PROGRAMMED DNA DAMAGE AND ITS ROLE IN ALZHEIMER'S DISEASE AND RELATED DEMENTIAS - NOT ALL DNA DAMAGE IS TOX…
Federal financial assistance recorded from USAspending. This is not a procurement contract.
Research this with AI
Research smarter with AI
Analyze opportunities and compare insights across leading AI models.
ASST_NON_R00AG080036_075 · REGENTS OF THE UNIVERSITY OF MICHIGAN · Department of Health and Human Services
Compare Multiple AI Models with SmartSoloExplore CaptureIQ IntelligenceAssistance award details
- Assistance award identifier
- ASST_NON_R00AG080036_075
- FAIN
- R00AG080036
- Recipient
- REGENTS OF THE UNIVERSITY OF MICHIGAN
- Awarding agency
- Department of Health and Human Services
- Funding agency
- Department of Health and Human Services
- Assistance listing (CFDA)
- 93.866
- Total obligated
- $742,018
- Period
- Sep 1, 2022 – May 31, 2027
- Fiscal year
- 2024
- Place of performance state
- MI
- Source file
- FY2024_All_Assistance_Full_20261006.zip
Description
PROGRAMMED DNA DAMAGE AND ITS ROLE IN ALZHEIMER'S DISEASE AND RELATED DEMENTIAS - NOT ALL DNA DAMAGE IS TOXIC, AS CELLS CAN INDUCE PROGRAMMED DNA DAMAGE TO REGULATE CORE CELL BIOLOGICAL PROCESSES, SUCH AS DNA DEMETHYLATION. ALTERED DNA DEMETHYLATION HAS BEEN OBSERVED IN ALZHEIMERâS DISEASE AND ALZHEIMERâS DISEASE RELATED DEMENTIASÂ (AD+ADRD), INCLUDING FRONTOTEMPORAL DEMENTIA (FTD), AND AGE-RELATED COGNITIVE DYSFUNCTION. YET, THE ROLE OF ACTIVE DNA DEMETHYLATION IN AD+ADRD REMAINS UNCLEAR. WE RECENTLY DISCOVERED THAT PROGRAMMED DNA DAMAGE OCCURS WITHIN NEURONAL ENHANCERS AND LIKELY PLAYS KEY ROLES IN ACTIVE DNA DEMETHYLATION AND EPIGENETIC REMODELING (WU, W,* HILL, SE,* NATHAN, WJ* ET AL., NATURE 2021). PRELIMINARY DATA SUGGEST THAT TRANSCRIPTION CONTROLS SITES OF PROGRAMMED DNA DAMAGE AND THAT AD+ADRD-LINKED PROTEINS ARE INVOLVED, INCLUDING TARDBP/TDP-43. LOSS OF TDP-43, A PATHOLOGIC HALLMARK OF FTD, LIMBIC-PREDOMINANT AGE-RELATED TDP-43 ENCEPHALOPATHY (LATE), AND DYSREGULATED IN MANY AD CASES, DECREASED PROGRAMMED DNA DAMAGE OR REPAIR, WHILE DEPLETION OF XRCC1, A DNA REPAIR PROTEIN LINKED TO A FAMILIAL NEURODEGENERATION, INCREASED REPAIR. THIS SUGGESTS THAT PROGRAMMED DNA DAMAGE IS CAREFULLY REGULATED IN AGING TO PREVENT AD+ADRD AND NEURODEGENERATION. IN THIS PROPOSAL, I WILL INVESTIGATE HOW PROGRAMMED DNA DAMAGE IS REGULATED AND THE CONSEQUENCES OF DYSREGULATION IN AD+ADRD AND AGE-RELATED NEURODEGENERATION. THE K99 PHASE RESEARCH WILL BE PERFORMED MAINLY AT THE NIH WITH PRIMARY MENTOR DR. WARD, WHOSE LAB USES MICE AND IPSC-DERIVED NEURONS TO STUDY NEURODEGENERATIVE DISEASES INCLUDING FTD. TO SUPPLEMENT MY PREVIOUS TRAINING IN IPSC-DERIVED NEURONS, CRISPR, AND LIVE CELL-IMAGING, I WILL ALSO LEARN ADVANCED GENOMICS (FROM CO-MENTOR DR. NUSSENZWEIG AND COLLABORATOR DR. CHEN), SINGLE-PARTICLE PALM IMAGING (FROM CO-MENTOR DR. LIPPINCOTT-SCHWARTZ) AND IN VIVO MOUSE MODELS (FROM DR. WARD AND COLLABORATOR DR. PETRUCELLI). THIS ADDITIONAL TRAINING AND IMMERSION INTO T