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: 10657082
• 负责人: Derya Unutmaz
• 金额: $ 9.08万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10657082
• 关键词: Affect; Award; Bacteria; Basic Science; Biological; Biological Markers; Blood; Cells; Chronic; Chronic Disease; Chronic Fatigue Syndrome; Clinical; Clinical Data; Clinical Research; Clinical Trials; Communities; Computational Biology; Databases; Diagnosis; Disease; Disease Progression; Epigenetic Process; Etiology; Future; Goals; Homeostasis; Human; Immune; Immune response; Immune system; Immunologics; Immunology; Inflammation; Knowledge; Link; Metabolic; Metabolism; Microbe; Neurologic Symptoms; Parents; Patients; Phenotype; Prospective cohort; Public Health; Research; Research Project Grants; Role; Sample Size; Sampling; Stimulus; Structure; System; Systems Biology; The Jackson Laboratory; clinical phenotype; cohesion; cohort; dysbiosis; effective therapy; genetic resource; immune activation; improved; metabolomics; microbial; microbiome; microbiota; mouse genetics; mouse model; multidisciplinary; novel therapeutic intervention; prospective; recruit; sample collection; sugar

PROJECT SUMMARY – FROM PARENT AWARD 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.

项目摘要 - 总体奖 我们提出了一个肌腱脑脊髓炎/慢性疲劳综合症协作研究中心 杰克逊实验室（JAX ME/CFS CRC）确定了基本机制 系统组件网络（微生物组，代谢和免疫系统）会导致或 恶化疾病。我/CFS是一种使人衰弱的疾病，缺乏广泛接受的管理疗法 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 对于免疫异常，人们认为这有助于疾病进展。微生物组 最近出现成为免疫扰动的潜在贡献者，因为它与免疫密切相关 激活和稳态以及宿主代谢变化，其营养不良与慢性有关 炎。代谢组学研究表明，与健康相比，ME/CFS患者的代谢状态改变了 对照可能对糖，能量水平，免疫球活性产生下游或相互影响的对照， 和微生物营养不良。但是，小样本量，缺乏凝聚力的临床数据和生物样品 收集以及整体关注网络组成部分的关注限制了这些研究的影响。 jax 我/CFS CRC试图使用多学科改变对我/CF的了解的景观 系统生物学方法以整合ME/CFS患者的表型和功能免疫变化 带有微生物组和代谢参数。我们假设免疫系统在 ME/CFS在两个主要因素上进行了预测：1）对Immunocell进行编程以异常反应 环境刺激，以及2）ME/CFS患者具有异常刺激免疫小球的微生物， 直接或通过代谢副产品。为了探究这一假设，我们构建了JAX ME/CFS CRC 大约有两个集成的研究项目，以及ME/CFS患者和健康对照组的前瞻性队列 纵向获得哪些血液，粪便样品和一系列临床参数。我们的中心将带来 我/CFS临床医生，免疫学专家，微生物组和计算生物学以及社区 利益相关者实现我们的科学目标，并最大程度地提高我们的研究对受到影响的人的影响 疾病。我们的目的是：1）开发一个综合的免疫，代谢组学和 ME/CFS患者的微生物组轮廓（临床研究项目）； 2）建立一个机械平台 关于ME/CFS微生物群和免疫响应（基础研究项目）角色的发现； 3）快速实施 招募ME/CFS前瞻性临床队列（临床核心）； 4）协调一个综合性， ME/CFS研究（管理员核心）中的多学科组。此外，我们将利用这两种科学 JAX的专业知识和庞大的鼠标遗传资源，以开发高度协作的CRC项目 了解表观遗传学的作用，开发用于微生物组免疫相互作用和神经系统的小鼠模型 症状。这些将允许患者诊断和未来临床试验的策略。

项目成果

Tuning of human MAIT cell activation by commensal bacteria species and MR1-dependent T-cell presentation.

• DOI: 10.1038/s41385-018-0072-x
• 发表时间: 2018-11
• 期刊: Mucosal immunology
• 影响因子: 8
• 作者: Tastan C;Karhan E;Zhou W;Fleming E;Voigt AY;Yao X;Wang L;Horne M;Placek L;Kozhaya L;Oh J;Unutmaz D
• 通讯作者: Unutmaz D

Functional Interrogation of Primary Human T Cells via CRISPR Genetic Editing.

• DOI: 10.4049/jimmunol.1701616
• 发表时间: 2018-09-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Chen X;Kozhaya L;Tastan C;Placek L;Dogan M;Horne M;Abblett R;Karhan E;Vaeth M;Feske S;Unutmaz D
• 通讯作者: Unutmaz D

Recoding the metagenome: microbiome engineering in situ.

• DOI: 10.1016/j.mib.2019.09.005
• 发表时间: 2019-08
• 期刊: Current opinion in microbiology
• 影响因子: 5.4
• 作者: Travis Whitfill;Julia Oh

Strains to go: interactions of the skin microbiome beyond its species.

• DOI: 10.1016/j.mib.2022.102222
• 发表时间: 2022-12
• 期刊: CURRENT OPINION IN MICROBIOLOGY
• 影响因子: 5.4
• 作者: Caldwell, Ryan;Zhou, Wei;Oh, Julia
• 通讯作者: Oh, Julia

SARS-CoV-2 specific antibody and neutralization assays reveal the wide range of the humoral immune response to virus.

• DOI: 10.1038/s42003-021-01649-6
• 发表时间: 2021-01-29
• 期刊: Communications biology
• 影响因子: 5.9
• 作者: Dogan M;Kozhaya L;Placek L;Gunter C;Yigit M;Hardy R;Plassmeyer M;Coatney P;Lillard K;Bukhari Z;Kleinberg M;Hayes C;Arditi M;Klapper E;Merin N;Liang BT;Gupta R;Alpan O;Unutmaz D
• 通讯作者: Unutmaz D