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.

计划2 ME/CFS亚型的分子特征 摘要 我们提出了迄今为止最全面的项目，以了解代谢和转录 发生在ME/CFS中的扰动。研究人员在代谢组学和功能方面具有广泛的专业知识， 基因组学，以及获得来自ME/CFS和对照个体的良好表征的队列的库存样品。 我们还将通过项目3获得直立位挑战前后获得的样本， 锻炼的有一些有趣的迹象，从以前的，有限的研究表明，这两个代谢组学 而转录组学的方法可以让我们深入了解这种知之甚少的疾病。转录研究 在对循环白细胞进行的ME/CFS中，表明免疫细胞功能障碍和 改变的代谢特性，但通常在有限数量的个体上进行，使用较少的 比我们在当前项目中提出的更先进的转录谱。已发表的代谢组学研究 ME/CFS一直显示异常的证据，以及脂质紊乱的证据。 代谢和神经递质相关的途径。项目共同负责人Fiehn已经生成了 50例ME/CFS病例和50例对照的初步数据，显示结果支持脂质和神经递质 代谢异常，特别是涉及复合脂质和色氨酸代谢物。联合领导Greally's 一个小组将研究与Fiehn相同的患者，对先前发表的研究进行随访，重点关注外周血管疾病。 血液单核细胞（PBMC）转录模式。Greally小组开发了一种方法， 使用单细胞转录组学参考数据结合已发表的分析算法来测量 来自RNA-seq数据的PBMC中细胞亚型的比例。这使得基因表达的变化， PBMCs的异常可归因于细胞亚型比例的变化，或归因于 一个基因这是第一次，两个不同但各自有趣的生物事件被 区别-与ME/CFS相关的细胞亚型和转录改变。我们的分析重点是 项目2中代谢组学和转录组学信息的整合，但我们也将探索 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开始将高体重 体重指数和高脂血症与外周血白细胞DNA甲基化的变化， 甲基化被发现是由肥胖和高脂质水平诱导的。这代表了意想不到的逆转 因果关系的结果，连接代谢组学和转录调控机制，并作为一个 为本项目的衔接研究奠定了基础。我们的两个小组在代谢组学和 功能基因组研究，我们现在将集中在这种极其困难的疾病，但与早期 结果产生的见解，表明这些分子方法的承诺，在理解和发现 治疗ME/CFS患者的干预措施