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）：慢性疲劳综合症（CFS）是一种复杂的多症状疾病，缺乏用于诊断或症状临床管理的客观血液生物标志物。直到最近，人们对感知肌肉疲劳和疼痛的外周过程仍知之甚少。然而，我们小组和其他人的动物模型研究已经阐明，离子通道受体复合物（包括酸感应离子通道 3 或 ASIC3、ATP 感应嘌呤能 2X 或 P2X 以及 TRPV1 或辣椒素受体）协同工作可以检测代谢增加肌肉工作的副产品（ATP、乳酸和 pH 值变化）。这些离子通道受体的数量不是固定的，但可以因炎症过程或运动而显着增加。在 R21 资助的支持下，我们完成了第一项转化研究，显示在 25 分钟适度运动（年龄预测最大心率的 70%）后，CFS 中这些受体的失调。使用运动后 0.5 至 48 小时的血液样本，CFS 患者（而非健康对照组）显示，白细胞上存在的这些疲劳感应离子通道受体的表达快速且持续增加，同时肾上腺素能 α-2a、β-1 和beta-2 受体以及促炎和抗炎细胞因子（Light 等，2009；White 等，2010）。我们最近还表明，这种运动后基因表达谱可以清楚地将慢性疲劳综合症患者与患有多发性硬化症或纤维肌痛但不伴有慢性疲劳综合症的患者区分开来。本研究将在我们现有的 178 名受试者数据库中再增加 140 名受试者（包括 70 名慢性疲劳综合症患者），该数据库已包括 50 名慢性疲劳综合症患者和 50 名对照者，所有研究均使用相同的适度运动挑战，并在运动前和运动后 4 次进行血液采样。我们计划使用全基因组微阵列和 qPCR 来检测目标基因，包括离子通道和肾上腺素受体、免疫基因，以及一些新基因，包括 XPR1、神经肽 Y、HPA 轴受体和转录因子。我们的目的是检查是否：1）使用严格的 STARD 标准进行生物标志物评估，使用我们的运动后基因表达谱可以将 CFS 患者与健康对照清楚地区分开来，2）CFS 患者也不同于重度抑郁症患者和患有抑郁症的患者。患有癌症相关疲劳的前列腺癌患者； 3) 这些特征可靠地区分了患有 CFS 的女性和男性，以及通过运动后 α-2a 肾上腺素受体表达的增加和减少来识别的 CFS 患者亚组。这项研究将对这些基因表达测量作为慢性疲劳综合征整体和关键亚组的诊断生物标志物进行强有力的测试。它还将为进一步对可能引发、维持或恶化 CFS 症状的失调途径进行转化研究奠定基础，并为有效的治疗干预提供潜在目标。公众健康相关性：尽管慢性疲劳综合症 (CFS) 的标志是使人衰弱，但其他主要症状包括劳累后症状恶化以及肌肉和关节慢性疼痛。我们最近报道（Light, White et al., 2009），CFS 患者在运动后感觉离子通道受体、肾上腺素能受体和某些免疫标志物的白细胞基因表达大幅增加，而健康受试者或多发性硬化症患者则没有，并且因此，该特征显示出作为 CFS 客观生物标志物的前景。本研究将通过比较 CFS 患者与临床抑郁症和前列腺癌患者以及健康对照的运动后基因表达谱，以及 CFS 亚组（包括基因表达定义的亚组和男性）来填补重要的知识空白。与女性 CFS 亚组相比。