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R21申请，提出了对慢性疲劳综合征（CFS）患者神经免疫和感觉失调的新型翻译研究，与我们的研究小组同时指导的动物模型研究并行进行。 CFS的主要症状是严重的持续疲劳，因为静止而无法忍受，运动后的疲劳和疼痛症状恶化或压力持续超过24小时。迄今为止，神经，内分泌和细胞因子的改变是基于这种过度的前后和后后疲劳和疼痛的基础，但某些生物标志物改变似乎在CFS患者的子集中似乎有所不同，表明异质性疾病疾病。由Alan Light指导的小鼠模型中的新型研究增强了ATP的潜在重要性，并最近确定了钠通道的潜在重要性，这些通道对ATP和乳酸响应后施用后疲劳和肌肉疼痛（酸感测电流或ASIC3，P2X5和TRPV1受体）。 Kathleen Light博士的先前临床研究表明，CFS患者与健康对照组的压力源以及CFS患者与纤维肌痛（FMS）的患者之间的肾上腺素能和细胞因子反应失调。因此，当前的翻译R21包括两项相关的试点研究，可以在两年内完成，这将为以后的全面研究奠定基础。试点研究1提议评估40例CFS患者中这些潜在失调的生物标志物的协调模式与年龄，性别，体重和久坐的生活方式相匹配的40个对照。在精神劳累和身体劳累和运动后24小时内，将在，期间和之后反复评估反应。生物标志物包括心血管肾上腺素能活性的指数（心率（HR）变异性，人力资源和血压（BP）对压力的反应性，总血管耐药性），肾上腺肾上腺素（肾上腺素和去甲肾上腺素），肾上腺皮质和肾上腺素（皮质菌和杂种），以及抗脉络性的抗菌素，并触及型抗毒素，并抗抗脉络性。血清水平和通过定量表达（通过实时PCR）的荧光微球免疫测定mRNA。实时PCR还将用于测量α-和β-肾上腺素，ASIC，TRPV和P2X受体表达的群体差异和与劳累相关的变化。生物标志物变化的模式将与患者自我报告的疲劳和疼痛水平的同时变化有关。在试点研究2中，我们建议使用强大的犹他州资源，即犹他州人口数据库，以探索CFS的家族/遗传成分（有和没有合并症FMS）。生物遗传学家Lisa Cannon-Albright博士将采用两种供犹他州族谱资源使用的方法。测试患者之间过度相关性的假设以及近距离亲戚和遥远的亲戚的相对风险的估计。家族性的重大发现将提供必要的试点证据，以支持搜索所涉及的倾向基因的重要性，并将确定可用于以后搜索易感基因座或特定药物或候选基因研究的高风险谱系资源。总之，这两个试点项目将对神经免疫和遗传生物标志物中的新方向提供潜在的宝贵初始测试，这些测试将增加有关CFS的原因和进展的知识。