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

项目摘要/摘要 据预测，美国65岁以上人口中有15%-20%的人会有认知障碍。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岁内患上AD 好几年了。因此，我们理解和识别年龄和AD相关认知机制的能力 拒绝告知发现有效的改善认知功能的治疗方法是至关重要的。这个 这项研究提案的长期目标是确定ACVR1C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，并通过自我定向的异常表观遗传转录抑制来维持 在女性和男性的大脑中。拟议的实验将检验ACVR1C代表 一种被年龄和阿尔茨海默病干扰的关键新机制，有助于年龄和阿尔茨海默病相关的认知 拒绝。K99阶段研究的目标是对ACVR1C和ACVR1C如何 SMAD下游信号调节衰老和AD男女大脑中的记忆。目标1将确定 Acvr1c在成人和老年脑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其他技能，接受切片电生理学培训，并开始在 测序方法：SnRNA-Seq和SnATAC-Seq。目标2将确定Acvr1c下游的作用 女性和男性AD相关记忆损害的信号转导。这将深化凯泽博士在AD方面的训练-- 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，凯泽博士将 还要完成测序培训，并获得分子技术方面的额外培训。除 在拟议的研究中，Keiser博士将在一个多样化的指导委员会的监督下从事一系列活动 旨在为她成功实现独立做好准备，包括以下方面的培训：宽厚的精神、科学的 写作、教学培训、演示文稿、教师申请和实验室管理。在R00阶段，Keiser博士 将应用训练来确定ACVR1C是否作为一种自我调节的表观遗传机制发挥作用 成年、衰老和阿尔茨海默病男女脑中基因的表达和记忆。Aim 2c将测试 增强Acvr1c将纠正AD大脑巩固过程中的下游信号。目标3将1)确定 Acvr1c在表观遗传中是如何调控的，2)将决定Acvr1c如何调控基因表达和 使用SnRNA-Seq和SnATACseq的染色质可及性。这些发现将1)将ACVR1C确定为一种新的 负责维持表观遗传功能障碍和抑制的自我调节机制 衰老和AD相关的认知功能障碍以及2)识别受该机制调控的新的基因靶点 都是值得进一步调查的。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，他进行独特的尖端研究，能够支持新的实验室和 处于有利地位，可以获得未来的R01资金。

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.