AGING, SOMATIC MUTATION, AND HEART DISEASE

Project: Research project

Project Details

Description

The leading cause of death in the US and most other developed
nations is heart disease, whose incidence rises sharply with age.
The heart muscle has a high requirement for energy, most of which
is generated by oxidative reactions that are carried out in
mitochondria. Recently, deletions and point mutations of the
mitochondrial DNA (mtDNA) have been associated with sporadic and
familial cardiomyopathy. Using sensitive new technologies, the
identical mtDNA deletions that cause cardiomyopathy in persons with
genetic disease can be detected at a lower frequency in normal
individuals. In normal individuals, the frequency of the deletions
rises strikingly in human,heart tissue with age, by more than 1000-
fold. Individuals with atherosclerosis have 10 to lOO fold higher
levels of this deletion than normal individuals. One possible
inference is that atherosclerosis induces oxidative stress which
induces mtDNA deletions; conversely individuals with higher
deletion levels might be more prone to atherosclerosis. In order to
lay the groundwork for experimental studies into the cause/effect
relationships of mtDNA deletion and point mutations and heart
disease, three specific aims are proposed: (1) to develop and
validate assay systems for the detection and quantification of
mtDNA deletion mutations in the laboratory rat and laboratory
mouse, (2) to test the association of particular deletions and
point mutations of mtDNA with particular cardiomyopathies in human
autopsy samples, (3) to address the correlation of dysfunctional
areas of human heart tissue with mtDNA structure by the SURF
technique, and (4) to develop an improved assay for rare point
mutations, with which to determine whether or not rare point
mutations accumulate in human heart mtDNA with age in humans and
rodents.
StatusFinished
Effective start/end date5/15/936/30/07

Funding

  • National Institutes of Health: $249,614.00
  • National Institutes of Health: $115,406.00
  • National Institutes of Health: $250,318.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $24,661.00
  • National Institutes of Health
  • National Institutes of Health: $252,348.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $252,532.00
  • National Institutes of Health
  • National Institutes of Health: $252,814.00
  • National Institutes of Health

ASJC

  • Medicine(all)

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