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

描述 ACVR1C 的表观遗传调控如何导致女性和男性的年龄和 AD 相关记忆障碍

基本信息

批准号：
10507237
负责人：
Ashley A Keiser
金额：
$ 10.97万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-15 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10507237
关键词：
Adult Affect Age Age-associated memory impairment Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Alzheimer&apos s disease risk American Animal Model Brain Chromatin Data Dominant-Negative Mutation Dorsal Elderly Electrophysiology (science)Epigenetic Process Faculty Family Female Foundations Functional disorder Funding Future Gene Expression Gene Targeting Goals Hippocampus (Brain)Impaired cognition Impairment Investigation Knowledge Lead Learning Life Expectancy Mediating Memory Memory Loss Memory impairment Mentors Molecular Molecular Biology Pathway interactions Phase Phenotype Population Positioning Attribute Process Regulation Repression Research Research Proposals Risk Factors Role Scientist Self-Direction Signal Transduction Signaling Molecule Slice Small Interfering RNA Small Nuclear RNA Structure Synaptic plasticity Techniques Testing Training Transforming Growth Factor beta Viral Virus Writing activin A aging brain cognitive function design effective therapy epigenetic regulation experimental study gene repression histone modification human old age (65+)improved knock-down long term memory male memory consolidation memory process mutant novel novel therapeutics overexpression programs receptor recruit sex skills transcriptome sequencing

项目摘要

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 investigation. The structured plan proposed here is designed to produce an independent, successful research scientist who performs unique cutting-edge research capable of supporting a new lab and is well-positioned to receive future R01 funding.

项目概要/摘要预计 65 岁以上的美国人口中有 15-20% 存在认知障碍。年龄是最强的风险因素。阿尔茨海默病 (AD) 预计 38% 的认知障碍老年人会在 5 年内患上阿尔茨海默病因此，我们理解和识别年龄和 AD 相关认知机制的能力。下降有助于发现改善认知功能的有效治疗方法，这一点至关重要。本研究计划的长期目标是确定 ACVR1C 是否具有自我调节机制的功能潜在的年龄和 AD 相关的认知功能障碍，其中下游调节变得随着年龄和 AD 的增加而受损，并通过自我导向的异常表观遗传转录抑制来维持拟议的实验将测试 ACVR1C 所代表的中心假设。一种关键的新机制，会随着年龄和 AD 的变化而被破坏，并有助于与年龄和 AD 相关的认知 K99 阶段研究的目标是对 ACVR1C 和下降的情况有一个基本的了解。下游 SMAD 信号调节衰老和 AD 女性和男性大脑中的记忆。 Acvr1c 在成人和衰老大脑的突触可塑性和记忆中的作用在这个过程中，Keizer 博士将进行研究。获得分子生物学的额外技能，接受切片电生理学的培训并开始她的培训测序方法：snRNA-Seq 和 snATAC-Seq 目标 2 将确定 Acvr1c 下游的作用。这将加深 Keiser 博士在 AD 方面的培训。在此期间，凯泽博士将与记忆力下降和阿尔茨海默病动物模型的使用有关；还完成测序培训并获得分子技术方面的额外培训。根据拟议的研究，凯泽博士将参与由多元化指导委员会监督的一系列活动旨在帮助她做好准备，成功实现独立，包括以下方面的培训：资助、科学在 R00 阶段，Keizer 博士负责写作、教学培训、演示、教师申请和实验室管理。将应用训练来确定 ACVR1C 是否作为介导的自我调节表观遗传机制发挥作用 Aim 2c 将测试成人、衰老和 AD 女性和男性大脑中的基因表达和记忆。增强 Acvr1c 将纠正 AD 大脑巩固过程中的下游信号传导，目标 3 将 1) 确定。 Acvr1c 如何受到表观遗传调控，并且将 2) 决定 Acvr1c 如何调控基因表达以及使用 snRNA-Seq 和 snATACseq 进行染色质可及性分析这些发现将 1) 确定 ACVR1C 是一种新型药物。负责维持表观遗传功能障碍和相关抑制的自我调节机制衰老和 AD 相关的认知功能障碍，2) 识别受该机制调节的新基因靶标值得未来研究。这里提出的结构化计划旨在产生一个独立的、成功的研究科学家，进行独特的前沿研究，能够支持新的实验室和处于有利地位，可以接受未来的 R01 资金。