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Role of Y-family DNA polymerase Pol kappa in aging and Alzheimer's disease

Award Number: R03AG081828
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2024
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Role of Y-family DNA polymerase Pol kappa in aging and Alzheimer's disease - Project Summary/Abstract Genomic stability is critical for cellular function, however, postmitotic cells such as highly metabolically active neurons face the biggest challenge as it must maintain its genome over organismal lifetime. DNA damage increases with age and is accelerated in Alzheimer’s disease (AD) and multiple neurodegenerative disorders. Hence specialized DNA polymerases have evolved to repair different DNA lesions that destabilize DNA helical structure and obstruct replication and transcription. The Y-family polymerases are unique in bypassing DNA damage and synthesizing DNA past specific lesions, thus recovering replication in dividing cells such as DNA Pol kappa (Polk) that can bypass DNA lesions in both S and G0 phase. Surprisingly, we observed high levels of Polk expression in non-dividing differentiated neuronal nuclei in the mice brain that mislocalizes to lysosomes with age and in mice with AD associated transgenes. Almost nothing is known about Polk in neurons and its role in the protracted aging process. Our long-term goal is to understand the role of Polk in combating the DNA damages caused by cumulative exogenous and endogenous stressors, maintenance of the central nervous system (CNS) genome and its relationship with AD. Here we will investigate Polk's role in neuronal nuclei, and how mislocalization of Polk impacts neuronal maintenance during aging and in AD. This will open a novel line of investigation of specialized Y-family DNA polymerases in age associated neuronal disorders like Alzheimer’s. Our central hypothesis is that Polk assists in multiple DNA damage response pathways to prevent genomic instability and combat constant accumulation of DNA damage in post-mitotic neurons, where its expression is critical in the neuronal nuclei. However, with aging and age-associated neuropathy decline in Polk's expression in the nucleus and concomitant accumulation in the lysosomes results in neuronal genomic instability. We will leverage our proteomics data to identify Polk associated proteins that work together as DNA damage response to sustain neuronal genomic stability. Unbiased proteomics in neuronal nuclei will be performed to identify novel Polk interactors. Overexpression of Polk in aging and AD genotype mice will investigate causal role of Polk in neuronal genomic stability. Specific Aim1 will test the hypothesis that Polk is associated with distinct DNA damage response pathways in neurons and identify novel interactors of Polk Specific Aim2 will test the hypothesis that recovering Polk's expression in neuronal nuclei can rescue genomic stability in aging and AD neurons


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 = $166,800 )
2025	2025	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Aging Research	001	2	5/13/2025	NON-COMPETING CONTINUATION	$166,800
2025	2024	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Aging Research	000	1	12/18/2024	NEW	$0
														Subtotal = $166,800

Issue Date FY: 2024 ( Subtotal = $166,800 )
2024	2024	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Aging Research	000	1	9/26/2024	NEW	$166,800
														Subtotal = $166,800

Grand Total All Awards = $333,600

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Role of Y-family DNA polymerase Pol kappa in aging and Alzheimer's disease

Award Number: R03AG081828

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/30/2024

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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