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

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.

项目总结/摘要 预计65岁以上的美国人口中有15-20%会出现认知障碍。年龄是最大的风险因素 对于阿尔茨海默病（AD），38%的认知受损老年人预计在5年内发展为AD。 年因此，我们理解和识别年龄和AD相关认知机制的能力 因此，发现改善认知功能的有效治疗方法至关重要。的 这项研究计划的长期目标是确定ACVR 1C是否作为一种自我调节机制发挥作用 潜在的年龄和AD相关的认知功能障碍，下游调节成为 随着年龄和AD而受损，并通过自我指导的异常表观遗传转录抑制来维持 在女性和男性的大脑中。拟议的实验将测试ACVR 1C代表的中心假设 一种关键的新机制，随着年龄和AD而被破坏，并有助于年龄和AD相关的认知 下降K99阶段研究的目标是对ACVR 1C和 下游SMAD信号调节衰老和AD女性和男性大脑中的记忆。目标1将确定 Acvr 1c在成人和衰老大脑中突触可塑性和记忆中的作用。在这个过程中，凯泽博士将 获得分子生物学方面的额外技能，接受切片电生理学方面的培训，并开始 测序方法：snRNA-Seq和snATAC-Seq。目标2将确定Acvr 1c下游的作用 在女性和男性中AD相关记忆障碍的信号传导。这将加深凯泽博士在AD方面的培训- 相关的记忆力下降和阿尔茨海默病动物模型的使用;在此期间，Keiser博士将 完成测序培训并获得分子技术方面的额外培训。除了有 建议的研究，凯泽博士将从事一系列活动，由一个多元化的指导委员会监督 旨在为她成功实现独立做好准备，包括培训： 写作、教学培训、演示、教师申请和实验室管理。在R 00阶段，Keiser博士 将应用培训，以确定ACVR 1C是否作为一种自我调节的表观遗传机制， 基因表达和记忆在成年，老龄化和AD女性和男性的大脑。Aim 2c将测试 增强Acvr 1c将在AD脑中巩固期间纠正下游信号传导。目标3：1）确定 Acvr 1c如何在表观遗传学上调节，2）确定Acvr 1c如何调节基因表达， 使用snRNA-Seq和snATACseq的染色质可及性。这些发现将1）将ACVR 1C鉴定为一种新的 自我调节机制负责维持表观遗传功能障碍和抑制相关 衰老和AD相关的认知功能障碍，以及2）鉴定由这种机制调节的新的基因靶点， 值得未来调查。这里提出的结构化计划旨在产生一个独立的， 成功的研究科学家谁执行独特的尖端研究能够支持一个新的实验室， 很有可能获得未来的R 01资金。