Topological Mapping of Immune, Microbiota, Metabolomic and Clinical Phenotypes to Reveal ME/CFS Disease Mechanisms - Basic Research Project

免疫、微生物群、代谢组学和临床表型的拓扑图绘制以揭示 ME/CFS 疾病机制 - 基础研究项目

• 批准号: 10011904
• 负责人: Julia S Oh
• 金额: $ 68.24万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10011904
• 关键词: Address; Bacteria; Basic Science; Biological Assay; Biological Markers; Cells; Chronic Fatigue Syndrome; Clinical; Clinical Research; Clinical Trials; Dendritic Cells; Development; Disease; Engineered Probiotics; Engineering; Epigenetic Process; Foundations; Fractionation; Functional disorder; Gene Expression Regulation; Genetic; Genetic Transcription; Goals; Harvest; High-Throughput RNA Sequencing; Immune; Immune response; Immune signaling; Immune system; Immunologics; Immunology procedure; Libraries; Link; Mass Spectrum Analysis; Mediating; Metabolic; Microbe; Molecular; Molecular Profiling; Output; Pathology; Pathway interactions; Patients; Phenotype; Research Project Grants; Resolution; Risk Factors; Running; Severity of illness; Side; Stimulus; T-Lymphocyte Subsets; Testing; Therapeutic; Work; base; cell type; clinical phenotype; design; dysbiosis; gut microbes; host microbiome; immune activation; immunopathology; immunoregulation; macrophage; metabolomics; microbial; microbial host; microbiome; microbiota; microorganism interaction; new therapeutic target; novel; overexpression; response; therapeutic target; transcriptomics

PROJECT SUMMARY BASIC RESEARCH PROJECT Our goal in this project is to investigate the molecular mechanisms by which the ME/CFS microbiome interacts with the immune system to cause disease. Abnormalities in immune activation are likely key contributors to ME/CFS disease severity. However, we do not know to what extent these abnormalities are: 1) microbial in origin, i.e., caused by microbial dysbiosis in ME/CFS patients; 2) caused by metabolites produced by microbiota that influence the immunological or metabolic pathophysiology; or 3) caused by genetic or environmental perturbation of immune sensitivity in ME/CFS patients. There is thus a strong need to identify the immune cells, bacteria, and molecular pathways that drive abnormal immune activation in ME/CFS. Here, we will interrogate microbes and immune cells harvested from ME/CFS patients through complementary pipelines, each designed to isolate one side of the microbe-immune axis. The microbial pipeline will compare ME/CFS- related bacteria collected from patients to bacteria from healthy controls using a set of relevant immune assays. The immune pipeline will compare immune cells collected from ME/CFS patients to healthy immune cells, exposing both to a battery of microbial triggers and immune cell activators. Together, these pipelines will pinpoint with molecular resolution the specific immune-mediated disease triggers unique to or significantly enriched in the ME/CFS condition. We expect to determine the relative contributions of microbes and immune cells toward the immune pathology observed in these patients. We also expect to identify how ME/CFS-related gut microbes impact different compartments of the immune system and to identify the immunomodulatory metabolite repertoire that underlies these interactions. This research project is highly synergistic with the clinical project, in that together they will establish microbial and immune correlates of ME/CFS disease severity and a framework for disease mechanisms. This project will also contribute to the goals of the CRC through: characterization of microbial and immune cellular and molecular mechanisms, identification of potential new therapeutic targets with characterized mechanism of action, and identification of potential microbial or transcriptional triggers, biomarkers, and risk factors. Our Specific Aims are: 1) To identify immunomodulatory bacterial strains from ME/CFS patients that may underlie immunopathology (Microbial Pipeline); and 2) To determine the response of ME/CFS patient immune cells to microbial modulators based on transcriptomic interrogation and epigenetic states (Immune Pipeline). Impact: By probing the immune responses of ME/CFS patients to microbial stimuli, we will define the molecular mechanisms by which ME/CFS-related gut microbes mediate immune activation. This work will also lay the foundation for rational discovery of therapeutics that target microbe-immune interactions, and development of engineered probiotics for ME/CFS treatment.

基础研究项目 我们在这个项目中的目标是研究ME/CFS微生物组的分子机制， 与免疫系统相互作用导致疾病。免疫激活的减少可能是关键 导致ME/CFS疾病严重程度的因素。然而，我们不知道这些异常在多大程度上是：1） 微生物来源，即，由ME/CFS患者中的微生物生态失调引起; 2）由产生的代谢产物引起 由影响免疫或代谢病理生理学的微生物群引起;或3）由遗传或 ME/CFS患者免疫敏感性的环境干扰。因此，迫切需要确定 免疫细胞，细菌和分子途径驱动ME/CFS中的异常免疫激活。这里我们 将通过互补的管道询问从ME/CFS患者中收获的微生物和免疫细胞， 每一个都被设计成隔离微生物免疫轴的一侧。微生物管道将比较ME/CFS- 使用一组相关的免疫测定将从患者收集的相关细菌与来自健康对照的细菌进行比较。 免疫管道将比较从ME/CFS患者收集的免疫细胞与健康免疫细胞， 同时暴露在一系列微生物触发物和免疫细胞激活物中。这些管道将共同确定 通过分子分辨率，特异性免疫介导的疾病触发物是唯一的或显著富集于 ME/CFS条件。我们希望确定微生物和免疫细胞对免疫系统的相对贡献。 在这些患者中观察到的免疫病理学。我们还希望确定ME/CFS相关的肠道微生物 影响免疫系统的不同区室，并确定免疫调节代谢物库 这些互动的基础。该研究项目与临床项目高度协同， 他们将共同建立ME/CFS疾病严重程度的微生物和免疫相关性， 疾病机制。该项目还将通过以下方式促进《儿童权利公约》的目标： 微生物和免疫细胞和分子机制，鉴定潜在的新的治疗靶点， 表征的作用机制，并鉴定潜在的微生物或转录触发因子， 生物标志物和风险因素。我们的具体目标是：1）鉴定免疫调节细菌菌株 ME/CFS患者，可能是免疫病理学的基础（微生物管道）;和2）为了确定 ME/CFS患者免疫细胞对基于转录组询问和表观遗传的微生物调节剂的作用 免疫管道（Immune Pipeline）影响：通过探测ME/CFS患者对微生物刺激的免疫反应， 我们将明确ME/CFS相关肠道微生物介导免疫激活的分子机制。 这项工作也将为合理发现针对微生物免疫的治疗方法奠定基础。 相互作用和开发用于ME/CFS治疗的工程益生菌。