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

项目摘要 这项F31提案的目的是为科罗拉多州立大学的博士生卡利·麦肯蒂提供支持 大学（CSU），而她训练成为一个独立的科学家进行研究与年龄有关的 神经变性在这个奖项的支持下，McEntee女士将决定是否减少腺苷 作用于RNA 1（ADAR 1）的脱氨酶导致双链RNA（dsRNA）的积累， 病原体相关的分子模式，导致先天免疫/炎症信号，在背景下， 脑老化和阿尔茨海默病（AD）。许多报道表明ADAR 1抑制dsRNA相关的 炎症并可调节寿命，以及由神经胶质细胞驱动先天免疫激活/神经炎症 细胞，如星形胶质细胞，是脑老化/AD的中心机制。申请人的初步数据显示， 脑老化/AD与ADAR 1水平降低相关， 星形胶质细胞导致来自基因组重复元件（RE）的转录物增加， 与衰老和神经变性有关，并易于形成dsRNA。因此，ADAR 1可能是一种 脑老化和/或AD神经炎症的重要调节因子，可能通过减少RE相关 dsRNA积累。然而，这一想法尚未得到研究。在这个项目中，McEntee女士建议 通过使用多个模型来测试ADAR 1的假设，获得有价值的翻译研究培训 减少RE衍生的双链RNA的有害影响，从而预防年龄/AD相关的疾病 目的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ADAR 1和dsRNA水平是否与神经炎症相关，进行总 RNA-seq和RNA免疫沉淀测序（RIP-seq），以鉴定参与 神经炎症，并将她的发现与现有的临床数据集交叉;以及目标2）增加 ADAR 1在重编程的人星形胶质细胞中的表达和衰老的临床前小鼠模型， 确定ADAR 1是否可以预防年龄/AD相关的神经炎症和认知功能障碍。女士 McEntee的直接目标是获得执行所需的基本经验和专业技能 在与年龄相关的神经退行性疾病领域的独立研究。她的长期目标是成为 一个学术，翻译研究人员调查老化的机制，有助于神经退行性疾病 疾病McEntee女士将在CSU拥有出色指导团队的最先进环境中接受培训。 发起人LaRocca博士具有广泛的研究衰老和神经退行性疾病的背景， 他是美国国立卫生研究院资助的科罗拉多州立大学健康生物实验室的负责人。在LaRocca博士的指导下， 咨询导师克里斯林克博士，罗恩Tjalkens，朱莉莫雷诺，和丹Lark，McEntee女士将能够 成功完成培训计划，支持她发展成为一名独立的科学家。

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.