Metabolic Biomarkers for Fibromyalgia: Administrative Supplement

纤维肌痛的代谢生物标志物：行政补充

• 批准号: 10861142
• 负责人: Laura A Frey Law
• 金额: $ 35.69万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10861142
• 关键词: Administrative Supplement; Adult; Affect; Age; Animal Model; Animals; Anti-Inflammatory Agents; Applications Grants; B-Lymphocytes; Bacteria; Biological Assay; Biological Markers; Blood specimen; Body mass index; Cell physiology; Cells; Chronic; Clinical; Clinical Sciences; Complex; DNA Methylation; Data; Development; Diagnostic; Diagnostic tests; Endotoxins; Environment; Epigenetic Process; Exercise; Extracellular Fluid; Fatigue; Fibromyalgia; Flow Cytometry; Funding; Future; Goals; Human; Immune; Immune system; Impaired cognition; Individual; Inflammatory; Institution; Interleukin-1 beta; Investigation; Ion Channel; Laboratories; Lipopolysaccharides; Lymphocyte; Macrophage; Measures; Mediating; Metabolic; Metabolic Marker; Methodology; Muscle; Muscle Contraction; Myeloid Cells; Natural Killer Cells; Pain; Parents; Perception; Peripheral Blood Mononuclear Cell; Phenotype; Physiological; Play; Quality of life; Reporting; Research; Research Personnel; Resources; Rest; Role; Sampling; Serum; Sleep Disorders; Stimulant; Symptoms; T-Lymphocyte; Techniques; Therapeutic; Time; Translating; Translational Research; United States National Institutes of Health; Work; biopsychosocial; career; cell type; chronic pain; clinical phenotype; cohort; cytokine; exercise program; expectation; immune activator; immune function; improved; inflammatory marker; insight; metabolome; metabolomics; methylation pattern; monocyte; multidisciplinary; novel; novel diagnostics; novel strategies; parent grant; response; sex; skills

Project Summary Fibromyalgia (FM) is a complex condition characterized by widespread pain - often induced by activity; fatigue; cognitive and sleep dysfunction. Activity-induced pain and fatigue in particular are significant barriers to participation in an effective exercise program and daily activities. Accordingly, improved understanding of the underlying mechanisms associated with symptomology could lead to novel approaches for effective management. This supplement will provide resources to perform preliminary analyses to investigate potential immune-related mechanisms of FM and their relationship to symptomology, particularly activity-induced pain. It has become clear that the immune system plays a key role in FM, with alterations related to clinical symptoms and activity-induced pain. However, prior studies have been equivocal in identifying specific immune cell types responsible for changes in inflammatory markers, specifically circulating cytokines, often with mixed results across studies. Further, immune cells do not work in isolation; the metabolic environment can alter immune cell phenotype, immune cells may alter the metabolic environment, and cross-talk between immune cells can occur. At the same time, epigenetic dysregulation of immune cells directly influences differentiation of immune cell phenotypes and subsets. In fact, altered DNA methylation patterns have been observed with FM; however, it is unclear which distinct cell types are involved. The primary goal of this proposal is to assess immune function using multiple assays in a single cohort of adults with FM relative to matched controls to generate pilot data for a future submission. We hypothesize that alterations in the immune system including phenotype of immune cells, evoked-release of IL-1β, and altered DNA methylation in monocytes, will occur in those with FM vs matched controls, and that these changes will relate to the clinical phenotypes of pain and fatigue. We further propose that the changes in cytokines will directly relate to the metabolome already collected in this project. This study will achieve the primary goal via two specific aims: Aim 1: Characterize the immune system using multiple techniques in FM and matched controls: 1) phenotype and quantification of monocytes, T-cells, B-cells and natural killer cells using spectral flow cytometry, 2) muscle metabolite-evoked release from monocytes, and 3) DNA methylation pattern and epigenetic age of monocytes; Aim 2: Determine the relationship of immune system and DNA methylation changes to the clinical phenotype and metabolome profiles in individuals with FM compared to matched controls. Our primary aim will focus on activity-induced pain, with secondary aims examining relationship with other symptoms, including fatigue. This research will provide new insights into underlying immune cell mechanisms in FM. These novel studies have the potential to identify diagnostic, and potentially therapeutic, FM biomarkers associated with immune cell function. The multi- institutional and multidisciplinary study team has the necessary expertise in clinical and translational science, immune function, and epigenetics to efficiently leverage data collected for the parent grant.

项目摘要 纤维肌痛（FM）是一种复杂的疾病，其特征是广泛的疼痛-通常由活动引起;疲劳; 认知和睡眠功能障碍。特别是活动引起的疼痛和疲劳是 参与有效的锻炼计划和日常活动。因此，增进对 与神经病学相关的潜在机制可能导致新的有效方法， 管理本补充文件将提供资源，以进行初步分析， FM的免疫相关机制及其与病理学的关系，特别是活动诱导的疼痛。它 现已清楚，免疫系统在FM中发挥着关键作用，其变化与临床症状相关 和活动引起的疼痛。然而，先前的研究在确定特定的免疫细胞类型方面一直模棱两可 负责炎症标志物的变化，特别是循环细胞因子，通常具有混合结果 跨研究。此外，免疫细胞不能孤立地工作;代谢环境可以改变免疫细胞 表型，免疫细胞可以改变代谢环境，并且免疫细胞之间的串扰可以 发生.同时，免疫细胞的表观遗传失调直接影响免疫细胞的分化， 细胞表型和亚群。事实上，在FM中已经观察到DNA甲基化模式的改变;然而， 还不清楚涉及哪些不同的细胞类型。该提案的主要目标是评估免疫 在FM成人的单个队列中使用多个测定相对于匹配的对照来产生试验性 为将来的提交提供数据。我们假设免疫系统的改变，包括表型的改变， FM患者会出现免疫细胞激活、IL-1β释放和单核细胞DNA甲基化改变 与匹配的对照组相比，这些变化将与疼痛和疲劳的临床表型有关。我们 进一步提出，细胞因子的变化将直接关系到已经收集的代谢组， 项目本研究将通过两个具体目标实现主要目标：目标1：表征免疫系统 在FM和匹配对照中使用多种技术：1）单核细胞，T细胞， B细胞和自然杀伤细胞，2）肌肉代谢物诱发的释放， 单核细胞，和3）单核细胞的DNA甲基化模式和表观遗传年龄;目的2：确定单核细胞的DNA甲基化模式和表观遗传年龄。 免疫系统和DNA甲基化变化与临床表型和代谢组的关系 与匹配的对照组相比，FM患者的特征。我们的主要目标将集中在活动引起的 疼痛，次要目的是检查与其他症状的关系，包括疲劳。这项研究将 为FM中潜在的免疫细胞机制提供了新的见解。这些新的研究有可能 鉴定与免疫细胞功能相关的诊断性和潜在治疗性FM生物标志物。多- 机构和多学科研究团队在临床和转化科学方面具有必要的专业知识， 免疫功能和表观遗传学，以有效地利用为父母补助金收集的数据。