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: 9769922
• 负责人: Julia S Oh
• 金额: $ 63.67万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9769922
• 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.

项目摘要基础研究项目 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以引起疾病。免疫激活异常可能是关键 我/CFS疾病严重程度的贡献者。但是，我们不知道这些异常在多大程度上：1） MI/CFS患者的微生物营养不良引起的微生物，即是由微生物营养不良引起的； 2）由产生​​的代谢产物引起 通过影响免疫学或代谢病理生理学的微生物群；或3）由遗传或 ME/CFS患者免疫敏感性的环境扰动。因此，很有必要确定 在ME/CFS中驱动异常免疫激活的免疫细胞，细菌和分子途径。在这里，我们 将通过互补管道从ME/CFS患者收集的微生物和免疫细胞询问微生物和免疫细胞， 每个设计都隔离了微生物免疫轴的一侧。微生物管道将比较我/cfs- 使用一组相关的免疫测定，从患者到健康对照的细菌的相关细菌。 免疫管道将比较从ME/CFS患者收集的免疫细胞与健康的免疫细胞， 暴露于微生物触发器和免疫细胞活化剂中。这些管道在一起可以确定 通过分子解决 ME/CFS条件。我们期望确定微生物和免疫细胞对 这些患者观察到的免疫病理。我们还希望确定我/CFS相关的肠道微生物 影响免疫系统的不同隔室，并确定免疫调节代谢物库 这是这些相互作用的基础。该研究项目与临床项目具有很高的协同作用，因为 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和一个框架 疾病机制。该项目还将通过：特征来促进CRC的目标 微生物和免疫细胞和分子机制，鉴定潜在的新治疗靶标具有 表征作用机理，并鉴定了潜在的微生物或转录触发器， 生物标志物和危险因素。我们的具体目的是：1）从 ME/CFS患者可能是免疫病理学的基础（微生物管道）； 2）确定 ME/CFS患者免疫细胞基于转录组询问和表观遗传学 状态（免疫管道）。影响：通过探测ME/CFS患者对微生物刺激的免疫反应， 我们将定义ME/CFS相关肠道微生物介导免疫激活的分子机制。 这项工作还将为靶向微生物免疫的理性发现奠定基础 与ME/CFS治疗的工程益生菌的相互作用和开发。