Brain mast cells and Chronic Fatigue Syndrome

脑肥大细胞与慢性疲劳综合症

• 批准号: 8090275
• 负责人: THEOHARIS C. THEOHARIDES
• 金额: $ 35万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8090275
• 关键词: Acute; Adrenal Glands; Affect; Amitriptyline; Anxiety; Biological Markers; Blood - brain barrier anatomy; Brain; Breeding; C57BL/6 Mouse; Calcium; Calcium ion; Cell physiology; Cell secretion; Cells; Child; Chronic; Chronic Fatigue Syndrome; Chymase; Cognitive; Complex; Corticotropin-Releasing Hormone; Development; Diagnosis; Disease; Drug Formulations; Emotional Stress; Encephalitis; Encephalomyelitis; Endocrine system; Fatigue; Female; Fibromyalgia; Flavonoids; Histamine; Histidine Decarboxylase; Hormonal; Human; Hypothalamic structure; IL8 gene; Immersion Investigative Technique; Immune; Immune system; Infection; Infectious Mononucleosis; Inflammation; Inflammatory; Interleukin-1; Interleukin-17; Interleukin-6; Interleukin-9; Interstitial Cystitis; Irritable Bowel Syndrome; Lead; Lipopolysaccharides; Luteolin; Malaise; Measures; Mediator of activation protein; Migraine; Mus; Muscle; Myalgia; Nerve; Nervous system structure; Neurasthenia; Neurons; Neuropeptides; Neurosecretory Systems; Neurotensin; Oils; Olives - dietary; Oral; Pathogenesis; Patients; Pattern; Peripheral; Pituitary Gland; Poly I-C; Post-Traumatic Stress Disorders; Prevalence; Production; Protocols documentation; Quercetin; Rattus; Reactive Oxygen Species; Reporting; Research; Role; Serum; Sleep disturbances; Somatostatin; Stimulus; Stress; Substance P; Swimming; Symptoms; TNF gene; Temporomandibular Joint Disorders; Testing; Thinking; Thymus Gland; Tissues; Toxin; Tricyclic Antidepressive Agents; UCP2 protein; Vacuum; Vascular Endothelial Growth Factors; Vascular Permeabilities; Viral; Virus Diseases; Water; absorption; base; beta-Endorphin; cytokine; effective therapy; gallocatechol; gastrointestinal; gastrointestinal symptom; human TSLP protein; hypothalamic-pituitary-adrenal axis; in vivo; innovation; mast cell; median eminence; mitochondrial dysfunction; novel; public health relevance; response; restraint stress; urocortin

DESCRIPTION (provided by applicant): Chronic Fatigue Syndrome (CFS) is a complex disease with a prevalence as high as 1%. CFS involves the nervous, hormonal and immune systems with symptoms that include fatigue, sleep disturbances, malaise, muscle aches, migraines, gastrointestinal complaints and cognitive problems. There may be some mitochondrial "dysfunction" in CFS patients. Many CFS patients demonstrate abnormal hypothalamic-pituitary- adrenal (HPA) axis activity, while stress worsens symptoms. Central and peripheral cytokines produced in response to viral infections or other inflammatory stimuli may be implicated, but there is no distinct pattern. CFS is often comorbid with other disorders that include fibromyalgia, interstitial cystitis (1C), irritable bowel syndrome (IBS), migraines and post-traumatic stress disorder. Neuroimmune interactions in CFS are still unknown creating a vacuum in diagnosis and treatment. Mast cells and their mediators have been implicated in all diseases that are comorbid with CFS. Brain mast cells are abundant in the median eminence where they are juxtaposed to corticotropin-releasing hormone (CRH)-positive neurons and CRH is secreted under stress and we showed that CRH activates mast cells through CRHR-1 leading to release of vascular endothelial growth factor (VEGF), increased vascular permeability and blood-brain-barrier (BBB) disruption. We recently showed an inverse relationship between expression of the mitochondrial uncoupling protein 2 (UCP2), which also regulates production of reactive oxygen species (ROS) and cytosolic calcium, and mast cell activation. There are no effective therapies for CFS. Tricyclic antidepressants have been reported to be beneficial, and our preliminary results indicate that only the tricyclic amitriptyline, and certain natural flavonoids can inhibit mast cell secretion and reduce intracellular calcium ion levels. Our hypothesis is that external triggers, along with CRH secreted by stress, activate diencephalic centers and mast cells, leading to release of proinflammatory and fatigue producing molecules, and these can be inhibited by select flavonoids. We will investigate: (1) the effect of CRH, viral poly(l:C), lipopolysaccharide (LPS), neurotensin (NT), substance P (SP) and thymus stromal lymphopoietin (TSMP) or restraint stress using female C57BL/6 mice on: (a) Fatigue using the forced water immersion test, (b) BBB disruption by measuring brain levels of the fluorescent marker AngioSense, as well as (c) Brain expression of histidine decarboxylase (HDC), CRN, beta-endorphin, IL-6, IL- 8, IL-17, somatostatin, TNF, mouse mast cell protease (MMCP), urocortin 2, UCP2 and VEGF; (2) The requirement for mast cells, for NT, SP, the CRHR involved, and the role of UCP2 in the endpoints studied in Aim 1 by using C57BL-derived WW mast cell deficient mice, NT -/- mice, SP -/- mice, CRHR-1; CRHR-2 -/- and UCP2 -/- mice, (3) Inhibitory effect of a flavonoid formulation containing luteolin/quercetin/olive kernel oil on endurance and brain biomarkers. The proposed research is hypothesis-driven, is based on strong preliminary evidence, is innovative with high likelihood for novel findings with applicability to humans. PUBLIC HEALTH RELEVANCE: Chronic Fatigue Syndrome (CFS) is neuroimmunoendocrine disorder with no definite pathogenesis or curative therapy presently available. Recent evidence suggests that CFS may be related to activation of a unique immune cell, the mast cell, which could disrupt gut-blood-brain barrier and lead to brain inflammation and release of fatigue causing molecules. The proposed research is expected to advance our understanding of how activation of brain mast cells can contribute to inflammation and CFS, as well as to the development of novel and effective treatments.

描述（由申请人提供）：慢性疲劳综合征（CFS）是一种复杂的疾病，患病率高达1%。CFS涉及神经、激素和免疫系统，症状包括疲劳、睡眠障碍、不适、肌肉疼痛、偏头痛、胃肠道不适和认知问题。CFS患者可能存在线粒体功能障碍。许多CFS患者表现出异常的下丘脑-垂体-肾上腺（HPA）轴的活动，而压力的症状。中枢和外周细胞因子产生的病毒感染或其他炎症刺激可能牵连，但没有明显的模式。CFS通常与其他疾病共病，包括纤维肌痛，间质性膀胱炎（1C），肠易激综合征（IBS），偏头痛和创伤后应激障碍。CFS中的神经免疫相互作用仍然是未知的，这在诊断和治疗方面造成了真空。肥大细胞及其介体与CFS共病的所有疾病有关。脑肥大细胞在正中隆起中丰富，在那里它们与促肾上腺皮质激素释放激素（CRH）阳性神经元并置，并且CRH在应激下分泌，并且我们表明CRH通过CRHR-1激活肥大细胞，导致血管内皮生长因子（VEGF）的释放、血管通透性增加和血脑屏障（BBB）破坏。我们最近发现，线粒体解偶联蛋白2（UCP 2）的表达，也调节活性氧（ROS）和胞浆钙的产生，肥大细胞活化之间的反比关系。没有有效的治疗CFS的方法。三环类抗抑郁药已被报道是有益的，我们的初步结果表明，只有三环阿米替林，和某些天然黄酮类化合物可以抑制肥大细胞分泌和降低细胞内钙离子水平。我们的假设是，外部触发因素，沿着由应激分泌的CRH，激活间脑中心和肥大细胞，导致促炎和疲劳产生分子的释放，这些可以被选择的黄酮类化合物抑制。我们将调查：（1）CRH、病毒聚（I：C）、脂多糖（LPS）、神经降压素（NT）、P物质（SP）和胸腺基质淋巴细胞生成素（TSMP）或束缚应激对雌性C57 BL/6小鼠的以下作用：（a）疲劳，使用强迫水浸试验，（B）通过测量荧光标记物AngioSense的脑水平来破坏BB B，以及（c）组氨酸脱羧酶（HDC）、CRN、β-内啡肽、IL-6、IL- 8、IL-17、生长抑素、TNF、小鼠肥大细胞蛋白酶（MMCP）、尿皮质素2（urocortin 2）、UCP 2和VEGF：（2）利用C57 BL衍生的WW肥大细胞缺陷小鼠、NT -/-小鼠、SP -/-小鼠、CRHR-1研究目的1中对肥大细胞、NT、SP、CRHR的需要以及UCP 2在终点中的作用; CRHR-2 -/-和UCP 2-/-小鼠，（3）含有木犀草素/槲皮素/橄榄仁油的类黄酮制剂对耐力和脑生物标志物的抑制作用。拟议的研究是假设驱动的，基于强有力的初步证据，具有创新性，很有可能获得适用于人类的新发现。 公共卫生关系：慢性疲劳综合征（CFS）是一种神经免疫内分泌紊乱性疾病，目前尚无明确的发病机制和有效的治疗方法.最近的证据表明，CFS可能与激活一种独特的免疫细胞肥大细胞有关，肥大细胞可能会破坏肠-血-脑屏障，导致大脑炎症和释放疲劳引起的分子。这项拟议的研究有望促进我们对脑肥大细胞活化如何促进炎症和CFS以及开发新型有效治疗方法的理解。