Project 5 will provide measurements of age-sensitive markers of collagen aging, metabolic status and oxidative stress int he group of 600 genotyped female UM-HET3 mice for studies of genetic linkage and biomarker validation. The test battery will also be performed on the 180 mice in Population 2, to see if mice selected for alleles that covey extended lifespan also show diminished level of protein glycation and oxidation. The set of tests includes measures of collagen glycation (furosine) and the glycoxidation products pentosidine and N/epsilon- carboxymethyl-lysine, whose rate of age-dependent increase is known from prior work to vary among inbred strains and to be sensitive to the age- retarding effects of calorie restriction. Data derived from Project 5 will confirm and extend pilot work suggesting that protein glycation and glycoxidation are under genetic control in the UM-HET3 mouse stock, and will show whether the genetic and non-genetic factors that influence these post-translational modifications also influence protein conformation (Project 4), affect the immune cells, muscle, and bone tissue (Projects 1, 2 and 3), and might be associated with individual differences in DNA sequence stability (Project 6). In addition, the data derived from Project 5 will permit a comprehensive evaluation of several indices of protein modification, including formation of methionine sulfoxide and the thermal stability of tail tendon collagen, a sensitive marker of collagen crosslinking. The relationships of these adducts to the other markers of metabolic state (pentosidine, furosine and CML), and their possible links to age- sensitive measures of immune, muscle, and bone function, will emerge from the combination of correlational and genetic analyses possible only within the context of a multi-component program.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
1P01AG016699-01
Application #
6156467
Study Section
Project Start
1999-05-01
Project End
2000-04-30
Budget Start
Budget End
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Burke, David T; Kozloff, Kenneth M; Chen, Shu et al. (2012) Dissection of complex adult traits in a mouse synthetic population. Genome Res 22:1549-57
Chisa, Jennifer L; Burke, David T (2007) Mammalian mRNA splice-isoform selection is tightly controlled. Genetics 175:1079-87
Hanlon, Philip; Lorenz, William Andrew; Shao, Zhihong et al. (2006) Three-locus and four-locus QTL interactions influence mouse insulin-like growth factor-I. Physiol Genomics 26:46-54
Harper, James M; Salmon, Adam B; Chang, Yayi et al. (2006) Stress resistance and aging: influence of genes and nutrition. Mech Ageing Dev 127:687-94
Harper, James M; Durkee, Stephen J; Smith-Wheelock, Michael et al. (2005) Hyperglycemia, impaired glucose tolerance and elevated glycated hemoglobin levels in a long-lived mouse stock. Exp Gerontol 40:303-14
Volkman, Suzanne K; Galecki, Andrzej T; Burke, David T et al. (2004) Quantitative trait loci that modulate femoral mechanical properties in a genetically heterogeneous mouse population. J Bone Miner Res 19:1497-505
Harper, James M; Galecki, Andrzej T; Burke, David T et al. (2004) Body weight, hormones and T cell subsets as predictors of life span in genetically heterogeneous mice. Mech Ageing Dev 125:381-90
Wisser, Kathleen C; Schauerte, Joseph A; Burke, David T et al. (2004) Mapping tissue-specific genes correlated with age-dependent changes in protein stability and function. Arch Biochem Biophys 432:58-70
Harper, James M; Galecki, Andrzej T; Burke, David T et al. (2003) Quantitative trait loci for insulin-like growth factor I, leptin, thyroxine, and corticosterone in genetically heterogeneous mice. Physiol Genomics 15:44-51
Bennett-Baker, Pamela E; Wilkowski, Jodi; Burke, David T (2003) Age-associated activation of epigenetically repressed genes in the mouse. Genetics 165:2055-62

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