ZBP1 activation

ZBP1激活

• 批准号: 10549766
• 负责人: Andrew Atwell Oberst
• 金额: $ 75.23万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10549766
• 关键词: ADAR1; Ablation; Adenosine; Amino Acid Substitution; Animal Model; Apoptosis; Attenuated; Autoimmune; Autoimmune Diseases; Autoimmunity; Binding; Cell Death; Cell Line; Cells; Cessation of life; DNA; DNA Binding Domain; Data; Deamination; Double-Stranded RNA; Enzymes; Generations; Genetic; Genetic Transcription; Genetic study; Goals; Host Defense; Human; Immune; Immunity; In Vitro; Infection; Inflammation; Inflammatory; Innate Immune Response; Innate Immune System; Inosine; Investigation; Lead; Ligand Binding Domain; Ligands; Ligation; Mediating; Modeling; Mus; Mutation; Nucleic Acids; Nucleotides; Output; Pathogenicity; Pathology; Pathway interactions; Patients; Phosphotransferases; Physiological; Point Mutation; Process; Protein Kinase Interaction; Proteins; RIPK1 gene; RNA; RNA Binding; RNA Editing; RNA Virus Infections; Receptor Activation; Research Personnel; Ribonucleoproteins; Role; Signal Transduction; Source; Sterility; Syndrome; TNF gene; Testing; Tumor Necrosis Factor Receptor; Viral; Virus; Virus Diseases; Work; Z-DNA Binding Protein; Z-Form DNA; antiviral immunity; attenuation; autoinflammatory; autoinflammatory diseases; base; clinical development; human model; in vivo; inhibitor; insight; loss of function; loss of function mutation; mouse model; pathogen; pathogenic virus; premature; prevent; pseudotoxoplasmosis syndrome; response; sensor; tool

Project Summary/Abstract The putative nucleotide sensor ZBP1 can trigger necroptotic cell death or transcriptional responses, and genetic studies indicate that this pathway is required for host defense against an array of viral pathogens. Furthermore, recent studies show that in some circumstances ZBP1 can become activated under sterile conditions, implicating endogenous cellular products as potential ZBP1 ligands. However, despite long study, the ligand responsible for activating ZBP1 and its interplay with other components of the nucleotide sensing machinery remain controversial, with double-stranded RNA, ribonucleoprotein, and viral Z-form nucleic acid species all suggested as ligand. ZBP1 shares its key nucleotide sensing domain with only one other mammalian protein, ADAR1. ADAR1 inactivates endogenous dsRNA species to limit autoinflammatory pathology, and mutations in ADAR1 in human patients lead to the severe autoimmune disease Acardi- Goutieres syndrome (AGS). We hypothesize that ADAR1 and ZBP1 compete for a common endogenous ligand, whose inactivation by ADAR1 is required to limit ZBP1 activation. In support of this idea, the pathology observed in a newly-developed mouse model of human ADAR1 mutation was fully rescued by ablation of ZBP1. This finding supports our hypothesis, and also implies that autoimmune pathology associated with loss of ADAR1 function is caused by activation of ZBP1-dependent inflammation and cell death. Using these observations as a starting point, the work proposed here will investigate ZBP1 activation and function by pursuing three Aims: First, we will use ADAR1 mutation and additional new mouse models to facilitate isolation and identification of an endogenous ZBP1 ligand. Second, we will assess the contribution of necroptosis as well as ZBP1-mediated inflammatory signaling to the pathology of an animal model of human AGS triggered by ADAR1 mutation, and test the ability of necroptosis inhibitors to ameliorate this pathology. Third, we will investigate the role of other dsRNA sensors, including MDA5 and PKR, to ZBP1 ligand formation and necroptotic pathway activation. Together this work will both reveal key aspects of ZBP1 function, and identify ZBP1-dependent necroptosis as a potentially treatable target to ameliorate AGS.

项目概要/摘要 假定的核苷酸传感器 ZBP1 可以触发坏死性细胞死亡或转录反应， 遗传学研究表明，该途径是宿主防御一系列病毒病原体所必需的。 此外，最近的研究表明，在某些情况下，ZBP1 可以在无菌条件下被激活。 条件，暗示内源性细胞产物作为潜在的 ZBP1 配体。然而，尽管经过长期的学习， 负责激活 ZBP1 的配体及其与核苷酸传感的其他组件的相互作用 机制仍然存在争议，包括双链RNA、核糖核蛋白和病毒Z型核酸 所有物种均建议作为配体。 ZBP1 仅与另一个共享其关键核苷酸传感结构域 哺乳动物蛋白 ADAR1。 ADAR1 灭活内源性 dsRNA 物种以限制自身炎症 ADAR1 的病理学和人类患者的突变会导致严重的自身免疫性疾病 Acardi- 古蒂埃综合征（AGS）。我们假设 ADAR1 和 ZBP1 竞争共同的内源性 配体，其被 ADAR1 失活是限制 ZBP1 激活所必需的。为了支持这一观点，病理学 在新开发的小鼠模型中观察到的人类 ADAR1 突变通过消除 ZBP1。这一发现支持了我们的假设，并且还暗示与损失相关的自身免疫病理学 ADAR1 功能的丧失是由 ZBP1 依赖性炎症激活和细胞死亡引起的。使用这些 以观察为起点，这里提出的工作将通过以下方式研究 ZBP1 的激活和功能： 追求三个目标：首先，我们将使用 ADAR1 突变和其他新的小鼠模型来促进 内源性 ZBP1 配体的分离和鉴定。其次，我们将评估 坏死性凋亡以及 ZBP1 介导的炎症信号对人类动物模型病理学的影响 由 ADAR1 突变触发的 AGS，并测试坏死性凋亡抑制剂改善这种病理的能力。 第三，我们将研究其他 dsRNA 传感器（包括 MDA5 和 PKR）对 ZBP1 配体形成的作用 和坏死性凋亡途径激活。这项工作将共同揭示 ZBP1 功能的关键方面，以及 确定 ZBP1 依赖性坏死性凋亡是改善 AGS 的潜在可治疗靶点。