NEURONAL CIRCUIT MAINTENANCE IN HEALTHY AGING - PROJECT SUMMARY THE OVERARCHING GOAL OF THIS STUDY IS TO ID…

Assistance award details

Assistance award identifier

ASST_NON_R00AG064042_075

FAIN

R00AG064042

Recipient

WASHINGTON UNIVERSITY, THE

Awarding agency

Department of Health and Human Services

Funding agency

Department of Health and Human Services

Assistance listing (CFDA)

93.866

Total obligated

$774,048

Period

Feb 1, 2021 – Jan 31, 2026

Fiscal year

2023

Place of performance state

MO

Source file

FY2023_All_Assistance_Full_20261006.zip

Description

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 (H2AX), 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