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

> **NIH NIH K99** · UNIVERSITY OF CALIFORNIA-IRVINE · 2023 · $109,716

## Abstract

Project Summary/Abstract
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 ACVR1C functions as a self-regulating mechanism
underlying age and AD-related 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 ACVR1C represents
a key novel mechanism that is disrupted with age and AD and contributes to age and AD-related cognitive
decline. The goal of the K99 phase research is to develop a foundational understanding of how ACVR1C and
downstream SMAD signaling regulates memory in the aging and AD female and male brain. Aim 1 will identify
the role of Acvr1c in synaptic plasticity and memory in the adult and aging brain. In this process, Dr. Keiser will
gain additional skills in molecular biology, receive training in slice electrophysiology and begin her training in
sequencing approaches: snRNA-Seq and snATAC-Seq. Aim 2 will identify the role of Acvr1c downstream
signaling in AD-related memory impairments in females and males. This will deepen Dr. Keiser’s training in AD-
related memory decline and the use of animal models of Alzheimer’s disease; during this period Dr. Keiser will
also complete sequencing training and gain additional training in molecular techniques. In addition to the
proposed research, Dr. Keiser will engage in a number of activities overseen by a diverse mentoring committee
designed to prepare her to successfully achieve independence, including training in: grantsmanship, scientific
writing, didactic training, presentations, faculty applications, and lab management. In the R00 phase, Dr. Keiser
will apply training to determine whether ACVR1C functions as a self-regulating epigenetic mechanism mediating
gene expression and memory in the adult, aging and AD female and male brain. Aim 2c will test whether
enhancing Acvr1c will rectify downstream signaling during consolidation in the AD brain. Aim 3 will 1) determine
how Acvr1c is epigenetically regulated in and will 2) determine how Acvr1c regulates gene expression and
chromatin accessibility using snRNA-Seq and snATACseq. These findings will 1) identify ACVR1C 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 that
are worthy of future investigati...

## Key facts

- **NIH application ID:** 10680466
- **Project number:** 5K99AG078501-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Ashley A Keiser
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $109,716
- **Award type:** 5
- **Project period:** 2022-08-15 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10680466

## Citation

> US National Institutes of Health, RePORTER application 10680466, Delineating how epigenetic regulation of ACVR1C contributes to age and AD-related memory impairments in females and males (5K99AG078501-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10680466. Licensed CC0.

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