Diagnostic Utility of mtDNA Content and Exercise Challenge in Veterans with GWI

线粒体DNA含量和运动挑战在GWI退伍军人中的诊断效用

• 批准号: 8507911
• 负责人: Michael J. Falvo
• 金额: --
• 依托单位: VA NEW JERSEY HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8507911
• 关键词: Accounting; Acute; Adult; Affect; Aromatic Polycyclic Hydrocarbons; Attention; Benzene; Biological Markers; Biological Process; Cardiopulmonary; Characteristics; Chronic; Chronic Fatigue Syndrome; Clinical; Coenzyme Q10; Communities; Conflict (Psychology); DNA Damage; Data; Diagnostic; Diagnostic tests; Disease; Electron Transport; Evidence based treatment; Exercise; Exercise stress test; Exposure to; Fatigue; Free Radical Scavengers; Functional disorder; Future; Gulf War; Headache; Hour; Human; Impaired cognition; Individual; Laboratories; Lead; Leukocytes; Literature; Malaise; Medical; Metabolic; Mitochondria; Mitochondrial DNA; Mitochondrial Diseases; Muscle; Nature; Nervous system structure; Pain; Particulate Matter; Performance; Peripheral; Physical therapy exercises; Pilot Projects; Ploidies; Production; Proliferating; Protocols documentation; Publishing; Reactive Oxygen Species; Recovery; Reporting; Respiratory Chain; Respiratory System; Rest; Role; Sensitivity and Specificity; Services; Sleep disturbances; Structure; Symptoms; System; Testing; Time; United States National Institutes of Health; Veterans; Work; antioxidant therapy; body system; cofactor; enzyme activity; experience; gastrointestinal; improved; meetings; mitochondrial dysfunction; mitochondrial membrane; muscular system; novel; novel diagnostics; respiratory; response; treatment strategy

DESCRIPTION (provided by applicant): One in four of the ~700,000 Veterans who served in the 1990 - 1991 Gulf War suffer from chronic multisystem illnesses, referred to as Gulf War Illness (GWI). GWI symptoms vary from fatigue and pain to cognitive dysfunction and sleep disturbances, but have been difficult to quantify and treat sometimes leading to their dismissal. That difficulty persists in characterizing what is known as GWI does not negate its existence. To this end, the scientific and medical communities are challenged to develop new diagnostic indicators that may lead to an enhanced understanding of the underlying pathophysiology of GWI and an ability to differentiate those with and without GWI. GWI is often characterized by its variability; however, there is some uniformity that warrants attention. For example, the diverse symptomatology involves multiple high-energy organ systems (e.g. muscular, central/autonomic nervous, respiratory, and gastrointestinal). Proper functioning of these systems requires efficiency on part of the mitochondria. According to the NIH, individuals with mitochondrial dysfunction or disease also present with a heterogeneous mix of symptoms that include exercise intolerance, fatigue, headache, and general weakness - symptoms shared with GWI. Additionally, mitochondrial DNA (mtDNA) damage is positively associated with exposure to particulate matter, benzene, and polycyclic aromatic hydrocarbons in humans. Therefore, analysis of mtDNA [and respiratory chain enzyme activity] may be an excellent candidate biomarker for endogenous and exogenous exposures of GWI. Damage to mtDNA would also likely affect exercise performance given the high-energy demands, resulting in profound fatigue and abnormal recovery. However, the literature in GWI has been mixed. Similar contradictory results have also been observed in individuals with chronic fatigue syndrome (CFS) - yet recent data suggests that these mixed results are accounted for by the limitation of a single exercise test which fails to consider the post-exertional malaise period characteristic to those with GWI and CFS. However, performing a second exercise test 24 hours after the first (i.e. repeated-bout) results in sizeable and significant differences between those with and without CFS. We suspect this repeated-bout exercise test paradigm will be of similar utility in this pilot study and be capable of differentiting those with and without GWI. [We propose to study independent and complementary markers of mitochondrial damage and dysfunction (i.e. mtDNA content, respiratory chain enzyme activity) and the response to a repeated-bout exercise test (i.e. breath-by-breath metabolic data, lactate, etc.) as a means of diagnostic testing for GWI.] Data derived from this pilot study may not only be important as potential objective indicators, but may also significantly improve our understanding of the GWI pathophysiology. Additionally, the potential translational merits could be rapid as efficacious treatment is currently available for mitochondrial dysfunction.

描述（由申请人提供）： 在 1990 年至 1991 年海湾战争中服役的约 700,000 名退伍军人中，四分之一患有慢性多系统疾病，称为海湾战争病 (GWI)。 GWI 症状多种多样，从疲劳和疼痛到认知功能障碍和睡眠障碍，但很难量化和治疗，有时会导致其被忽视。这种困难仍然存在于表征 所谓的GWI并不能否定它的存在。为此，科学界和医学界面临着开发新的诊断指标的挑战，这些指标可能会增强对 GWI 潜在病理生理学的理解，并能够区分患有和不患有 GWI 的人。 GWI 通常具有可变性的特点；然而，有一些一致性值得关注。例如，不同的症状涉及多个高能器官系统（例如肌肉、中枢/自主神经、呼吸和胃肠道）。这些系统的正常运作需要部分线粒体的效率。根据 NIH 的数据，患有线粒体功能障碍或疾病的个体也会出现多种不同的症状，包括运动不耐受、疲劳、头痛和全身无力——这些症状与 GWI 共有。此外，线粒体 DNA (mtDNA) 损伤与人类接触颗粒物、苯和多环芳烃呈正相关。因此，mtDNA [和呼吸链酶活性] 分析可能是 GWI 内源性和外源性暴露的极好的候选生物标志物。 鉴于高能量需求，线粒体 DNA 的损伤也可能会影响运动表现，导致严重疲劳和恢复异常。然而，GWI 中的文献褒贬不一。在患有慢性疲劳综合症 (CFS) 的个体中也观察到了类似的矛盾结果 - 但最近的数据表明，这些混合结果是由单一运动测试的局限性造成的，该测试未能考虑慢性疲劳综合症患者的运动后不适期特征。 GWI 和 CFS。然而，在第一次运动测试（即重复测试）后 24 小时进行第二次运动测试，会导致患有 CFS 的人和不患有 CFS 的人之间存在相当大且显着的差异。我们怀疑这种重复运动测试范式在本试验研究中将具有类似的效用，并且能够区分有和没有 GWI 的人。 [我们建议研究线粒体损伤和功能障碍的独立和互补标记（即 mtDNA 含量、呼吸链酶活性）以及对重复运动测试的反应（即每次呼吸代谢数据、乳酸等）， GWI 诊断测试的一种手段。] 从这项试点研究中获得的数据可能不仅作为潜在的客观指标很重要，而且还可能显着提高我们对 GWI 病理生理学的理解。此外，由于目前可以有效治疗线粒体功能障碍，因此潜在的转化价值可能会很快。