Oxidative Stress and Neuroinflammation: Co-conspirators in ME/CFS Pathophysiology

氧化应激和神经炎症：ME/CFS 病理生理学的共谋者

• 批准号: 10237223
• 负责人: Dikoma C Shungu
• 金额: $ 17.88万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10237223
• 关键词: Antioxidants; Applications Grants; Automobile Driving; Binding; Biocompatible Materials; Biological Assay; Blood specimen; Brain; Cardiopulmonary; Cells; Cerebrospinal Fluid; Cerebrovascular Circulation; Chronic; Chronic Fatigue Syndrome; Clinical; Complement; Complex; Data; Diagnosis; Diagnostic tests; Disease; Ensure; Exercise Test; Exertion; Fatigue; Fibromyalgia; Functional disorder; Gene Expression; Glutathione; Grant; Headache; Image; Immune; Immune System Diseases; Impairment; Inflammation; Irritable Bowel Syndrome; Knowledge; Ligands; Light; Link; Magnetic Resonance Spectroscopy; Malaise; Measures; Medical; Modeling; Multiple Chemical Sensitivity; Musculoskeletal Pain; N-acetylaspartate; Neuraxis; Outcome Measure; Oxidation-Reduction; Oxidative Stress; Pathogenicity; Patients; Peripheral; Persian Gulf Syndrome; Phosphocreatine; Phosphorus; Positron-Emission Tomography; Protons; Psychophysics; Public Health; Publishing; Questionnaires; Research; Rest; Scanning; Series; Short-Term Memory; Sleep disturbances; Sore Throat; Standardization; Symptoms; Techniques; Testing; Tissues; Uncertainty; Validation; Ventricular; Virulence Factors; base; circulating biomarkers; cohort; comorbidity; cytokine; functional disability; healthy volunteer; in vivo; indexing; inflammatory marker; inorganic phosphate; metabolomics; mitochondrial dysfunction; multidisciplinary; neurobiological mechanism; neuroimaging; neuroimaging marker; neuroinflammation; radioligand; specific biomarkers; symptomatology; synergism

PROJECT SUMMARY- PROJECT 1 Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex and medically unexplained illness, characterized by severe and debilitating fatigue that is not ameliorated by rest, and a constellation of symptoms, including musculoskeletal pain, sore throat, headaches, impaired concentration and short-term memory, and sleep disturbances. There are no scientifically validated tests for the illness, nor are there widely accepted therapies, leading to a great deal of uncertainty among clinicians when evaluating patients with prolonged, unexplained, and debilitating psycho-physical fatigue. Discovery of ME/CFS-specific biomarkers that can advance our understanding of the illness and its pathogenic mechanisms, differentiate the disorder from overlapping or comorbid diagnoses, and identify potential treatment targets is, therefore, currently a pressing and unmet research and public health need. The overall objective of this component of the present ME/CFS Collaborative Research Centers (CRCs) (U54) grant proposal is to begin filling this knowledge gap by using advanced neuroimaging techniques to test and then validate a pathophysiological model of ME/CFS which posits that oxidative stress and neuroinflammation and, possibly, a secondary mitochondrial dysfunction, are intertwined mechanisms in the etiopathogenesis of the disorder. Specifically, this study will aim to: (a) use proton magnetic resonance spectroscopy (1H MRS) to measure in vivo brain levels of glutathione (GSH) -- the most abundant antioxidant in the central nervous system – as a marker of oxidative stress; (b) use 1H MRS to measure in vivo brain levels of lactate and N-acetylaspartate (NAA) as markers of mitochondrial dysfunction; (c) use 31P MRS to measure in vivo brain levels of ATP, creatine phosphate (PCr) and inorganic phosphate (Pi) as complementary indices of mitochondrial dysfunction; (d) use in vivo brain 11C-(R)-PK11195 positron emission tomography (PET) to measure the binding potential of the ligand as a marker of neuroinflammation; and (f) measure circulating markers of neuroinflammation and oxidative stress for corroborating the proposed neuroimaging biomarkers. To ensure that the effects of the disease rather than those of the cohorts will be investigated, all the proposed neuroimaging scans and blood samples assays will be performed before and following symptom provocation with cardiopulmonary exercise tests (CPET), known to trigger post-exertional malaise (PEM) in ME/CFS patients. If successfully completed, the proposed research will have the potential to shed new light onto the neurobiological mechanisms and underpinnings of ME/CFS to advance our understanding of the illness, and establish ME/CFS-specific biomarkers for differentiating the disorder from overlapping or comorbid diagnoses, and identifying potential treatment targets.

项目摘要--项目1 肌痛性脑脊髓炎/慢性疲劳综合征(ME/CFS)是一种复杂的、医学上无法解释的疾病， 以严重和衰弱的疲劳为特征，不能通过休息来改善，以及一系列症状， 包括肌肉骨骼疼痛、喉咙痛、头痛、注意力不集中和短期记忆障碍，以及 睡眠障碍。目前还没有对这种疾病进行科学验证的测试，也没有被广泛接受的测试 治疗方法，导致临床医生在评估长期、 无法解释的，令人衰弱的身心疲劳。ME/CFS特异性生物标记物的发现 加深对本病及其致病机制的认识，将本病与 因此，目前迫切需要重叠或并存的诊断，并确定潜在的治疗目标 以及未得到满足的研究和公共卫生需求。本ME/CFS这一构成部分的总体目标 合作研究中心(CRCs)(U54)拨款提案旨在通过以下方式开始填补这一知识缺口 先进的神经成像技术用于测试并验证ME/CFS的病理生理模型，该模型假设 氧化应激和神经炎症，可能还有继发性线粒体功能障碍，都是 在疾病的病因中相互交织的机制。具体地说，这项研究的目标是：(A)使用质子 磁共振波谱(1HMRS)测量活体脑内谷胱甘肽(GSH)水平--最 中枢神经系统中丰富的抗氧化剂--作为氧化应激的标志；(B)使用~1H MRS 体内测定脑组织乳酸和N-乙酰天冬氨酸(NAA)水平，作为线粒体功能障碍的标志； (C)使用31P MRS测量活体脑内ATP、磷酸肌酸(PCr)和无机磷(PI)的水平 作为线粒体功能障碍的补充指标；(D)在体内使用脑11C-(R)-PK11195正电子 放射断层扫描(PET)测量作为神经炎症标志物的配体的结合潜力； 和(F)测量神经炎症和氧化应激的循环标志物，以证实所提出的 神经成像生物标志物。以确保疾病的影响而不是队列的影响 调查后，所有拟议的神经成像扫描和血样分析将在 在症状激发后进行心肺运动试验(CPET)，已知会触发运动后 ME/CFS患者的不适(PEM)。如果成功完成，拟议的研究将有可能 对ME/CFS的神经生物学机制和基础进行新的了解，以促进我们的 了解疾病，并建立ME/CFS特异性生物标记物，用于区分疾病和 重叠或并存的诊断，并确定潜在的治疗目标。