Stress and Neuroimmune Dysergulation in Chronic Fatigue Patients

慢性疲劳患者的压力和神经免疫失调

• 批准号: 7126226
• 负责人: Kathleen C Light
• 金额: $ 15.44万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7126226
• 关键词: biomarker; clinical research; cytokine; exercise; fatigue; genes; genetics; lighting; muscle; pain; receptor; rest; stress; stressor

DESCRIPTION (provided by applicant): This is an R21 application proposing novel translational investigations into neuroimmune and sensory dysregulation in patients with Chronic Fatigue Syndrome (CFS), to be performed in parallel with guiding animal model research also directed by our research group. The principal symptom of CFS is severe persistent fatigue unrelieved by rest, with a worsening of fatigue and pain symptoms after exercise or stress that persists more than 24 hours. To date, the neural, endocrine, and cytokine alterations that underlie this excessive pre- and post-exertion fatigue and pain are not well-defined, but some biomarker alterations appear to differ in subsets of CFS patients, indicating a heterogeneous disorder. Novel on-going research in mouse models directed by Dr. Alan Light reinforces the potential importance of ATP and recently identified sodium channels that respond to ATP and lactic acid in post- exertional fatigue and muscle pain (Acid Sensing Inward Current or ASIC3, P2X5 and TRPV1 receptors). Prior clinical research by Dr. Kathleen Light indicates adrenergic and cytokine response dysregulation during stressors in CFS patients vs. healthy controls, and between patients with CFS vs. fibromyalgia (FMS). Thus, the current translational R21 includes two related pilot studies that can be completed in 2 years that will lay the groundwork for a later full investigation. Pilot Study 1 proposes to assess coordinated patterns of these potentially dysregulated biomarkers in 40 CFS Patients vs. 40 Controls matched for age, sex, weight and sedentary lifestyle. Responses will be repeatedly assessed, before, during and immediately after mental exertion and physical exertion and 24 hours after exercise. Biomarkers include indexes of cardiovascular adrenergic activity (heart rate (HR) variability, HR and blood pressure (BP) reactivity to stress, and total vascular resistance), adrenomedullary (epinephrine and norepinephrine), adrenocortical (cortisol and ACTH), and ten pro- and anti-inflammatory cytokines/immune markers, measured by multiplexed fluorescent microsphere immunoassay of serum levels and by quantitative expression (via real-time PCR) of mRNA. Real-time PCR will also be used to measure group differences and exertion-related changes in expression of alpha- and beta-adrenergic, ASIC, TRPV and P2X receptors. Patterns of biomarker changes will be related to concurrent changes in the patient self-reported levels of fatigue and pain. In Pilot Study 2, we propose to use a powerful Utah resource, the Utah Population Database, to explore the familial/genetic component of CFS (with and without comorbid FMS). Biogeneticist Dr. Lisa Cannon-Albright will employ two methodologies developed for use with the Utah genealogy resource; a test of the hypothesis of excess relatedness among patients, and estimation of relative risks in close and distant relatives. Significant findings of familiality will provide necessary pilot evidence supporting the importance of a search for the predisposition genes involved, and will identify high-risk pedigree resources that could be used in a later search for predisposition loci, or in specific medication or candidate gene studies. Together, these two pilot projects will provide a potentially invaluable initial test of new directions in both neuroimmune and genetic biomarkers that will add to knowledge about the causes and progression of CFS.

描述（由申请人提供）：这是一项R21申请，提出对慢性疲劳综合征（CFS）患者的神经免疫和感觉失调进行新的翻译研究，与我们研究小组指导的动物模型研究平行进行。CFS的主要症状是严重的持续疲劳，休息无法缓解，运动或压力后疲劳和疼痛症状恶化，持续超过24小时。迄今为止，神经，内分泌和细胞因子的变化，这种过度的前和后劳累和疼痛的基础是没有明确的，但一些生物标志物的变化似乎不同的CFS患者的子集，表明异质性疾病。由Alan Light博士指导的小鼠模型中正在进行的新研究加强了ATP的潜在重要性，最近发现了在运动后疲劳和肌肉疼痛中对ATP和乳酸做出反应的钠通道（酸感应内向电流或ASIC 3，P2 X5和TRPV 1受体）。Kathleen Light博士先前的临床研究表明，CFS患者与健康对照组以及CFS患者与纤维肌痛（FMS）患者在压力刺激期间肾上腺素能和细胞因子反应失调。因此，目前的翻译R21包括两个相关的试点研究，可以在2年内完成，这将为以后的全面调查奠定基础。初步研究1建议评估40名CFS患者与40名年龄，性别，体重和久坐生活方式匹配的对照组中这些潜在失调的生物标志物的协调模式。将在脑力劳动和体力劳动之前、期间和之后立即以及运动后24小时重复评估反应。生物标志物包括心血管肾上腺素能活动指数（心率（HR）变异性、HR和血压（BP）对应激的反应性以及总血管阻力）、肾上腺髓质（肾上腺素和去甲肾上腺素），肾上腺皮质（皮质醇和ACTH），以及10种促炎和抗炎细胞因子/免疫标志物，通过血清水平的多重荧光微球免疫测定和通过mRNA的定量表达（通过实时PCR）来测量。实时PCR还将用于测量α-和β-肾上腺素能、ASIC、TRPV和P2 X受体表达的组差异和运动相关变化。生物标志物变化模式将与患者自我报告的疲劳和疼痛水平的同时变化相关。在初步研究2中，我们建议使用一个强大的犹他州资源，犹他州人口数据库，探讨CFS的家族/遗传组成部分（有和没有共病FMS）。生物遗传学家丽莎坎农奥尔布赖特博士将采用两种方法开发的使用与犹他州家谱资源;一个测试的假设过度相关的患者，并估计相对风险的近亲和远亲。家族性的重大发现将提供必要的试点证据，支持搜索易感基因的重要性，并将确定高风险的谱系资源，可用于以后的搜索易感基因座，或在特定的药物或候选基因的研究。总之，这两个试点项目将为神经免疫和遗传生物标志物的新方向提供潜在的宝贵初步测试，这将增加对CFS病因和进展的了解。