DNA REPAIR, MUTATIONS AND CELLULAR AGING

  • Hasty, Edward P (PI)
  • Hoeijmakers, J.A.N. (PI)
  • Campisi, Judith (PI)
  • Hasty, Edward Paul (PI)
  • van Steeg, Harry (PI)
  • Yousin, Suh (PI)
  • Vijg, J.A.N. (PI)
  • Hoeijmakers, J.A.N. (PI)
  • Campisi, Judith (PI)

Project: Research project

Project Details

Description

The long-term objective of this program project is to elucidate the role of genome stability mechanisms in longevity and healthy aging. For this purpose, the biological impact of mouse mutants modeling human nucleotide excision repair syndromes and other major DNA repair pathways will be studied, focusing on spontaneous DNA damage, mutations and cellular senescence. Spontaneous forms of DNA damage, i.e., oxidative damage and cross-links, will be studied directly in genomic DNA from organs and tissues of the mouse mutants, using established biochemical methods. Somatic mutations will be assessed using an established lacZ- plasmid transgene mouse model to be crossbred with the repair mutants. To specifically assess the effect of DNA damage and/or mutations on transcription competence, novel mouse models will be constructed to allow in situ analysis as well as recovery and complete characterization of actively transcribed reporter loci. To study senescence in cultured cells and possibly also in organs and tissues, a novel transgenic mouse model harboring a transcriptional control element of senescence, SnRE, will be used. Reporter mice and DNA repair mutants will be crossed to permit direct comparison of molecular and cellular end points in one and the same animal. Finally, both mutations and cellular senescence will also be studied in primary fibroblasts from the human homologs of the repair mutants. The studies will be supported by an animal core, responsible for establishment of a cell and tissue bank. It is expected that the results of this study will provide a rational basis for designing strategies to lower DNA damage and mutational loads with age.
StatusFinished
Effective start/end date4/1/994/30/19

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

ASJC

  • Medicine(all)

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