Role of ADAR1 and dsRNA in age-related neuroinflammation and Alzheimers disease

ADAR1 和 dsRNA 在年龄相关神经炎症和阿尔茨海默病中的作用

基本信息

批准号：
10752386
负责人：
Cali Madison McEntee
金额：
$ 3.97万
依托单位：
COLORADO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-17 至 2026-07-16
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10752386
关键词：
Adenosine Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease patient Astrocytes Award Base Pairing Bioinformatics Biology Blood Brain Cell Culture Techniques Cells Clinical Data Colorado Data Data Set Dementia Development Disease Double Stranded RNA Virus Double-Stranded RNA Elderly Encephalitis Environment Enzymes Event Fibroblasts Funding Gene Expression Genes Genome Genomics Gliosis Goals Human Immune Immunoprecipitation Impaired cognition Inflammation Inflammatory Inosine Interferons Investigation Laboratories Link Longevity Measures Mentors Modeling Molecular Mus Nerve Degeneration Neurodegenerative Disorders Neuroglia Pathway interactions Pattern Proteins Publishing RNA Binding RNA immunoprecipitation sequencing Regulation Repetitive Sequence Reporting Research Research Training Role Scientist Signal Transduction Small Interfering RNA Source Testing Therapeutic Training Transcript Translating Translational Research Tretinoin United States National Institutes of Health Universities Work adeno-associated viral vector age related age related neurodegeneration age related neuroinflammation aged aging brain biobank brain health brain tissue cognitive function cognitive testing combat doctoral student dsRNA adenosine deaminase experience healthspan human disease human subject immune activation inflammatory marker knock-down melanoma mouse model neuroinflammation novel marker pathogen pre-clinical programs skills therapeutic target transcriptome transcriptome sequencing transcriptomics translational scientist

项目摘要

PROJECT SUMMARY The purpose of this F31 proposal is to provide support for Cali McEntee, a doctoral student at Colorado State University (CSU), while she trains to become an independent scientist conducting research on age-related neurodegeneration. With support from this award, Ms. McEntee will determine if reductions in adenosine deaminase acting on RNA 1 (ADAR1) lead to the accumulation of double-stranded RNA (dsRNA), a pathogen-associated molecular pattern that causes innate immune/inflammatory signaling, in the context of brain aging and Alzheimer’s disease (AD). Numerous reports show that ADAR1 suppresses dsRNA-related inflammation and may modulate lifespan, and that innate immune activation/neuroinflammation driven by glial cells, like astrocytes, is a central mechanism of brain aging/AD. The applicant’s preliminary data show that brain aging/AD are associated with reductions in ADAR1 levels, and that reducing ADAR1 expression in astrocytes leads to an increase in transcripts from genomic repetitive elements (RE), which are increasingly implicated in aging and neurodegeneration and predisposed to form dsRNA. As such, ADAR1 may be an important regulator of neuroinflammation with brain aging and/or AD, perhaps by reducing RE-associated dsRNA accumulation. However, this idea has not been investigated. In this project, Ms. McEntee proposes to gain valuable translational research training by using multiple models to test the hypothesis that ADAR1 reduces the deleterious effects of RE-derived dsRNA and thereby protects against age/AD-related neuroinflammation by: Aim 1) using directly reprogramed human astrocytes from healthy young/older adults and AD patients to determine if ADAR1 and dsRNA levels are related to neuroinflammation, performing total RNA-seq and RNA immunoprecipitation sequencing (RIP-seq) to identify RE-derived dsRNAs involved in neuroinflammation, and intersecting her findings with existing clinical datasets; and Aim 2) increasing expression of ADAR1 in reprogrammed human astrocytes and a pre-clinical mouse model of aging to determine if ADAR1 protects against age/AD-related neuroinflammation and cognitive dysfunction. Ms. McEntee’s immediate goal is to gain the fundamental experience and professional skills necessary to perform independent research in the field of age-related neurodegenerative diseases. Her long-term goal is to become an academic, translational researcher investigating mechanisms of aging that contribute to neurodegenerative disease. Ms. McEntee will train in a state-of-the-art environment with an exceptional mentoring team at CSU. The sponsor, Dr. LaRocca, has an extensive background studying aging and neurodegenerative diseases and directs the NIH-funded Healthspan Biology Laboratory at CSU. Under the guidance of Dr. LaRocca and consulting mentors Drs. Chris Link, Ron Tjalkens, Julie Moreno, and Dan Lark, Ms. McEntee will be able to successfully complete the training plan, supporting her development into an independent scientist.

项目概要此 F31 提案的目的是为科罗拉多州立大学博士生 Cali McEntee 提供支持大学（科罗拉多州立大学），同时她接受培训成为一名独立科学家，从事与年龄相关的研究在该奖项的支持下，麦肯蒂女士将确定腺苷是否会减少。作用于 RNA 1 (ADAR1) 的脱氨酶导致双链 RNA (dsRNA) 的积累，引起先天免疫/炎症信号传导的病原体相关分子模式大量报告表明 ADAR1 抑制 dsRNA 相关的大脑衰老和阿尔茨海默病 (AD)。炎症并可能调节寿命，以及由神经胶质细胞驱动的先天免疫激活/神经炎症细胞，如星形胶质细胞，是大脑衰老/AD的核心机制。申请人的初步数据表明，大脑衰老/AD 与 ADAR1 水平降低有关，并且 ADAR1 表达降低星形胶质细胞导致基因组重复元件（RE）的转录物增加，这些重复元件越来越多 ADAR1 与衰老和神经退行性疾病有关，并且易于形成 dsRNA，因此，ADAR1 可能是一种大脑衰老和/或 AD 神经炎症的重要调节因子，可能是通过减少 RE 相关的然而，McEntee 女士提议在这个项目中尚未对这一想法进行研究。通过使用多个模型来测试 ADAR1 的假设，获得有价值的转化研究培训减少 RE 衍生的 dsRNA 的有害影响，从而预防与年龄/AD 相关的疾病神经炎症：目标 1) 使用来自健康年轻人/老年人的直接重编程的人星形胶质细胞和 AD 患者以确定 ADAR1 和 dsRNA 水平是否与神经炎症相关，执行总 RNA-seq 和 RNA 免疫沉淀测序 (RIP-seq) 用于鉴定 RE 衍生的 dsRNA 神经炎症，并将她的发现与现有的临床数据集相交叉；目标 2) 增加； ADAR1 在重编程的人星形胶质细胞和临床前衰老小鼠模型中的表达确定 ADAR1 是否可以预防年龄/AD 相关的神经炎症和认知功能障碍。 McEntee 的近期目标是获得执行任务所需的基本经验和专业技能她的长期目标是成为与年龄相关的神经退行性疾病领域的独立研究人员。一位学术转化研究人员，研究导致神经退行性疾病的衰老机制麦肯蒂女士将在科罗拉多州立大学优秀的指导团队的最先进的环境中进行训练。发起人 LaRocca 博士拥有广泛的衰老和神经退行性疾病研究背景，在 LaRocca 博士的指导下领导 NIH 资助的科罗拉多州立大学 Healthspan 生物学实验室。咨询导师 Chris Link 博士、Ron Tjalkens、Julie Moreno 和 Dan Lark、McEntee 女士将能够顺利完成培养计划，支持她发展成为一名独立科学家。