Chromatin architecture disruption and the vicious cycle of aging
Ended Project Grant Awarded Last action
- Award ID
- R56AG082796
- Recipient
-
Trustees Of Boston University UEI FBYMGMHW4X95
- Awarding agency
-
National Institute on Aging
National Institutes of Health, Department of Health and Human Services
- Obligated
- $412,500
Award facts
- Assistance listing
- 93.866 Aging Research
- Completion date
- Originally
- Place of performance
- Massachusetts, USA
Award details come from USAspending.gov.
Description
- Abstract
- Changes in nuclear/chromatin architecture are a hallmark of aging. Disruption of the nuclear lamina and associated heterochromatin are commonly observed in various aging contexts, including premature aging diseases, cellular senescence, and normative aging. These structural changes were proposed to trigger the transcriptional derepression of at least two subsets of genes: line-1 (L1) and genes lacking CPG islands (CGI- genes). Increased transcription of L1, the only active retrotransposable elements (rtes) in humans, and the failure of its surveillance mechanism result in cytosolic RTE cdna formation via reverse transcription that causes chronic sterile inflammation in aged tissues. In parallel, we have shown that heterochromatin decondensation in aged cells causes uncontrolled expression of CGI- genes, which generally associate with heterochromatin in normal conditions (misexpression of CGI- genes). Aberrant activation of CGI- genes drives various age- associated degenerative changes, including previously established hallmarks of aging, ranging from cellular loss of functional identity and increased transcriptional noise, age-associated secretory phenotypes to chronic inflammation. These prior observations propose that chromatin architecture disorganization and the resulting L1 and CGI- gene activation play as a master instigator of multivariate hallmarks of aging. Our preliminary analysis suggests that this relationship is not unidirectional; L1 activation and CGI- gene misexpression would mutually activate each other and, furthermore, facilitate chromatin architecture disruption. This proposed study will test the novel hypothesis that the mutual activations among RTE/CGI- genes/nuclear architecture form a "vicious cycle" intensifying physiological deterioration during aging. In aim 1, we will validate the mutual activation effects between chromatin architecture disruption and RTE activation during normative aging. Aim 2 will test the hypothesis that age-associated L1 activation facilitates physiological deterioration by triggering CGI- gene misexpression. In aim 3, we will test the hypothesis that the secretome of aged cells with disrupted chromatin architectures can locally/systemically propagate nuclear architecture disruption and L1 activation.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $0 | |
| Original award | $412,500 |
Quick answers
Who received award R56AG082796?
R56AG082796 was awarded to Trustees Of Boston University by National Institute on Aging (National Institutes of Health) on September 20, 2023.
How much is award R56AG082796 worth?
$412,500 has been obligated on R56AG082796.
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