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

基本信息

批准号：
8236553
负责人：
Kathleen C Light
金额：
$ 33.64万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-15 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8236553
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

项目摘要

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. PUBLIC HEALTH RELEVANCE: Although debilitating fatigue is the hallmark of Chronic Fatigue Syndrome (CFS), other central symptoms include post-exertional worsening of symptoms, and chronic pain in muscles and joints. We recently reported (Light, White et al., 2009) that CFS patients show large post-exercise increases in leukocyte gene expression of sensory ion channel receptors, adrenergic receptors and certain immune markers while healthy subjects or patients with Multiple Sclerosis do not, and thus this profile shows promise as an objective biomarker for CFS. The present investigation will fill an important knowledge gap by comparing this post-exercise gene expression profile in CFS patients vs. patients with clinical depression and prostate cancer as well as healthy controls, and also in CFS subgroups, including gene expression-defined subgroups and male vs. female CFS subgroups.

描述（由申请人提供）：慢性疲劳综合征（CFS）是一种复杂的多症障碍，缺乏客观的基于血液的生物标志物，用于诊断或症状临床管理。直到最近，还不清楚感测肌肉疲劳和疼痛的外围过程。然而，我们小组和其他人的动物模型研究澄清说，一个复合物的离子通道受体（包括酸感应离子通道-3或ASIC3，ATP - 敏感性嘌呤能2X或P2X以及TRPV1或Capsaicin受体）一起工作可以检测到肌肉中肌肉中的代谢副产品的增加（ATP，Lactate和ph，Lactate and ph Cransic and Ph）。这些离子通道受体的数量不是固定的，但可以响应炎症过程或运动而明显增加。在R21赠款的支持下，我们完成了第一项翻译研究，以显示中度运动25分钟后CFS中这些受体的失调（占年龄预测的最大心率的70％）。 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).我们最近还表明，这种运动后的基因表达谱清楚地将CFS患者与没有合并症的多发性硬化症或纤维肌痛的患者分化。本研究将在我们现有的178名受试者的数据库中增加140名受试者（包括70名CFS患者），这些受试者已经包括50名CFS患者和50个对照，所有受试者均使用相同的适度运动挑战进行了研究，并在运动前和运动后4次进行了血液采样。我们计划使用全基因组微阵列加上QPCR以及靶向基因，包括离子通道和肾上腺素能受体，免疫基因，以及几种新基因，包括XPR1，神经肽Y，HPA轴受体和转录因子。我们的目的是检查：1）使用严格的明星标准进行生物标志物评估，CFS患者可以使用我们的运动后基因表达谱与健康对照明显区分开，2）CFS患者与患有主要抑郁症患者的患者和患有癌症相关疲劳患者的前抑郁症患者也有所不同； 3）这些特征可可靠地区分女性与CFS的男性，以及通过运动后增加的CFS患者亚组与α-2A肾上腺素能受体表达的降低相对于降低。这项研究将对这些基因表达度量进行有力测试，作为整体和关键亚组中CFS的诊断生物标志物。它还将为可能引发，维持或恶化CFS症状的失调途径的进一步转化研究奠定基础，并为有效的治疗干预提供潜在的靶标。公共卫生相关性：尽管使疲劳是慢性疲劳综合征（CFS）的标志，但其他核心症状包括症状后症状恶化，肌肉和关节的慢性疼痛。我们最近报道（Light，White等，2009），CFS患者表明，运动后基因表达的运动后基因表达大量增加，感觉离子通道受体，肾上腺素能受体和某些免疫标记物，而健康的受试者或多发性硬化症患者则没有，因此，这一特征表现为CFS的客观生物标志物。本研究将通过比较CFS患者与临床抑郁症和前列腺癌的患者以及健康对照组以及CFS亚组（包括基因表达定义定义的亚组和男性CFS vs.女性CFS与女性CFS）中的运动后基因表达谱，填补重要的知识差距。