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

项目概要 我们建议在以下地点设立肌痛性脑脊髓炎/慢性疲劳综合征合作研究中心： 杰克逊实验室（JAX ME/CFS CRC），以确定三- 系统的组成网络-微生物组，代谢和免疫系统-相互作用， 加剧疾病。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 免疫异常，这被认为是有助于疾病的进展。微生物组 最近出现作为一个潜在的贡献者免疫扰动，因为它是密切相关的免疫 激活和稳态以及宿主代谢变化，其生态失调与慢性 炎症代谢组学研究表明，与健康人相比，ME/CFS患者的代谢状态改变 控制，这可能对糖，能量水平，免疫细胞活性， 和微生物生态失调。然而，样本量小，缺乏连贯的临床数据和生物样本 由于收集的资料有限，而且总体上侧重于网络的一个组成部分，这些研究的影响有限。阿贾克斯 ME/CFS CRC旨在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 微生物组和代谢参数。我们假设免疫系统在 ME/CFS基于两个主要因素：1）免疫细胞被编程为对 环境刺激，和2）ME/CFS患者携带异常刺激免疫细胞的微生物， 直接或通过代谢副产物。为了探究这个假设，我们构造了JAX ME/CFS CRC 围绕两个综合研究项目和一个ME/CFS患者和健康对照的前瞻性队列， 所述血液、粪便样本和一系列临床参数是纵向采集的。我们的中心将带来 ME/CFS临床医生，免疫学，微生物组学和计算生物学专家以及社区 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影响的人的影响。 疾病我们的目标是：1）建立一个全面的和前瞻性的免疫，代谢组学数据库， ME/CFS患者的微生物组谱（临床研究项目）; 2）建立机制平台， 发现ME/CFS微生物群和免疫反应的作用（基础研究项目）; 3）快速实施 ME/CFS前瞻性临床队列（临床核心）的招募;以及4）协调整合， ME/CFS研究的多学科小组（管理核心）。此外，我们还将利用科学 利用JAX的专业知识和丰富的小鼠遗传资源，开发高度协作的CRC间项目， 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系统的小鼠模型 症状总之，这些将为患者诊断和未来的临床试验提供策略。

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.