The rationale of this Program Project is that spontaneous DMA damage drives major components of the aging process, through direct adverse effects, but more likely by inducing genome maintenance responses, resulting in senescence, apoptosis and/or genomic and epigenomic errors. The long-term objectives of Project 2 are to test the hypothesis that somatic DMA alterations, including genome rearrangements and epigenomic changes, causally contribute to aging by gradually dysregulating gene expression leading to cell functional decline and degeneration and eventually to age-related pathologies, including but not limited to cancer.
In Specific Aim 1 of the renewal application we first plan to significantly broaden the scope of the molecular endpoints thus far analyzed. For that purpose, in collaboration with Project 1, we will measure spontaneous DMA damage, changes in CpG island methylation and transcriptional noise levels in tissues of normal and DMA repair-deficient, prematurely aging mice.
In Specific Aim 2 we will further study DMA double-strand breaks, as a potentially important intermediate in generating genome instability, dysregulated gene expression and cellular senescence in mouse and human primary fibroblast cultures (with projects 3, 4 and 5).
In Specific Aim 3, we propose to combine functional assessment of a single cell with genome-wide analyses of its transcriptome, epigenome and genome. Successful pursuit of these Specific Aims should provide new insight into the role of genome maintenance as a determinant of aging, with a focus on the relationships among various molecular and cellular end points.

Public Health Relevance

Random DMA mutations and epimutations accumulate with age and may cause a general dysregulation of gene expression leading to functional decline, disease and death. The increased insight into such mechanisms obtained in this project will lead to new strategies for facilitating healthy aging by preventing or eradicating age-related diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG017242-16
Application #
8437201
Study Section
Special Emphasis Panel (ZAG1-ZIJ-5)
Project Start
Project End
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
16
Fiscal Year
2013
Total Cost
$329,884
Indirect Cost
$131,159
Name
Albert Einstein College of Medicine
Department
Type
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
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