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Investigation of Self-Nucleic Acids as a Trigger for Neuroinflammation

自身核酸作为神经炎症触发因素的研究

基本信息

批准号：
10630287
负责人：
Hachung Chung
金额：
$ 41万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10630287
关键词：
ADAR1 Affect Alu Elements Amyotrophic Lateral Sclerosis Astrocytes Autoimmune Diseases Autoimmunity Binding Biological Biology Brain Cell Death Cell Differentiation process Cells Cerebrospinal Fluid Collaborations DNA Data Set Detection Development Disease Double-Stranded RNA Early identification Elements Enzymes Etiology Event Exhibits Frontotemporal Dementia Genomic approach Genomics Goals Homeostasis Host Defense Mechanism Human IFNAR1 gene Immune response Immunology Inflammation Inflammatory Inflammatory Response Innate Immune Response Innate Immune System Interferon Type I Interferon alpha Interferons Invaded Investigation Knock-out Laboratories Left Life Ligands Measures Mediating Messenger RNA Microglia Molecular Motor Neurons Mutation Neurobiology Neurodegenerative Disorders Neurologic Dysfunctions Neurons Nucleic Acids Patients Pattern recognition receptor Predisposition Primates Production Psyche structure RNA RNA Editing RNA-Binding Proteins Receptor Activation Repetitive Sequence Research Role Serum Signal Transduction Source Specificity Structure Symptoms Techniques Testing Universities Viral Virus Diseases autoinflammatory diseases brain dysfunction cell type cytokine cytotoxicity dosage effective therapy experience experimental study fluorescence imaging gene product human stem cells immunogenic innovation insight microbial nerve stem cell neural neuroinflammation new therapeutic target novel therapeutic intervention nucleic acid detection pathogen physically handicapped prevent pseudotoxoplasmosis syndrome receptor stem cell technology stem cells transcriptome viral DNA viral RNA viral detection

项目摘要

PROJECT SUMMARY Pattern recognition receptors (PRRs) are an essential component of the innate immune system responsible for detecting invading pathogens and activating appropriate immunological responses. A significant proportion of PRRs are specialized in detecting viral DNA or RNA. Since DNA and RNA are the basic building blocks of life across all species, an intriguing and widely unexplored question emerges: Can PRRs detect endogenous (self) DNA or RNA, and what is the biological significance of self-nucleic acid detection? My laboratory at Columbia University seeks to understand the biological significance of self-RNA sensing by PRRs during both homeostasis and disease, and to further elucidate how self-RNA sensing is regulated to prevent autoimmune disorders. Research on Aicardi-Goutières syndrome (AGS) uncovered the causal role of self-nucleic acid mediated PRR activation in autoimmunity. AGS symptoms `mimic' viral infection, as patients exhibit elevated levels of type I interferon (IFN), a potent antiviral cytokine produced when PRRs detect viral nucleic acids. Mutations in the RNA editing enzyme ADAR1 can cause AGS. ADAR1 introduces A-to-I edits in cellular double-stranded RNAs (dsRNAs), and prior studies demonstrated that ADAR1 deficiency leads to aberrant activation of PKR and MDA5, two PRRs widely known to sense viral dsRNAs and trigger potent antiviral immune responses. These findings gave rise to the idea that during ADAR1 deficiency, self-RNAs become mistaken as viral RNAs, triggering PRR activation and downstream antiviral and inflammatory responses. Intriguingly, AGS mainly affects the brain, where elevated type I IFN production is observed, and most patients are left with mental and physical disabilities due to damage to the brain. ADAR1 and many PRRs are ubiquitously expressed in all cells, but it is puzzling why the neural compartment is particularly vulnerable to dysregulated inflammation. Currently the underlying molecular mechanisms that predispose the brain to inflammation are poorly defined. Our long-term goal is to define the role of self-RNAs in triggering neuroinflammation. We will determine if dsRNA sensing PRRs contribute to constitutive type I IFN expression in human neural cells, including neurons (Aim 1). Then, we will determine the abundance and subcellular localization of dsRNAs in neurons: during homeostasis and RNA dysregulation (Aim 2). We will also elucidate the molecular mechanism by which ADAR1 restricts self-RNAs from activating PRRs in neural cells (Aim 3). In this application our rich experience in immunology and RNA biology will be applied to neurobiology. We will utilize cutting edge human stem cell technology, neural cell differentiation techniques, and high-throughput genomics in collaboration with leading experts in their field. These studies can help identify early molecular events that trigger inflammation in the brain, which may lead to discovery of new therapeutic targets to treat AGS. More broadly, these studies may provide insight into how inflammation arises in other neurodegenerative diseases such as ALS (amyotrophic lateral sclerosis) or frontotemporal dementia (FTD), where perturbation of RNA-binding protein dosage or expanded RNA repeat elements can cause disease.

项目摘要模式识别受体（PRR）是先天免疫系统的重要组成部分，负责检测入侵的病原体并激活适当的免疫应答。很大一部分 PRR专门用于检测病毒DNA或RNA。因为DNA和RNA是生命的基本组成部分在所有的物种中，一个有趣的和广泛未探索的问题出现了：PRRs能否检测内源性（自我）是DNA还是RNA，自体核酸检测的生物学意义是什么？我在哥伦比亚的实验室大学试图了解PRR在体内平衡和体内平衡过程中自我RNA传感的生物学意义。和疾病，并进一步阐明如何自我RNA传感调节，以防止自身免疫性疾病。 Aicardi-Goutières综合征（AGS）的研究揭示了自身核酸介导的PRR的因果作用激活自身免疫。AGS症状“模仿”病毒感染，因为患者表现出I型水平升高干扰素（IFN），一种有效的抗病毒细胞因子，当PRR检测到病毒核酸时产生。RNA中的突变编辑酶ADAR 1可以导致AGS。ADAR 1在细胞双链RNA中引入A-to-I编辑（dsRNA），并且先前的研究表明ADAR 1缺陷导致PKR和MDA 5的异常激活，这两种PRR被广泛认为是感测病毒dsRNA并触发有效的抗病毒免疫应答的。这些发现提出了这样的观点，即在ADAR1缺陷期间，自身RNA被误认为病毒RNA，触发PRR 激活和下游抗病毒和炎症反应。有趣的是，AGS主要影响大脑，其中观察到I型IFN产生升高，并且大多数患者留下精神和身体残疾由于大脑受损。ADAR 1和许多PRR在所有细胞中普遍表达，但令人困惑的是，为什么神经区室特别容易受到失调性炎症的影响。目前，底层使大脑易患炎症的分子机制还不清楚。我们的长期目标是定义自身RNA在触发神经炎症中的作用。我们将确定dsRNA传感PRR是否有助于在人神经细胞包括神经元中的组成型I型IFN表达（目的1）。那就确定dsRNA在神经元中的丰度和亚细胞定位：在稳态和RNA 失调（目标2）。我们还将阐明ADAR 1限制自身RNA的分子机制，激活神经细胞中的PRR（目的3）。我们在免疫学和RNA生物学方面的丰富经验将应用于神经生物学。我们将利用尖端的人类干细胞技术，神经细胞分化技术和高通量基因组学与领先的专家在其领域的合作。这些研究可以帮助识别引发大脑炎症的早期分子事件，这可能导致发现新的治疗AGS的治疗靶点。更广泛地说，这些研究可能会提供炎症如何发生的见解在其他神经退行性疾病如ALS（肌萎缩侧索硬化症）或额颞叶痴呆中， (FTD)其中RNA结合蛋白剂量的扰动或扩增的RNA重复元件可引起疾病。