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Neuronal Circuit Maintenance in Healthy Aging

Award Number: R00AG064042
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2021
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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Neuronal Circuit Maintenance in Healthy Aging - Project Summary The overarching goal of this study is to identify new mechanisms that preserve neuronal function with age. As the world's aging population steadily increases, the number of diagnoses for neurodegenerative disease and dementia is projected to more than double within the next 30 years, underscoring our immediate need to understand the cellular and molecular basis of brain aging. Atrophy of the connections that mediate neuronal communication leads to aberrant activity within neural circuits in the aging brain. How changes in activity modify the properties of aging neurons is not yet clear. The brain adapts to neuronal activity in part via the induction of new gene expression programs encoding critical cell-type-specific mediators of circuit plasticity. Whether re-engaging the regulators of these gene programs in aging brains can ameliorate declining neuronal function remains unknown. The bHLH-PAS transcription factor NPAS4 constitutes a major regulator of activity-dependent gene programs in both mice and humans. NPAS4 integrates into the NuA4/TIP60 acetyltransferase protein complex, a transcriptional co-activator and DNA repair complex, which has been linked to learning and memory in invertebrates. Intriguingly, activity-dependent elements targeted by NPAS4 transiently acquire a chromatin mark of DNA damage signaling upon neuronal activation (γH2AX), raising the possibility that NPAS4 may function at these sites to help repair damage resulting from activity-driven transcription. In preliminary data, I discovered that Npas4 knockout mice die prematurely with signs of cell stress in the hippocampus. This study will examine the hypothesis that the newly identified NPAS4:NuA4 complex has evolved a protective role to promote the sustained functionality of neurons by maintaining transcriptional control and genome stability at activity-dependent gene loci. I will examine age-dependent changes to Npas4 regulation and activity- dependent gene induction across neuronal cell types (Aim 1, K99) and identify critical gene targets of this complex in activated neurons (Aim 2, K99). During the R00 phase, I will expand upon these ideas to explore a novel role for this activity-dependent protein complex in the repair of directed DNA damage at enhancers and promoters, and will examine how this directed DNA repair activity changes with age (Aim 3, K99). In the long term, I will leverage the datasets, and new skills in bioinformatics and neurobiology acquired during the K99 training period, to identify new mechanisms and molecules that preserve cell-type-specific function in the nervous system. My ultimate goal is to design targeted strategies to slow or reverse decline in the neuronal subtypes most susceptible to age-dependent diseases.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $244,018 )
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Aging Research	000	5	1/9/2025	NON-COMPETING CONTINUATION	$224,099
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Aging Research	001	5	8/4/2025	NON-COMPETING CONTINUATION	$19,919
														Subtotal = $244,018

Issue Date FY: 2024 ( Subtotal = $283,488 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Aging Research	002	4	6/14/2024	NON-COMPETING CONTINUATION	$24,900
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Aging Research	001	4	1/16/2024	NON-COMPETING CONTINUATION	$224,099
2024	2023	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Aging Research	000	3	12/11/2023	EXTENSION WITH OR WITHOUT FUNDS	$34,489
														Subtotal = $283,488

Issue Date FY: 2023 ( Subtotal = $248,932 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Aging Research	000	3	2/9/2023	EXTENSION WITH OR WITHOUT FUNDS	$248,932
														Subtotal = $248,932

Grand Total All Awards = $776,438

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Neuronal Circuit Maintenance in Healthy Aging

Award Number: R00AG064042

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/01/2021

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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