(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.

Public Health Relevance

(CORE B) Core B will perform the mouse studies for all projects and ensures uniformity for genetic background and a strong environment for longevity studies. These studies will address the impact growth, clean double strand breaks, cellular senescence and cell preservation have on genome stability and its impact on aging, lifespan and healthspan.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
2P01AG017242-17A1
Application #
8742951
Study Section
Special Emphasis Panel (ZAG1)
Project Start
Project End
Budget Start
2014-09-30
Budget End
2015-04-30
Support Year
17
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Type
DUNS #
City
Bronx
State
NY
Country
United States
Zip Code
Lau, Cia-Hin; Suh, Yousin (2018) In vivo epigenome editing and transcriptional modulation using CRISPR technology. Transgenic Res 27:489-509
Wiley, Christopher D; Schaum, Nicholas; Alimirah, Fatouma et al. (2018) Small-molecule MDM2 antagonists attenuate the senescence-associated secretory phenotype. Sci Rep 8:2410
Quispe-Tintaya, Wilber; Lee, Moonsook; Dong, Xiao et al. (2018) Bleomycin-induced genome structural variations in normal, non-tumor cells. Sci Rep 8:16523
H├ębert, Jean M; Vijg, Jan (2018) Cell Replacement to Reverse Brain Aging: Challenges, Pitfalls, and Opportunities. Trends Neurosci 41:267-279
Wiley, Christopher D; Flynn, James M; Morrissey, Christapher et al. (2017) Analysis of individual cells identifies cell-to-cell variability following induction of cellular senescence. Aging Cell 16:1043-1050
Milholland, Brandon; Dong, Xiao; Zhang, Lei et al. (2017) Differences between germline and somatic mutation rates in humans and mice. Nat Commun 8:15183
Baar, Marjolein P; Brandt, Renata M C; Putavet, Diana A et al. (2017) Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging. Cell 169:132-147.e16
Milholland, Brandon; Suh, Yousin; Vijg, Jan (2017) Mutation and catastrophe in the aging genome. Exp Gerontol 94:34-40
La Fata, G; van Vliet, N; Barnhoorn, S et al. (2017) Vitamin E Supplementation Reduces Cellular Loss in the Brain of a Premature Aging Mouse Model. J Prev Alzheimers Dis 4:226-235
Zhu, Yizhou; Tazearslan, Cagdas; Suh, Yousin (2017) Challenges and progress in interpretation of non-coding genetic variants associated with human disease. Exp Biol Med (Maywood) 242:1325-1334

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