Stress and Neuroimmune Dysergulation in Chronic Fatigue Patients

描述(申请人提供)：这是一份R21申请，建议对慢性疲劳综合征(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指导性动物模型研究并行进行。慢性疲劳综合征的主要症状是严重的持续性疲劳，休息不能缓解，运动或应激后持续24小时以上的疲劳和疼痛症状恶化。到目前为止，导致运动前后过度疲劳和疼痛的神经、内分泌和细胞因子的改变还没有明确的定义，但一些生物标记物的改变似乎在CFS患者的亚群中不同，表明这是一种异质性疾病。Alan Light博士正在对小鼠模型进行的新研究加强了ATP的潜在重要性，最近发现在劳后疲劳和肌肉疼痛(酸感内向电流或ASIC3、P2X5和TRPV1受体)中对ATP和乳酸做出反应的钠通道。凯瑟琳·莱特博士先前的临床研究表明，CFS患者与健康对照组、CFS患者与纤维肌痛(FMS)患者之间的应激源中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，可以在两年内完成，这将为以后的全面调查奠定基础。初步研究1建议在40名CFS患者和40名年龄、性别、体重和久坐不动的生活方式相匹配的对照组中评估这些潜在的失调生物标志物的协调模式。在精神和体力消耗之前、期间和之后立即以及运动后24小时，将反复评估反应。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、心率和血压(BP)对应激的反应性和总血管阻力)、肾上腺髓质(肾上腺素和去甲肾上腺素)、肾上腺皮质激素(皮质醇和ACTH)以及10个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分析和mRNA的定量表达(通过实时荧光聚合酶链式反应)来测量。实时定量聚合酶链式反应也将被用来测量组间差异和与运动相关的α和β肾上腺素能、ASIC、TRPV和P2X受体的表达变化。生物标记物的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有关。在初步研究2中，我们建议使用犹他州强大的资源，犹他州人口数据库，来探索CFS(合并和不合并FMS)的家族/遗传成分。生物遗传学家丽莎·坎农-奥尔布赖特博士将使用为犹他州家谱资源开发的两种方法：测试患者之间过度亲缘关系的假设，以及估计近亲和远亲的相对风险。熟悉性的重要发现将提供必要的试点证据，支持搜索所涉及的易感基因的重要性，并将识别高危家系资源，这些资源可用于后来的易感基因座搜索，或用于特定的药物或候选基因研究。总之，这两个试点项目将为神经免疫和遗传生物标记物的新方向提供一个潜在的宝贵的初步测试，这将增加对CFS的原因和进展的了解。

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.