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

• 批准号: 10680466
• 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
• 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/10680466
• 关键词: Adult; Affect; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' s disease risk; American; Animal Model; Brain; Chromatin; Cytoplasm; Data; Dominant-Negative Mutation; Dorsal; Elderly; Electrophysiology (science); Epigenetic Process; Faculty; Family; Female; Functional disorder; Funding; Future; Gene Expression; Gene Targeting; Goals; Hippocampus; Impaired cognition; Impairment; Investigation; Knowledge; 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; 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; single nucleus RNA-sequencing; skills; transcriptome sequencing; Adult; Affect; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' s disease risk; American; Animal Model; Brain; Chromatin; Cytoplasm; Data; Dominant-Negative Mutation; Dorsal; Elderly; Electrophysiology (science); Epigenetic Process; Faculty; Family; Female; Functional disorder; Funding; Future; Gene Expression; Gene Targeting; Goals; Hippocampus; Impaired cognition; Impairment; Investigation; Knowledge; 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; 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; single nucleus RNA-sequencing; skills; transcriptome sequencing

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.

项目摘要/摘要 预计美国65％以上的美国人口中有15-20％被认知受损。年龄是强大的风险因素 对于阿尔茨海默氏病（AD），有38％的认知受损的老年人预计将在5个以下发展AD 年。因此，我们理解和识别年龄和与广告相关的认知基本机制的能力 拒绝使发现有效治疗以改善认知功能至关重要。 这项研究建议的长期目标是确定ACVR1C是否充当自我调节机制 认知功能中的基本年龄和与广告相关的障碍，下游调节变为 因年龄和AD而受损，并通过自我指导的异常表观转录表示来维持 在女性和男性大脑中。提出的实验将测试ACVR1C代表的中心假设 一个关键的新颖机制，随着年龄和AD的破坏而破坏，并为年龄和广告相关的认知贡献 衰退。 K99阶段研究的目标是对ACVR1C和 下游SMAD信号传导调节衰老和AD女性和男性大脑的记忆。 AIM 1将确定 ACVR1C在成人大脑和衰老大脑中的突触可塑性和记忆中的作用。在此过程中，Keizer博士将 获得分子生物学的额外技能，接受切片电生理学培训，并开始接受培训 测序方法：snRNA-seq和snatac-seq。 AIM 2将确定下游ACVR1C的作用 女性和男性与广告相关记忆障碍的信号传导。这将加深Keizer博士在广告中的培训 相关记忆下降和阿尔茨海默氏病动物模型的使用；在此期间，Keizer博士将 还完成测序训练并获得分子技术的额外训练。除了 拟议的研究，Keizer博士将从事一项不同的心理委员会监督的许多活动 旨在使她准备成功实现独立性，包括：授予技巧，科学培训 写作，教学培训，演讲，教师申请和实验室管理。在R00阶段，Keizer博士 将应用训练以确定ACVR1C是否作为介导的自我调节的表观遗传机制的作用 成人，衰老和AD女性和男性大脑的基因表达和记忆。 AIM 2C将测试是否 增强ACVR1C将在AD大脑合并过程中纠正下游信号传导。目标3将确定 ACVR1C如何表观遗传调节并将在2）确定ACVR1C如何调节基因表达和 使用snRNA-seq和snatacseq的染色质可及性。这些发现将1）将ACVR1C识别为新颖 负责维持表观遗传功能障碍和表达的自我调节机制 衰老和与广告相关的认知功能障碍以及2）确定由这种机制调节的新型基因靶标， 是未来投资的宝贵。此处提出的结构化计划旨在产生独立的， 成功的研究科学家，他执行独特的尖端研究，能够支持新实验室和 位置良好，可以获得未来的R01资金。