer, Silvan R; Greer, Kimberly; Wolf, Norman S (2011) Age-related cataract in dogs: a biomarker for life span and its relation to body size. Age (Dordr) 33:451-60
Pearson, Kevin J; Baur, Joseph A; Lewis, Kaitlyn N et al. (2008) Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab 8:157-68
Wolf, Norman; Pendergrass, William; Singh, Narendra et al. (2008) Radiation cataracts: mechanisms involved in their long delayed occurrence but then rapid progression. Mol Vis 14:274-85
Pendergrass, William R; Penn, Phil E; Possin, Daniel E et al. (2006) Cellular debris and ROS in age-related cortical cataract are caused by inappropriate involution of the surface epithelial cells into the lens cortex. Mol Vis 12:712-24
Melov, Simon; Wolf, Norman; Strozyk, Dorothea et al. (2005) Mice transgenic for Alzheimer disease beta-amyloid develop lens cataracts that are rescued by antioxidant treatment. Free Radic Biol Med 38:258-61
Pendergrass, William; Penn, Philip; Possin, Daniel et al. (2005) Accumulation of DNA, nuclear and mitochondrial debris, and ROS at sites of age-related cortical cataract in mice. Invest Ophthalmol Vis Sci 46:4661-70
Wolf, Norman; Penn, Philip; Pendergrass, William et al. (2005) Age-related cataract progression in five mouse models for anti-oxidant protection or hormonal influence. Exp Eye Res 81:276-85
Pendergrass, W; Wolf, N; Poot, M (2004) Efficacy of MitoTracker Green and CMXrosamine to measure changes in mitochondrial membrane potentials in living cells and tissues. Cytometry A 61:162-9
Chang, Jinsook; Van Remmen, Holly; Ward, Walter F et al. (2004) Processing of data generated by 2-dimensional gel electrophoresis for statistical analysis: missing data, normalization, and statistics. J Proteome Res 3:1210-8
Wolf, Norman; Galecki, Andrzej; Lipman, Ruth et al. (2004) Quantitative trait locus mapping for age-related cataract severity and synechia prevalence using four-way cross mice. Invest Ophthalmol Vis Sci 45:1922-9

Showing the most recent 10 out of 18 publications