Project 2: Molecular signatures for ME/CFS sub-types

项目 2：ME/CFS 亚型的分子特征

• 批准号: 10246407
• 负责人: John Greally
• 金额: $ 26.43万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-22 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10246407
• 关键词: Abbreviations; Acids; Affect; Algorithms; Amino Acids; Area; Arthralgia; Bile Acids; Biochemical Pathway; Biogenic Amines; Biological; Cell physiology; Cells; Ceramides; Characteristics; Chemical Structure; Choline; Chronic Fatigue Syndrome; Clinical; Complex; DNA Methylation; Data; Descriptor; Disease; Down-Regulation; Encyclopedias; Energy Metabolism; Epigenetic Process; Equilibrium; Etiology; Event; Exercise; Exercise Tolerance; Fatty Acids; Foundations; Functional disorder; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic Transcription; Genome; Goals; Headache; High Pressure Liquid Chromatography; Hour; Hydroxyl Radical; Hyperlipidemia; Immune; Immune system; Individual; Inflammation; Intervention; Investigation; Ketone Bodies; Laboratories; Lead; Leukocytes; Link; Lipids; Liquid Chromatography; Mass Spectrum Analysis; MeSH Thesaurus; Measurement; Measures; Memory Loss; Messenger RNA; Metabolic; Molecular; Molecular Profiling; Myalgia; Neurotransmitters; Obesity; Outcome; Oxides; Pathogenesis; Pathway Analysis; Pathway interactions; Patients; Pattern; Peripheral Blood Mononuclear Cell; Phospholipids; Plasma; Property; Publishing; RNA; RNA Sequences; Research; Research Personnel; Rest; Sampling; Source; Sphingomyelins; Statistical Methods; Steroids; Structure; Symptoms; Techniques; Testing; Thinness; Time; Transcript; Transcription Alteration; Triglycerides; Tryptophan; Variant; acylcarnitine; cohort; computerized tools; exhaustion; functional genomics; high body mass index; insight; lipid metabolism; metabolic profile; metabolomics; microbiome; molecular marker; neurotransmitter metabolism; peripheral blood; repository; single-cell RNA sequencing; statistics; stressor; sugar; tandem mass spectrometry; text searching; therapy development; time of flight mass spectrometry; transcriptome sequencing; transcriptomics; trimethyloxamine; ultra high pressure; validation studies

Project 2 Molecular signatures for ME/CFS sub-types Abstract We propose the most comprehensive project to date to understand the metabolic and transcriptional perturbations that occur in ME/CFS. The investigators have extensive expertise in metabolomics and functional genomics, and access to banked samples from well-characterized cohorts of ME/CFS and control individuals. We will also have access, through Project 3, to samples obtained before and after orthostatic challenge and exercise. There are some intriguing indications from prior, limited studies that suggest that both metabolomic and transcriptomic approaches could yield insights into this poorly understood disorder. Transcriptional studies in ME/CFS performed on circulating leukocytes have indicated a combination of immune cell dysfunction and altered metabolic properties, but have generally been performed on limited numbers of individuals using less advanced transcriptional profiling than we propose in the current project. Published metabolomic studies in ME/CFS have consistently revealed evidence for abnormalities, with evidence for disturbances in lipid metabolism and neurotransmitter-related pathways in particular. Project Co-Lead Fiehn has generated preliminary data for 50 ME/CFS cases and 50 controls, showing results that support lipid and neurotransmitter metabolism abnormalities, in particular involving complex lipids and tryptophan metabolites. Co-Lead Greally’s group will study the same patients as Fiehn, following up on prior published studies with a focus on peripheral blood mononuclear cell (PBMC) transcriptional patterns. The Greally group has developed an approach that uses single cell transcriptomic reference data in combination with a published analytical algorithm to measure the proportions of cell subtypes in PBMCs from RNA-seq data. This allows a gene expression change in PBMCs to be attributed to either a change in cell subtype proportion, or to a genuine alteration in expression of a gene. This allows, for the first time, two distinct but individually interesting biological events to be distinguished – the cell subtype and transcriptional alterations associated with ME/CFS. Our analytical focus is on the integration of the metabolomic and the transcriptomic information in Project 2, but we will also explore the associations with the clinical and laboratory data generated in the other projects, allowing us to link with microbiome and clinical variability. We note that the epigenetics field has recently begun to link both high body mass index and hyperlipidemia with changes in DNA methylation of peripheral blood leukocytes, with the DNA methylation found to be induced by both obesity and high lipid levels. This represented an unexpected reverse causation outcome that links metabolomic and transcriptional regulatory mechanisms, and serves as a foundation for the linked studies of this Project. Our two groups have extensive expertise in metabolomic and functional genomic research, which we will now be focusing on this extremely difficult disorder, but with early results yielding insights that indicate the promise of these molecular approaches in understanding and finding interventions to treat individuals with ME/CFS.

项目2 我/CFS子类型的分子特征 抽象的 我们提出了迄今为止最全面的项目，以了解代谢和转录 ME/CFS中发生的扰动。研究人员在代谢组学和功能方面拥有广泛的专业知识 基因组学，以及从ME/CFS和对照个体的特征良好的同类人群中获取库存样本。 我们还将通过项目3访问到处于敌对挑战之前和之后获得的样本， 锻炼。先验有限的研究有一些有趣的迹象表明，这两种代谢组 转录组方法可以对这种理解不良的疾病产生见解。转录研究 在循环白细胞上进行的me/cf中，已表明免疫细胞功能障碍和 代谢特性改变了，但通常是在有限数量的个人上进行的 高级转录分析比我们在当前项目中的建议。已发表的代谢组学研究 我/CF始终揭示了异常的证据，并有脂质灾难的证据 新陈代谢和神经递质相关的途径。 Project Coe Lead Fiehn已产生 50 ME/CFS病例和50个控件的初步数据，显示了支持脂质和神经递质的结果 代谢异常，特别是涉及复杂的脂质和色氨酸代谢产物。共同领导 小组将研究与Fiehn相同的患者，跟进先前发表的研究，重点是周围 血液单核细胞（PBMC）转录模式。大型小组已经开发了一种方法 将单细胞转录组参考数据与已发布的分析算法结合使用来测量 RNA-Seq数据中PBMC中细胞亚型的比例。这允许基因表达在变化 PBMC归因于细胞亚型比例的变化，或者是由 一个基因。这首先允许两个不同但个体有趣的生物学事件是 区分 - 与ME/CFS相关的细胞亚型和转录改变。我们的分析重点是 关于代谢组学和项目2中的转录组信息的整合，但我们还将探索 与其他项目中产生的临床和实验室数据的关联，使我们能够与 微生物组和临床变异性。我们注意到，表观遗传学领域最近已经开始联系两个高体 质量指数和高脂血症随周围血液白细胞的DNA甲基化变化，DNA 甲基化发现肥胖和高脂质水平诱导。这代表了意外的反向 连接代谢组和转录调节机制的因果结果，并用作 该项目链接研究的基础。我们的两个小组在代谢组学方面拥有广泛的专业知识和 功能性基因组研究，我们现在将重点放在这种非常困难的疾病上，但是早期 结果产生了见解，表明这些分子方法在理解和发现方面的希望 用我/CFS对待个人的干预措施。