Consequences of mtDNA damage to age-related degenerative processes

Project: Research project

Project Details

Description

? DESCRIPTION (provided by applicant): During the course of accomplishing the previous specific aims, we found that a relatively brief expression of a mitochondrial targeted restriction endonuclease, ubiquitously in mice, generates double strand breaks (DSB) in the mtDNA of the different tissues. MtDNA levels recovered from this transient event and no abnormal phenotypes were observed in the weeks following the molecular insult. However, later in life mice developed a phenotype resembling accelerated aging. Initial characterization showed a reduction in progenitor cell pools. These observations, together with other recent reports led us to hypothesize that progenitor cells are targets of mtDNA damage. We also obtained preliminary data showing that p53-associated pathways are involved in the mechanism leading to a reduction of progenitor cell pools after mtDNA transient insults. We propose a series of experiments to rigorously test this hypothesis in mouse and cultured cells. We will also develop a valuable model of mice with heteroplasmic mtDNA deletions, which will be used to unveil the role of mtDNA deletions in aging. These models will be shared with the research community. We expect that these studies will increase our understanding the role of mtDNA damage in aging.
StatusFinished
Effective start/end date6/1/1012/31/19

Funding

  • National Institute on Aging: $327,672.00
  • National Institute on Aging: $284,898.00
  • National Institute on Aging: $334,013.00
  • National Institute on Aging: $301,480.00
  • National Institute on Aging: $301,480.00
  • National Institute on Aging: $301,480.00
  • National Institute on Aging: $332,754.00
  • National Institute on Aging: $314,675.00
  • National Institute on Aging: $431,801.00

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