ABSTRACT (CORE B) Core B will provide support for the Program's mouse studies. This core will transition from the RIVM in Bilthoven to The University of Texas Health Science Center at San Antonio. Current projects will remain Bilthoven while new projects will be conducted in at the Barshop Center in San Antonio. This new location is ideal since it is one of three sites for the NIH Intervention Testing Program that tests drugs for lifespan enhancing activity and since it is one of five NIH-funded Nathan Shock Centers of Excellence in the Basic Biology of Aging. Core B will conduct lifespan and cross-sectional analyses for a variety of interventions that include growth diminution (dietary restriction and rapamycin), Sac1-induced double strand breaks, observation and clearance of p16-expressing cells and depletion of cell preservation microRNAs. The Nathan Shock Center Health Span and Functional Assessment Core located at the Barshop Center will use variety of assays to measure health. Core B will use a uniform genetic background for all analyses. All mice will be F1 generation from an FVB x C57Bl/6J cross. This background eliminates problems found with isogenic backgrounds like embryonic lethality and dermatitis. Core B will utilize two mouse models mutated for either ERCC1 (ercc1-/ ?7) or KU80 (ku80-/-). ERCC1 is a 3' endonuclease that incises 5' to helix distorting lesions during nucleotide excision repair and removes 3' flaps during crosslink repair. This 3' flap removal also enables some forms of DSB that require removal of heterology from the end like single strand annealing. KU80 is a member of nonhomologous end joining (NHEJ) that repairs clean DSBs. Thus, each model tests a different aspect of DNA repair. Core B found both ercc1-/ ?7 and ku80-/- models exhibited a shortened life span with a comparable progeroid phenotype, with the ercc1-/ ?7 model being more severe. It is possible these mouse models could be used to test longevity and health promoting interventions at a more affordable cost than wild type mice. In addition to the lifespan and cross-sectional analyses, Core B will generate new mouse models that include transgenic mice with an inducible Sac1 expression cassette, a new and improved 3MR to detect and kill p16-expressing cells, overexpression of a cell preservation microRNA and a SNP associated with centenarians. These analyses and models serve all Projects.
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