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Delineating how epigenetic regulation of ACVR1C contributes to age and AD-related memory impairments in females and males

Award Number: R00AG078501
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 11/01/2024
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Delineating how epigenetic regulation of ACVR1C contributes to age and AD-related memory impairments in females and males - PROJECT SUMMARY (See instructions): 15-20% of the US population 65+ is predicted to be cognitively impaired. Age serves as the strongest risk factor for Alzheimer's Disease (AD) with 38% of cognitively impaired older adults predicted to develop AD within 5 years. Therefore, our ability to understand and identify mechanisms underlying age and AD-related cognitive decline that inform discovery of effective treatments for improving cognitive function is of utmost importance. The long-term goal of this research proposal is determine whether ACVR1 C functions as a self-regulating mechanism underlying age and ADrelated impairments in cognitive function where, downstream regulation becomes impaired with age and AD, and is maintained through self-directed aberrant epigenetic transcriptional repression in the female and male brain. The proposed experiments will test the central hypothesis that ACVR1 C represents a key novel mechanism that is disrupted with age and AD and contributes to age and AD-related cognitive decline. In the K99 phase of this award, I found that a member of the TGFr.. signaling family Acvr1c, serves as a bidirectional regulator of long-lasting forms of synaptic plasticity and long-term memory which becomes impaired with increasing age and in AD. Overriding this impairment through overexpression of Acvr1c in the dorsal hippocampus ameliorates impairments in long term memory and synaptic plasticity identified in aging and 5xFAD mice In the ROD phase, I will continue to investigate the role of Acvr1c in age and AD-related memory function. I will determine whether ACVR1 C functions as a self-regulating epigenetic mechanism mediating gene expression and memory in the adult, aging and AD female and male brain. To better understand how downstream ACVR1 C signaling may be contributing to impairments in age and AD-related memory formation we will first characterize how SMAD2 (phosphorylated by ACVR1C and forms a complex with SMAD4 to regulate gene expression) changes after learning in the adult, aging, and AD brain. We will determine whether enhancing ACVR1C function rectifies impairments in downstream SMAD signaling that occurs with aging and AD. Next, I will characterize epigenetic regulation of Acvr1c and the impact of enhancing Acvr1c function. I will identify how ACVR1C regulates gene expression and chromatin accessibility by performing snRNA-Seq and snATAC Seq following viral manipulations which enhance or repress Acvr1c function. These findings will 1) identify ACVR1 C as a novel self-regulating mechanism responsible for maintaining epigenetic dysfunction and repression associated with aging and AD-related cognitive dysfunction and 2) identify novel gene targets regulated by this mechanism which provide insight for therapeutic intervention.


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 = $248,495 )
2025	2025	ARIZONA STATE UNIVERSITY	660 S MILL AVENUE STE 204	TEMPE	AZ	85281	MARICOPA	USA	Aging Research	002	3	8/12/2025	EXTENSION WITH OR WITHOUT FUNDS	$19,919
2025	2025	ARIZONA STATE UNIVERSITY	660 S MILL AVENUE STE 204	TEMPE	AZ	85281	MARICOPA	USA	Aging Research	000	3	3/25/2025	EXTENSION WITH OR WITHOUT FUNDS	$224,100
2025	2025	ARIZONA STATE UNIVERSITY	660 S MILL AVENUE STE 204	TEMPE	AZ	85281	MARICOPA	USA	Aging Research	001	3	4/8/2025	EXTENSION WITH OR WITHOUT FUNDS	$4,476
														Subtotal = $248,495

Grand Total All Awards = $248,495

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Delineating how epigenetic regulation of ACVR1C contributes to age and AD-related memory impairments in females and males

Award Number: R00AG078501

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 11/01/2024

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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