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

基本信息

批准号：
10021943
负责人：
Brenda L. Bass
金额：
$ 118.24万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
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/10021943
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

项目摘要

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.

项目摘要/摘要所有动物都具有强大的先天免疫响应，取决于其识别病毒双重的能力滞留的RNA（dsRNA）作为外国。然而，动物细胞还编码并表达dsRNA，该细胞dsRNA 必须将其区分为“自我”，以防止异常的免疫反应。行动的腺苷死亡 RNA或ADARS脱氨酸dsRNA将其标记为自我并防止异常的免疫响应。以这种身份 ADAR充当“先天免疫检查点”（IIC），最近的研究表明，ADAR活动的减少在肿瘤中，释放了这种IIC，引起了导致细胞死亡的免疫反应。 ADAR是唯一知道的IIC 迄今免疫疗法。比较系统发育分析将通过分子生物学和生物化学实验以识别缓解剂，例如ADAR，以防止不适当的部署抗病毒防御和古代不相容性，例如可能激活抗病毒的无脊椎动物蛋白当引入脊椎动物时的响应。哺乳动物细胞和小鼠以及无脊椎动物的实验模型有机体C. exemans将提供广泛的系统发育采样，以识别，测试和比较新的IIC。工程的鼠标和细胞系在手中，并进行了既定测定法，以监视对免疫的影响两种动物的途径。已知的DSRNA结合蛋白，以及通过免疫沉淀鉴定的蛋白策略将通过系统发育测定作为IIC的测试优先考虑。体外生物化学实验，并结构分析将指导随后的系统发育比较。哺乳动物ADAR1 P150 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，并尚未报告IG-I手臂的IIC。识别RIG-I部门IIC的策略将专注于酶已知可以修改RNA的5'末端，RNA是RIG-I识别的已知表位。提议的结晶研究将是对肿瘤发生实验模型中候选IIC的评估。