Vascular and Skeletal Muscle Function in Gulf War Veterans Illness

海湾战争退伍军人疾病中的血管和骨骼肌功能

• 批准号: 8387855
• 负责人: Scott Kinlay
• 金额: --
• 依托单位: VA BOSTON 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 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8387855
• 关键词: Acetylcholine; Adenosine; Affect; Anaerobic Threshold; Arteries; Behavior; Biochemical; Biogenesis; Biopsy; Blood Vessels; Boston; Bromides; Cardiac Catheterization Procedures; Cardiopulmonary; Case-Control Studies; Categories; Cholinesterase Inhibitors; Chronic; Chronic Disease; Clinical; Cluster Analysis; Cognition; Cognitive; Cohort Studies; Congestive Heart Failure; Data; Diagnostic; Dilator; Endothelium; Endothelium-Dependent Relaxing Factors; Environmental Exposure; Exercise; Exercise stress test; Exposure to; Fatigue; Functional disorder; Gene Expression; Gene Expression Regulation; Genes; Gulf War; Intervention; Intra-Arterial Infusions; Laboratories; Lead; Leg; Lower Extremity; Measures; Medical; Methodology; Mitochondria; Molecular; Moods; Muscle; Muscle Fatigue; Muscle Fibers; Muscle function; Musculoskeletal; Nitroglycerin; Nuclear; Nuclear Receptors; Oxygen; Peripheral; Peripheral Vascular Diseases; Pesticides; Physiological; Pilot Projects; Play; Recruitment Activity; Regulation; Reporting; Research; Research Design; Respiratory physiology; Reverse Transcriptase Polymerase Chain Reaction; Role; Sarin; Skeletal Muscle; Study Subject; Symptoms; Techniques; Testing; Thigh structure; Toxic Environmental Substances; Transcription Coactivator; Ultrasonography; Vasodilator Agents; Veterans; Walking; base; case control; chronic pain; cohort; design; femoral artery; functional disability; inhibitor/antagonist; insight; meetings; neuropsychological; novel; public health relevance; pyridostigmine; respiratory; response; uptake; Acetylcholine; Adenosine; Affect; Anaerobic Threshold; Arteries; Behavior; Biochemical; Biogenesis; Biopsy; Blood Vessels; Boston; Bromides; Cardiac Catheterization Procedures; Cardiopulmonary; Case-Control Studies; Categories; Cholinesterase Inhibitors; Chronic; Chronic Disease; Clinical; Cluster Analysis; Cognition; Cognitive; Cohort Studies; Congestive Heart Failure; Data; Diagnostic; Dilator; Endothelium; Endothelium-Dependent Relaxing Factors; Environmental Exposure; Exercise; Exercise stress test; Exposure to; Fatigue; Functional disorder; Gene Expression; Gene Expression Regulation; Genes; Gulf War; Intervention; Intra-Arterial Infusions; Laboratories; Lead; Leg; Lower Extremity; Measures; Medical; Methodology; Mitochondria; Molecular; Moods; Muscle; Muscle Fatigue; Muscle Fibers; Muscle function; Musculoskeletal; Nitroglycerin; Nuclear; Nuclear Receptors; Oxygen; Peripheral; Peripheral Vascular Diseases; Pesticides; Physiological; Pilot Projects; Play; Recruitment Activity; Regulation; Reporting; Research; Research Design; Respiratory physiology; Reverse Transcriptase Polymerase Chain Reaction; Role; Sarin; Skeletal Muscle; Study Subject; Symptoms; Techniques; Testing; Thigh structure; Toxic Environmental Substances; Transcription Coactivator; Ultrasonography; Vasodilator Agents; Veterans; Walking; base; case control; chronic pain; cohort; design; femoral artery; functional disability; inhibitor/antagonist; insight; meetings; neuropsychological; novel; public health relevance; pyridostigmine; respiratory; response; uptake

DESCRIPTION (provided by applicant): Gulf War Veterans Illness (GWVI) is a constellation of symptoms reported by Gulf War Veterans shortly after their return from deployment in 1991. Clinical diagnostic criteria for GWVI are based on chronic multisystem illness (CMI) criteria, which are based on statistical symptom cluster analysis resulting in three categories: fatigue, mood/ cognition, and musculoskeletal symptoms. Currently, approximately 40% of Gulf War Veterans (over 1/4 million Veterans) have GWVI by these criteria. The pathophysiological mechanisms underlying GWVI are not understood, and insights into the mechanisms of GWVI could lead to novel concepts, methodologies for study, and treatment interventions. Our Pilot study will assess three facets of vascular and skeletal muscle function in 25 cases with GWVI and 25 Veteran controls without GWVI. The purpose of the proposed three-year pilot study is to determine whether lower extremity (leg) endothelial function, exercise functions, and skeletal muscle mitochondrial gene regulation are different among Veterans with GWVI compared to Veterans' without this illness. Endothelial dysfunction, skeletal muscle functional impairment, and dysregulation of mitochondrial genes are plausible mechanisms for GWVI as exposure to anticholinesterase inhibitors during the Gulf War may affect these functions to cause symptoms of fatigue and other musculoskeletal symptoms. We will recruit subjects from a well characterized cohort of Gulf War Veterans (the Fort Devens Cohort). Approximately 60% of Gulf War Veterans in this cohort meet clear CMI criteria for GWVI. Symptoms and exposure to pesticides, pyridostigmine bromide, and low level sarin exposure are well documented in these cohorts. Cases and controls will have femoral artery microvascular endothelial function assessed invasively in the cardiac catheterization laboratory using Doppler flow wire and intravascular ultrasound. We will use this technique to measure flow and artery responses to intra-arterial infusions of the endothelium-dependent vasodilator acetylcholine 10-6M, the microvascular endothelium-independent dilator adenosine, and the large artery vasodilator nitroglycerin. The PI has a long track record in this type of research. After 1 week, subjects will have an extensive skeletal muscle functional assessment using cardiopulmonary exercise testing to measure anaerobic threshold, objective strength and fatigue assessments, and the 6-minute walk test. One week after this study, subjects will have a skeletal muscle biopsy from the thigh. This will be analyzed for muscle fiber type, and RT-PCR to assess nuclear and mitochondrial genes responsible for regulating mitochondrial respiratory function. The overall aim is to assess differences in pathophysiological and muscle mechanisms, which will allow us to design a more definitive MERIT Review proposal to assess differences in these functions and test potential treatments targeting these mechanisms. This Pilot study may also provide insights into other chronic illness characterized by fatigue and other musculoskeletal symptoms, such as peripheral vascular disease and congestive heart failure.

描述（由申请人提供）： Gulf War Veterans Illness (GWVI) is a constellation of symptoms reported by Gulf War Veterans shortly after their return from deployment in 1991. Clinical diagnostic criteria for GWVI are based on chronic multisystem illness (CMI) criteria, which are based on statistical symptom cluster analysis resulting in three categories: fatigue, mood/ cognition, and musculoskeletal symptoms.目前，通过这些标准，约有40％的海湾退伍军人（超过1/40万退伍军人）拥有GWVI。 GWVI的病理生理机制尚不清楚，对GWVI机制的见解可能导致新颖的概念，研究方法和治疗干预措施。我们的试点研究将评估25例GWVI和25例没有GWVI的老将对照的血管和骨骼肌功能的三个方面。 拟议的三年试点研究的目的是确定下肢（腿）内皮功能，运动功能和骨骼肌线粒体基因调节的调节与没有这种疾病的退伍军人相比，GWVI的退伍军人之间是否有所不同。内皮功能障碍，骨骼肌功能障碍和线粒体基因的失调是GWVI的合理机制，因为在海湾战争中暴露于抗雪氧化氢酶抑制剂时可能会影响这些功能以引起疲劳和其他肌肉骨骼骨骼症状。 我们将从墨西哥湾退伍军人（Fort Devens Cohort）中招募的臣民。该队列中约60％的海湾退伍军人符合GWVI的明确CMI标准。在这些队列中，症状和暴露于农药，吡啶斯汀溴溴和低水平的沙林暴露。 病例和对照组将使用多普勒流线和血管内超声检查在心脏导管实验室中对股动脉微血管内皮功能进行侵入式评估。我们将使用该技术来测量对内皮依赖性血管舒张剂乙酰胆碱的动脉内输注的流动和动脉反应10-6m，微血管内皮依赖性扩张剂腺苷和大动脉降压剂硝酸脂肪素。 PI在此类研究中具有很长的记录。 1周后，受试者将使用心肺运动测试进行广泛的骨骼肌功能评估，以测量厌氧阈值，客观强度和疲劳评估以及6分钟的步行测试。 这项研究后一周，受试者将进行大腿的骨骼肌活检。这将被分析 对于肌肉纤维类型和RT-PCR，用于评估负责调节线粒体呼吸功能的核和线粒体基因。 总体目的是评估病理生理和肌肉机制的差异，这将使我们能够设计一个更确定的优点审查建议，以评估这些功能的差异并测试针对这些机制的潜在治疗方法。这项试点研究还可以提供有关其他慢性疾病的见解，其特征是疲劳和其他肌肉骨骼症状，例如周围血管疾病和充血性心力衰竭。