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: 8678699
• 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/8678699
• 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年的70万退伍军人中，有四分之一患有慢性多系统疾病，被称为海湾战争疾病（GWI）。 GWI症状从疲劳和疼痛到认知功能障碍和睡眠障碍不等，但很难量化和治疗有时会导致他们解雇。这个困难仍然存在于表征 所谓的GWI并没有否定其存在。为此，科学和医学界面临挑战，要开发新的诊断指标，这可能会增强对GWI潜在的病理生理学的理解，并具有区分有和没有GWI的人的能力。 GWI通常以其可变性为特征。但是，有一些统一性值得关注。例如，多样化的症状涉及多个高能器官系统（例如肌肉，中央/自主神经，呼吸道和胃肠道）。这些系统的正确运行需要在线粒体的一部分中效率。根据NIH的说法，线粒体功能障碍或疾病的个体也表现出异质的症状混合，包括运动不耐受，疲劳，头痛和一般弱点 - 与GWI共同的症状。另外，线粒体DNA（mtDNA）损伤与人类中的颗粒物，苯和多环芳族烃的暴露呈正相关。因此，MTDNA [和呼吸链酶活性]的分析可能是GWI内源性和外源性暴露的极好的候选生物标志物。 鉴于高能量的需求，对MTDNA的损害也可能影响运动性能，从而导致严重的疲劳和异常恢复。但是，GWI中的文献混杂在一起。在患有慢性疲劳综合征（CFS）的个体中也观察到了类似的矛盾结果 - 但是最近的数据表明，这些混合的结果是通过单次运动测试的限制来解释的，该测试未能考虑GWI和CFS患者的效率不适。但是，在第一次（即重复出手）24小时（即反复出战）后进行第二次运动测试会导致有和没有CF的患者之间存在很大差异。我们怀疑这种重复的锻炼测试范例在这项试点研究中将具有相似的效用，并且能够与有和没有GWI的人不同。 [我们建议研究线粒体损伤和功能障碍（即mtDNA含量，呼吸链酶活性）的独立和互补标记，以及对重复进行锻炼测试的反应（即，逐呼吸的代谢数据，乳酸等）的响应可能是对GWI的诊断可能不明显的。提高我们对GWI病理生理学的理解。此外，由于目前可用于线粒体功能障碍的有效治疗，因此潜在的翻译优点可能很快。