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.

项目摘要/摘要 假定的核苷酸传感器ZBP1可以触发死灵细胞死亡或转录反应， 遗传研究表明，这种途径是针对一系列病毒病原体的宿主防御所必需的。 此外，最近的研究表明，在某些情况下，ZBP1可以在无菌下激活 条件，将内源性细胞产物作为潜在的ZBP1配体。但是，尽管很长一段研究， 负责激活ZBP1的配体及其与核苷酸传感的其他成分的相互作用 机械仍然有争议，具有双链RNA，核糖核蛋白和病毒Z形核酸 物种都被认为是配体。 ZBP1仅与另一个共享其关键核苷酸传感域 哺乳动物蛋白，ADAR1。 ADAR1使内源性DSRNA物种失活以限制自身炎症 病理学和ADAR1的突变导致严重的自身免疫性疾病痛苦 Goutieres综合征（AGS）。我们假设ADAR1和ZBP1争夺共同的内源性 配体，其灭活ADAR1需要限制ZBP1激活。为了支持这个想法，病理 通过消融完全挽救了新发达的人ADAR1突变的小鼠模型。 ZBP1。这一发现支持我们的假设，也暗示与损失相关的自身免疫性病理 ADAR1功能的函数是由ZBP1依赖性炎症和细胞死亡的激活引起的。使用这些 观察作为起点，此处提出的工作将研究ZBP1激活和功能 追求三个目标：首先，我们将使用ADAR1突变和其他新鼠标模型来促进 内源性ZBP1配体的分离和鉴定。第二，我们将评估 坏死作用以及ZBP1介导的炎症信号传导至人类动物模型的病理学 AGS由ADAR1突变触发，并测试坏死抑制剂改善该病理学的能力。 第三，我们将研究其他DSRNA传感器（包括MDA5和PKR）在ZBP1配体形成中的作用 和坏死途径激活。这项工作一起将揭示ZBP1功能的关键方面，以及 识别ZBP1依赖性坏死作用是改善AG的潜在可治疗靶标。