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

免疫、微生物群、代谢组学和临床表型的拓扑图揭示 ME/CFS 疾病机制

• 批准号: 9769916
• 负责人: Derya Unutmaz
• 金额: $ 211.29万
• 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/9769916
• 关键词: Affect; Bacteria; Basic Science; Biological; Biological Markers; Blood; Cells; Chronic; Chronic Disease; Chronic Fatigue Syndrome; Clinical; Clinical Data; Clinical Research; Clinical Trials; Collaborations; Communication; Communities; Complex; Computational Biology; Data; Data Analyses; Data Set; Databases; Development; Diagnosis; Disease; Disease Progression; Engineered Probiotics; Ensure; Epigenetic Process; Etiology; Feedback; Future; Genetic Transcription; Goals; Homeostasis; Human; Immune; Immune response; Immune system; Immunologics; Immunology; Individual; Inflammation; Knowledge; Leadership; Link; Maintenance; Maps; Metabolic; Metabolism; Metadata; Methods; Microbe; Molecular; Mus; Neurologic Symptoms; Ontology; Pathogenesis; Patient Self-Report; Patients; Phenotype; Pilot Projects; Probiotics; Prospective cohort; Public Health; Reporting; Research; Research Project Grants; Role; Sample Size; Sampling; Serum; Stimulus; Stratification; Structure; Symptoms; System; Systems Biology; Testing; The Jackson Laboratory; Therapeutic; Time; clinical biomarkers; clinical phenotype; cohesion; cohort; design; disease phenotype; dysbiosis; effective therapy; genetic resource; immune activation; improved; metabolomics; microbial; microbiome; microbiota; mouse model; multidisciplinary; novel therapeutic intervention; outcome forecast; outreach; pathogen; patient subsets; prospective; recruit; response; restoration; sample collection; stool sample; success; sugar

PROJECT SUMMARY OVERALL We propose a Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Collaborative Research Center at The Jackson Laboratory (JAX ME/CFS CRC) to identify the fundamental mechanisms by which a tri- component network of systems—the microbiome, metabolism and the immune system—interact to cause or exacerbate disease. ME/CFS is a debilitating illness that lacks widely accepted therapies for its management as well as meaningful understanding of its biological underpinnings. Mounting evidence indicates a significant role for immunological abnormalities, which are thought to contribute to disease progression. The microbiome recently emerged as a potential contributor to immune perturbations, as it is intimately linked with immune activation and homeostasis as well as host metabolic changes, and its dysbiosis has been linked to chronic inflammation. Metabolomic studies suggest altered metabolic states in ME/CFS patients compared to healthy controls, which could have downstream—or reciprocal—effects on sugar, energy levels, immune cell activity, and microbial dysbiosis. However, small sample sizes, lack of cohesive clinical data and biological sample collection, and overall focus on one component of the network has limited the impact of these studies. The JAX ME/CFS CRC seeks to transform the landscape of knowledge of ME/CFS using a multi-disciplinary systems biology approach to integrate phenotypic and functional immune changes in ME/CFS patients with microbiome and metabolic parameters. We hypothesize that the immune system's etiological role in ME/CFS is predicated on two major factors: 1) that immune cells are programmed to respond aberrantly to environmental stimuli, and 2) that ME/CFS patients harbor microbes that aberrantly stimulate immune cells, either directly or through metabolic byproducts. To probe this hypothesis, we structured the JAX ME/CFS CRC around two integrated research projects and a prospective cohort of ME/CFS patients and healthy controls in which blood, fecal samples and a range of clinical parameters are acquired longitudinally. Our Center will bring together ME/CFS clinicians, experts in immunology, microbiome, and computational biology, and community stakeholders to achieve our scientific goals and maximize the impact of our research on those affected by the disease. Our Aims are: 1) Develop a comprehensive and prospective database of immune, metabolomics and microbiome profiles of ME/CFS patients (Clinical Research Project); 2) Establish a platform for mechanistic discoveries on role of ME/CFS microbiota and immune response (Basic Research Project); 3) Rapidly implement recruitment of the ME/CFS prospective clinical cohort (Clinical Core); and 4) Coordinate an integrative, multidisciplinary group in ME/CFS research (Admin Core). In addition, we will capitalize on both on scientific expertise and vast mouse genetic resource of the JAX to develop highly collaborative inter-CRC projects to understand role of epigenetics, developing mouse models for microbiome-immune interactions and neurological symptoms. Together, these will allow strategies for patient diagnosis and future clinical trials.

项目总体概要 我们提议在以下地点建立肌痛性脑脊髓炎/慢性疲劳综合症合作研究中心： 杰克逊实验室（JAX ME/CFS CRC）确定了三重的基本机制 系统的组成网络——微生物组、新陈代谢和免疫系统——相互作用，导致或 ME/CFS 是一种使人衰弱的疾病，缺乏广泛接受的治疗方法。 以及对其生物学基础的有意义的理解越来越多的证据表明了其重要作用。 用于免疫异常，这被认为有助于疾病进展。 最近出现作为免疫扰动的潜在因素，因为它与免疫密切相关 激活和稳态以及宿主代谢变化，其生态失调与慢性 代谢组学研究表明，与健康人相比，ME/CFS 患者的代谢状态发生了改变。 控制，这可能对糖、能量水平、免疫细胞活性产生下游或相互影响， 然而，样本量小，缺乏有凝聚力的临床数据和生物样本。 收集以及对网络某一组成部分的总体关注限制了这些研究的影响。 ME/CFS CRC 寻求利用多学科的方法来改变 ME/CFS 的知识格局 整合 ME/CFS 患者表型和功能性免疫变化的系统生物学方法 我们了解了免疫系统在微生物组和代谢参数中的病因学作用。 ME/CFS 取决于两个主要因素：1) 免疫细胞被编程为对以下因素做出异常反应： 环境刺激，2) ME/CFS 患者体内含有异常刺激免疫细胞的微生物， 为了探究这一假设，我们构建了 JAX ME/CFS CRC。 围绕两个综合研究项目以及 ME/CFS 患者和健康对照的前瞻性队列 我们中心将纵向采集血液、粪便样本和一系列临床参数。 ME/CFS 超级明星、免疫学、微生物组和计算生物学专家以及社区聚集在一起 利益相关者实现我们的科学目标，并最大限度地发挥我们的研究对受该问题影响的人们的影响 我们的目标是： 1) 开发一个全面的、前瞻性的免疫、代谢组学和疾病数据库。 ME/CFS患者的微生物组概况（临床研究项目2）建立机制平台； 关于 ME/CFS 微生物群和免疫反应的作用的发现（基础研究项目）；3）快速实施 招募 ME/CFS 前瞻性临床队列（临床核心）；以及 4) 协调综合、 ME/CFS 研究的多学科小组（管理核心）此外，我们将利用两者的科学优势。 JAX 的专业知识和丰富的小鼠遗传资源可高度开发 CRC 间的协作项目， 了解表观遗传学的作用，开发微生物组-免疫相互作用和神经学的小鼠模型 总之，这些将为患者诊断和未来的临床试验提供策略。