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: 8667935
• 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/8667935
• 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; 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; endothelial dysfunction; 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）： 海湾战争退伍军人疾病（GWVI）是海湾战争退伍军人在1991年从部署返回后不久报告的一系列症状。GWVI的临床诊断标准基于慢性多系统疾病（CMI）标准，该标准基于统计症状聚类分析，分为三类：疲劳、情绪/认知和肌肉骨骼症状。目前，根据这些标准，大约40%的海湾战争退伍军人（超过1/4百万退伍军人）患有GWVI。 GWVI的病理生理机制尚不清楚，深入了解GWVI的机制可能会产生新的概念，研究方法和治疗干预措施。我们的初步研究将评估三个方面的血管和骨骼肌功能的25例GWVI和25名退伍军人对照无GWVI。 这项为期三年的试点研究的目的是确定下肢（腿部）内皮功能，运动功能和骨骼肌线粒体基因调控是否与GWVI退伍军人相比，退伍军人没有这种疾病。内皮功能障碍、骨骼肌功能损害和线粒体基因失调是GWVI的合理机制，因为海湾战争期间暴露于抗胆碱酯酶抑制剂可能影响这些功能，导致疲劳症状和其他肌肉骨骼症状。 我们将从特征鲜明的海湾战争退伍军人队列（德文斯堡队列）中招募受试者。大约60%的海湾战争退伍军人在这个队列符合明确的CMI标准GWVI。在这些队列中，症状和暴露于农药、溴化吡啶斯的明和低水平沙林暴露都有很好的记录。 病例组和对照组将在心导管实验室中使用多普勒血流导丝和血管内超声对股动脉微血管内皮功能进行有创评估。我们将使用这种技术来测量血流和动脉对动脉内输注内皮依赖性血管扩张剂乙酰胆碱10- 6 M、微血管内皮非依赖性扩张剂腺苷和大动脉血管扩张剂硝酸甘油的反应。PI在这类研究中有着悠久的记录。 1周后，受试者将进行广泛的骨骼肌功能评估，使用心肺运动试验测量无氧阈值、客观力量和疲劳评估以及6分钟步行试验。 本研究后一周，受试者将接受大腿骨骼肌活检。这将被分析 用于肌纤维类型，以及RT-PCR以评估负责调节线粒体呼吸功能的核和线粒体基因。 总体目标是评估病理生理和肌肉机制的差异，这将使我们能够设计更明确的MERIT审查提案，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。这项初步研究还可以提供对以疲劳和其他肌肉骨骼症状为特征的其他慢性疾病的见解，如外周血管疾病和充血性心力衰竭。