POST-EXERCISE ION CHANNEL GENE EXPRESSION BIOMARKERS IN CFS

CFS 运动后离子通道基因表达生物标志物

• 批准号: 8530964
• 负责人: Kathleen C Light
• 金额: $ 31.85万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8530964
• 关键词: ASIC channel; Address; Adrenergic Agents; Adrenergic Receptor; Adult; Affect; Age; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Arthralgia; Autonomic Dysfunction; Behavior; Behavioral; Biological Markers; Blood; Blood specimen; Brain; Cancer Patient; Capsaicin; Chronic; Chronic Fatigue Syndrome; Clinical; Clinical Management; Complex; Data; Databases; Diagnosis; Diagnostic; Disabled Persons; Disease; Disease remission; Economics; Endogenous depression; Environmental Risk Factor; Evaluation; Exercise; Family; Fatigue; Female; Fibromyalgia; Foundations; Functional disorder; Gender; Gene Expression; Gene Expression Profile; Gene Targeting; Genes; Genomics; Grant; Health; Hour; Hyperalgesia; Immune; Immunologic Markers; Individual; Inflammation; Inflammatory; Intervention; Investigation; Ion Channel; Joints; Knowledge; Leukocytes; Light; Link; Major Depressive Disorder; Malignant Neoplasms; Malignant neoplasm of prostate; Maximum Heart Rate; Measures; Memory; Metabolic; Moderate Exercise; Molecular Profiling; Multiple Sclerosis; Muscle; Muscle Fatigue; Myalgia; NIH Program Announcements; Neural Pathways; Pain; Pathway interactions; Patients; Peripheral; Physiological; Process; Publishing; Recording of previous events; Reporting; Research; Rest; Sampling; Scientist; Sensory; Sensory Receptors; Signal Transduction; Subgroup; Sympathetic Nervous System; Symptoms; TRPV1 gene; Temperature; Testing; Therapeutic Intervention; Time; Translational Research; Woman; Work; adrenergic; alpha-adrenergic receptor; base; beta-2 Adrenergic Receptors; beta-adrenergic receptor; capsaicin receptor; chronic pain; cytokine; innovation; male; meetings; men; neuropeptide Y; novel; receptor; receptor expression; response; sensory system; transcription factor; translational study

DESCRIPTION (provided by applicant): Chronic fatigue syndrome (CFS) is a complex multisymptom disorder that lacks objective blood-based biomarkers to use in diagnosis or clinical management of symptoms. Until recently, the peripheral processes involved in sensing muscle fatigue and pain were unknown; however, animal model studies by our group and others have clarified that a complex of ion channel receptors (including Acid Sensing Ion Channel-3 or ASIC3, ATP-sensing Purinergic 2X or P2X, and TRPV1 or capsaicin receptors) working together can detect increased metabolic by-products of work in muscle (ATP, lactate and pH changes). The numbers of these ion channel receptors are not fixed but can increase markedly in response to inflammatory processes or exercise. Supported by an R21 grant, we completed the first translational study to show dysregulation of these receptors in CFS after 25 min of moderate exercise (at 70% of age-predicted maximum heart rate). Using blood samples from 0.5 through 48 hours after exercise, CFS patients but not healthy controls showed both rapid and sustained increases in expression of these fatigue-sensing ion channel receptors present on leukocytes, together with increases in adrenergic alpha-2a, beta-1 and beta-2 receptors, and of both pro- and anti-inflammatory cytokines (Light, et al., 2009; White et al, 2010). We also recently showed that this post-exercise gene expression profile clearly differentiated patients with CFS from those with multiple sclerosis or fibromyalgia without comorbid CFS. The present study will add 140 additional subjects (including 70 CFS patients) to our existing database of 178 subjects that already includes 50 CFS patients and 50 controls, all studied using the same moderate exercise challenge, with blood sampling before and at 4 times after exercise. We plan to use both full genomic microarrays plus qPCR with targeted genes including ion channel and adrenergic receptors, immune genes, plus several new genes including XPR1, neuropeptide Y, HPA axis receptors, and transcription factors. Our aims are to examine whether: 1) using stringent STARD criteria for biomarker evaluation, CFS patients can be clearly differentiated from healthy controls using our post-exercise gene expression profiles, 2) CFS patients also differ from patients with major depressive disorder and patients with prostate cancer who have cancer-related fatigue; 3) these profiles reliably differentiate women vs. men with CFS, and subgroups of CFS patients identified by post-exercise increases vs. decreases in alpha-2a adrenergic receptor expression. This investigation will provide a strong test of these gene expression measures as diagnostic biomarkers in CFS as a whole and in key subgroups. It will also lay a foundation for further translational research on dysregulated pathways that may initiate, maintain or worsen symptoms of CFS, and provide potential targets for effective therapeutic intervention.

描述（由申请人提供）：慢性疲劳综合征（CFS）是一种复杂的多症状疾病，缺乏用于诊断或临床症状管理的客观血液生物标志物。直到最近，参与感觉肌肉疲劳和疼痛的外周过程还不清楚;然而，我们小组和其他人的动物模型研究已经阐明，（包括酸敏感离子通道-3或ASIC 3、ATP敏感嘌呤能2X或P2 X和TRPV 1或辣椒素受体）一起工作可以检测肌肉中增加的代谢副产物（ATP、乳酸盐和pH值变化）。这些离子通道受体的数量不是固定的，但可以在炎症过程或运动中显着增加。在R21基金的支持下，我们完成了第一项转化研究，以显示在25分钟的适度运动（70%的年龄预测最大心率）后CFS中这些受体的失调。使用运动后0.5至48小时的血液样品，CFS患者而非健康对照显示存在于白细胞上的这些疲劳感测离子通道受体的表达的快速和持续增加，以及肾上腺素能α-2 α、β-1和β-2受体以及促炎细胞因子和抗炎细胞因子的增加（Light，et al.，2009;白色等人，2010）。我们最近还发现，这种运动后基因表达谱清楚地区分了CFS患者与多发性硬化症或纤维肌痛患者，而没有合并CFS。本研究将在我们现有的178例受试者数据库中增加140例受试者（包括70例CFS患者），该数据库已经包括50例CFS患者和50例对照，所有研究均使用相同的中度运动挑战，在运动前和运动后4次采血。我们计划使用全基因组微阵列加qPCR与靶基因，包括离子通道和肾上腺素能受体，免疫基因，加上几个新的基因，包括XPR 1，神经肽Y，HPA轴受体和转录因子。我们的目的是检验：1）使用严格的STARD标准进行生物标志物评估，CFS患者是否可以通过我们的运动后基因表达谱与健康对照明确区分，2）CFS患者是否也与患有癌症相关疲劳的重度抑郁症患者和前列腺癌患者不同; 3）这些特征可靠地区分患有CFS的女性与男性，以及通过运动后α-2a肾上腺素能受体表达的增加与减少鉴定的CFS患者亚组。这项研究将提供一个强有力的测试，这些基因表达的措施作为诊断生物标志物在CFS作为一个整体，并在关键亚组。这也将为进一步的转化研究奠定基础，这些研究可能启动、维持或恶化CFS症状的失调途径，并为有效的治疗干预提供潜在的靶点。

项目成果

Dysregulation of leukocyte gene expression in women with medication-refractory depression versus healthy non-depressed controls.

• DOI: 10.1186/1471-244x-13-273
• 发表时间: 2013-10-21
• 期刊: BMC psychiatry
• 影响因子: 4.4
• 作者: Iacob E;Light KC;Tadler SC;Weeks HR;White AT;Hughen RW;Vanhaitsma TA;Bushnell L;Light AR
• 通讯作者: Light AR

Effect of Pregabalin on Cardiovascular Responses to Exercise and Postexercise Pain and Fatigue in Fibromyalgia: A Randomized, Double-Blind, Crossover Pilot Study.

普瑞巴林对纤维肌痛患者运动和运动后疼痛和疲劳的心血管反应的影响：一项随机、双盲、交叉试点研究。

• DOI: 10.1155/2015/136409
• 发表时间: 2015
• 期刊: Pain research and treatment
• 作者: White,AndreaT;Light,KathleenC;Bateman,Lucinda;Hughen,RonaldW;Vanhaitsma,TimothyA;Light,AlanR
• 通讯作者: Light,AlanR

Differing leukocyte gene expression profiles associated with fatigue in patients with prostate cancer versus chronic fatigue syndrome.

• DOI: 10.1016/j.psyneuen.2013.08.008
• 发表时间: 2013-12
• 期刊: PSYCHONEUROENDOCRINOLOGY
• 影响因子: 3.7
• 作者: Light, Kathleen C.;Agarwal, Neeraj;Lacob, Eli;White, Andrea T.;Kinney, Anita Y.;VanHaitsma, Timothy A.;Aizad, Hannah;Hughen, Ronald W.;Bateman, Lucinda;Light, Alan R.
• 通讯作者: Light, Alan R.