Unlocking evolutionarily latent immune functions for treating disease

解锁进化上潜在的免疫功能来治疗疾病

• 批准号: 10240664
• 负责人: Brenda L. Bass
• 金额: $ 114.83万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10240664
• 关键词: ADAR1; Affect; Animal Model; Animals; Antiviral Agents; Antiviral Response; Autoimmunity; Binding; Biochemical; Biochemistry; Biological; Biological Assay; Biological Process; Caenorhabditis elegans; Candidate Disease Gene; Cell Death; Cells; Chemicals; Communicable Diseases; Complement; Conflict (Psychology); Detection; Disease; Double-Stranded RNA; Engineering; Enzymes; Epitopes; Evaluation; Evolution; Experimental Models; Family; Future; Genes; Genetic; Genome; Goals; Hand; Homologous Gene; Immune; Immune response; Immunity; Immunoprecipitation; Immunotherapy; In Vitro; Innate Immune Response; Interferons; Intervention; Invaded; Invertebrates; Knowledge; Logic; Malignant Neoplasms; Mammalian Cell; Mammals; Masks; Mediating; Medical; Molecular; Molecular Biology; Monitor; Mouse Cell Line; Mus; Orthologous Gene; Outcome; Pathway interactions; Pattern; Phosphoric Monoester Hydrolases; Phosphorylation; Phylogenetic Analysis; Population; Proteins; RNA; RNA Interference; RNA-Directed RNA Polymerase; Recording of previous events; Reporting; Role; Sampling; Scientist; Signal Transduction; Source; Specificity; Structure; Substrate Specificity; Testing; Vertebrates; Viral; Virus; Work; arm; base; checkpoint modulation; comparative; design; ds RNA-Binding Proteins; dsRNA adenosine deaminase; experimental study; immune function; innate immune checkpoint; innate immune pathways; innovation; insight; member; prevent; response; sensor; theories; therapy outcome; tripolyphosphate; tumor; tumorigenesis

Project Summary/Abstract All animals possess a robust innate immune response that depends on their ability to recognize viral double- stranded RNA (dsRNA) as foreign. Yet, animal cells also encode and express dsRNA, and this cellular dsRNA must be distinguished as “self” to prevent an aberrant immune response. Adenosine deaminases that act on RNA, or ADARs, deaminate dsRNA to mark it as self and prevent an aberrant immune response. In this capacity ADARs serve as an ”Innate Immune Checkpoint” (IIC), and recent studies reveal that a decrease in ADAR activity in tumors releases this IIC, eliciting an immune response that leads to cell death. ADARs are the only IIC known to date, and proposed studies are designed to fill this gap in knowledge towards the goal of new immunotherapies. Comparative phylogenetic analyses will be complemented with molecular biology and biochemistry experiments to identify mitigators, such as ADARs, that prevent inappropriate deployment of antiviral defense, and ancient incompatibilities, such as invertebrate proteins that may activate an antiviral response when introduced into vertebrates. Experiments in mammalian cells and mice, and the invertebrate model organism, C. elegans, will provide a wide phylogenetic sampling to identify, test, and compare new IICs. Engineered mice and cell lines are in hand, and established assays are in place, to monitor effects on the immune pathway of both animals. Known dsRNA binding proteins, as well as those identified by immunoprecipitation strategies, will be prioritized by phylogenetic assays for testing as IICs. In vitro biochemistry experiments, and structural analyses, will guide subsequent rounds of phylogenetic comparisons. Mammalian ADAR1 p150 prevents an interferon response by modulating the MDA5 arm of the vertebrate innate immune pathway, and IICs for the RIG-I arm have not been reported. Strategies to identify IICs for the RIG-I arm will focus on enzymes known to modify the 5' terminus of RNA, a known epitope for RIG-I recognition. The culmination of proposed studies will be the evaluation of candidate IICs in experimental models of tumorigenesis.

项目概要/摘要 所有动物都拥有强大的先天免疫反应，这取决于它们识别病毒双链的能力。 然而，动物细胞也编码和表达 dsRNA，并且这种细胞 dsRNA 是外来的。 必须将其区分为“自身”，以防止作用于腺苷脱氨酶的异常免疫反应。 RNA 或 ADAR 使 dsRNA 脱氨基，将其标记为自身并以此防止异常的免疫反应。 ADAR 充当“先天免疫检查点”(IIC)，最近的研究表明 ADAR 活性下降 ADAR 是唯一已知的 IIC，它会在肿瘤中释放这种 IIC，引发免疫反应，从而导致细胞死亡。 迄今为止，拟议的研究旨在填补这一知识空白，以实现新的目标 比较系统发育分析将得到分子生物学和免疫疗法的补充。 生物化学实验来确定缓解剂，例如 ADAR，以防止不当部署 抗病毒防御和古老的不相容性，例如可能激活抗病毒药物的无脊椎动物蛋白 在哺乳动物细胞和小鼠以及无脊椎动物中进行实验时的反应。 模式生物秀丽隐杆线虫将提供广泛的系统发育采样来识别、测试和比较新的 IIC。 工程小鼠和细胞系已在手，已建立的测定方法也已到位，以监测对免疫的影响 已知的 dsRNA 结合蛋白，以及通过免疫沉淀鉴定的蛋白。 策略，将优先通过系统发育分析进行 IIC 测试，以及 结构分析，将指导后续几轮哺乳动物 ADAR1 p150 的系统发育比较。 通过调节脊椎动物先天免疫途径的 MDA5 臂来防止干扰素反应，并且 RIG-I 臂的 IIC 尚未报道 识别 RIG-I 臂的 IIC 的策略将集中于酶。 已知可修饰 RNA 的 5' 末端，这是 RIG-I 识别的已知表位。 研究将在肿瘤发生实验模型中评估候选 IIC。