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...