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: 7282738
• 负责人: Kathleen C Light
• 金额: $ 18.69万
• 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 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7282738
• 关键词: ASIC channel; Acids; Address; Adrenergic Agents; Adrenergic Receptor; Age; Anemia; Animal Experimentation; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Autonomic nervous system; Bicycling; Biochemical; Biological Assay; Biological Markers; Blood Pressure; Blood specimen; Candidate Disease Gene; Cardiovascular system; Catecholamines; Chronic; Chronic Fatigue Syndrome; Clinic; Clinical Research; Clinical Trials; Clinics and Hospitals; Condition; Contracts; Corticotropin; Data; Databases; Defect; Diagnosis; Disease; Distant; Dose; Elements; Endocrine; Epidemiologic Studies; Epinephrine; Exclusion; Exercise; Exercise stress test; Exertion; Fatigue; Fibromyalgia; Gender; Genealogy; Genes; Genetic; Healthcare Systems; Heart Rate; Hereditary Disease; Hour; Hydrocortisone; Hypothyroidism; Immune System Diseases; Immune system; Immunoassay; Immunologic Markers; Individual; Inflammatory; Inherited; Interleukin-6; Investigation; Ion Channel; Knowledge; Lactic acid; Leadership; Life; Life Style; Light; Link; Malignant Neoplasms; Measures; Messenger RNA; Methodology; Methods; Microspheres; Modeling; Mus; Muscle; Muscle Fatigue; Myalgia; Nature; Neuraxis; Neurons; Neurosecretory Systems; Norepinephrine; Oncogenes; Onset of illness; P2X-receptor; Pain; Pain-Free; Palliative Care; Pathway interactions; Patient Self-Report; Patients; Pattern; Peripheral; Pharmaceutical Preparations; Phenotype; Physical Examination; Physiological Processes; Pilot Projects; Polymerase Chain Reaction; Population; Population Database; Predisposition; Principal Investigator; Process; Propranolol; Protocols documentation; Psyche structure; Psychophysiology; Recovery; Recurrence; Registries; Regulation; Relative (related person); Relative Risks; Reporting; Research; Research Personnel; Resources; Rest; Risk; Role; Role playing therapy; Saline; Secondary to; Sensory; Series; Serum; Signal Transduction; Sodium Channel; Speech; Spinal Ganglia; Stress; Study Subject; Subgroup; Susceptibility Gene; Symptoms; Syndrome; System; TRPV1 gene; Techniques; Temporomandibular Joint Disorders; Testing; Time; Universities; Up-Regulation; Utah; Vascular resistance; Weight; Work; acute stress; adrenergic; base; biological adaptation to stress; capsaicin receptor; chronic pain; chronic widespread pain; cytokine; day; experience; ganglion cell; genetic analysis; genetic epidemiology; genetic pedigree; hypothalamic-pituitary-adrenal axis; indexing; interest; mRNA Expression; man; mouse model; novel; novel strategies; patient registry; programs; purinoceptor P2X5; receptor; relating to nervous system; response; sedentary; sex; 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）：这是一份R21申请，提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转化研究，与我们研究小组指导的指导动物模型研究同时进行。CFS的主要症状是严重的持续性疲劳，不能休息缓解，在运动或压力后持续超过24小时的疲劳和疼痛症状恶化。迄今为止，神经、内分泌和细胞因子的改变是导致这种过度运动前和运动后疲劳和疼痛的根本原因，但一些生物标志物的改变似乎在CFS患者的亚群中有所不同，表明这是一种异质性疾病。在Alan Light博士的指导下，在小鼠模型中进行的新研究强化了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ASIC3， P2X5和TRPV1受体）。Kathleen Light博士先前的临床研究表明，在CFS患者与健康对照，以及CFS患者与纤维肌痛（FMS）患者之间，应激源时肾上腺素和细胞因子反应失调。因此，目前的转化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。试点研究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。在脑力劳动和体力劳动之前、期间和之后以及运动后24小时，将反复评估患者的反应。生物标志物包括心血管肾上腺素能活性（心率（HR）变异性、HR和血压（BP）应激反应性和血管总阻力）、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）和十种促炎性和抗炎性细胞因子/免疫标志物，这些指标通过血清水平的多重荧光微球免疫测定和mRNA的定量表达（通过实时PCR）来测量。Real-time PCR还将用于测量α -和β -肾上腺素能、ASIC、TRPV和P2X受体表达的组差异和运动相关变化。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步变化有关。在试点研究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，来探索CFS的家族/遗传成分（伴有和不伴有FMS）。生物遗传学家Lisa Cannon-Albright博士将采用两种开发用于犹他州家谱资源的方法；检验患者之间过度亲缘关系的假设，并估计近亲和远亲的相对风险。熟悉性的重大发现将提供必要的先导证据，支持寻找相关易感基因的重要性，并将确定高风险谱系资源，可用于以后寻找易感基因位点，或用于特定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志物的新方向提供潜在的宝贵初步测试，这将增加对慢性疲劳综合症病因和进展的了解。

项目成果

Genetics and Gene Expression Involving Stress and Distress Pathways in Fibromyalgia with and without Comorbid Chronic Fatigue Syndrome.

• DOI: 10.1155/2012/427869
• 发表时间: 2012
• 期刊: Pain research and treatment
• 作者: Light KC;White AT;Tadler S;Iacob E;Light AR
• 通讯作者: Light AR

Gene expression alterations at baseline and following moderate exercise in patients with Chronic Fatigue Syndrome and Fibromyalgia Syndrome.

• DOI: 10.1111/j.1365-2796.2011.02405.x
• 发表时间: 2012-01
• 期刊: Journal of internal medicine
• 影响因子: 11.1
• 作者: Light AR;Bateman L;Jo D;Hughen RW;Vanhaitsma TA;White AT;Light KC
• 通讯作者: Light KC

Differences in metabolite-detecting, adrenergic, and immune gene expression after moderate exercise in patients with chronic fatigue syndrome, patients with multiple sclerosis, and healthy controls.

慢性疲劳综合征患者、多发性硬化症患者和健康对照者适度运动后代谢物检测、肾上腺素能和免疫基因表达的差异。

• DOI: 10.1097/psy.0b013e31824152ed
• 发表时间: 2012
• 期刊: Psychosomatic medicine
• 影响因子: 3.3
• 作者: White,AndreaT;Light,AlanR;Hughen,RonaldW;Vanhaitsma,TimothyA;Light,KathleenC
• 通讯作者: Light,KathleenC