This is a request competitive revision of the parent grant R01 AG019787 in response to Notice Number (NOT-OD-09-058): NIH Announces the Availability of Recovery Act Funds for Competitive Revision. The goal of the parent application is to study mechanisms responsible for age-related degenerative processes and in particular, to test the hypothesis that mutations in mitochondrial DNA (mtDNA) are involved in the aging process, especially in brain aging. The parent proposal is particularly focused on mtDNA deletions, i.e. mutations resulting from removal of large DNA segments from the mitochondrial genome. These mutations are involved in a number of inherited degenerative mitochondrial diseases and have been hypothesized to play a role in the aging of brain, muscle and potentially other tissues. The processes that result in the generation of deletions in mtDNA are subject to intense research, but remain a matter of debate. A limitation of the parent grant is the lack of studies of the sources of mtDNA mutations. Work encompassed by the parent grant permitted to build several so-called mutational profiles of mtDNA deletions, i.e. the distributions of the positions of the deleted segments along the mitochondrial genome. This work hinted that mutational profiles of mtDNA deletions differ between different types of samples, which imply that deletions in different types of samples may be generated by different mechanisms. This revision will pursue two specific aims. First, the technology necessary for efficient studies of mutational profiles will be developed and used to confirm the preliminary finding of the differences among mutational profiles. Second, comparison of mutational profiles of aged brain tissue with profiles of a panel of samples that carry specific defects in mtDNA metabolism, mitochondrial dynamics or are subjected to oxidative stress will be used to test various hypotheses regarding the sources of mtDNA deletions in human aging and disease.
Aging and aging of the brain in particular imposes increasing burden on the society, however, molecular mechanisms leading to deteriorative changes in the brain are poorly understood. This revision seeks to determine the sources of deletions in mitochondrial DNA that are increasingly implicated in the aging process.
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