Chronic Fatigue Syndrome: 2006
Keyword: Chronic Fatigue Syndrome
1. Grant Number:
1R01AR054647-01
PI Name:
LORTON, DIANNE
PI Email:
PI Title:
HEAD AND PRINCIPAL SCIENTIST
Project Title:
Human Spinal Cord Glial Cytokines and Chronic Pain
Abstract: DESCRIPTION (provided by applicant): Fibromyalgia (FM) is characterized by chronic pain, tenderness, and stiffness in skeletal muscle. FM afflicts 4 to 6 million people in the US, 80% of which are women. Chronic fatigue syndrome (CFS) is very similar to FM. About 75% of patients meeting the diagnostic criteria of CFS also meet the diagnostic criteria for FM. There is a linear increase in the prevalence of FM up to the eighth decade of life. Chronic pain in FM patients is not well managed in the clinic, severely affects their quality of life, and limits mobility and motor activities. We are proposing to establish a tissue bank to make brain and spinal cord tissue available to study FM. Further, we propose to use the collected spinal cord tissue to determine the extent to which chronic pain in FM patients is associated with glial activation and concomitant proinflammatory cytokine production. Glial activation is linked in animal models to pain facilitation. While studying rodent pain models has proven fruitful, there is a critical need to extend investigations from rodents to humans. Rodent studies predict that glial activation and glial proinflammatory products (e.g. tumor necrosis factor (TNF), interleukin-1 (IL-1) and IL-1B) will be key spinal mediators in human chronic pain. It is critical to test the extent that glia are involved in human pain regulation. It cannot be assumed based on animal data that glial activation and their proinflammatory cytokine products are associated with human chronic pain. Mechanisms of pain facilitation elucidated using animal models have at times proven disappointing when applied to human chronic pain. This is a critical problem because until this information becomes available, it will not be possible to develop drugs targeting glial activation or their inflammatory products for chronic pain treatment. The studies also will extend our knowledge of basic mechanisms in FM pain. The objectives of this application are 1) to increase enrollment of FM patients into the brain donation program at the Sun Health Research Institute (SHRI), collect relevant clinical data and to obtain blood, cerebrospinal fluid, spinal cords and brains from enrolled patients rapidly after death and 2) to determine the extent to which FM patients have glial activation or proinflammatory cytokine production in pain-processing areas of the brain and spinal cord using the tissue collected. These objectives will be fulfilled by completing the following Specific Aims: 1) we will actively recruit and enroll FM patients into the existing brain/spinal cord donation program at SHRI. 2) We will assess the extent to which there is immunohistochemical, mRNA or protein evidence of glial activation and proinflammatory cytokine production in spinal tissues of FM patients compared to age matched pain free controls. A research team that uniquely combines experts in pain research, FM, neurology, neuropsychology and personnel with extensive expertise with a neuroscience clinical research center and CMS tissue donation program have been assembled to complete these Aims.
Thesaurus Terms:
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Institution:
SUN HEALTH RESEARCH INSTITUTE
10515 W SANTA FE DRSUN CITY, AZ 85351
Fiscal Year:
2006
Department:
PHARMACOL & EXPER THERAPEUTICS
Project Start:
25-SEP-2006
Project End:
31-AUG-2010
ICD:
NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
IRG:
ZRG1
1. Grant Number:
1R21NS057821-01
PI Name:
LIGHT, KATHLEEN C.
PI Email:
PI Title:
PROFESSOR OF PSYCHIATRY
Project Title:
Stress and Neuroimmune Dysergulation in Chronic Fatigue Patients
IRG:
ZRG1
Abstract: 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 a- and |3-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.
Thesaurus Terms:
There are no thesaurus terms on file for this project.
Institution:
UNIVERSITY OF UTAH
75 South 2000 EastSALT LAKE CITY, UT 84112
Fiscal Year:
2006
Department:
ANESTHESIOLOGY
Project Start:
01-SEP-2006
Project End:
31-AUG-2008
ICD:
NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
IRG:
ZRG1
1. Grant Number:
1R21AA016701-01
PI Name:
THEOHARIDES, THEOHARIS C.
PI Email:
PI Title:
PROFESSOR OF PHARMACOLOGY, INTERNAL MEDICINE
Project Title:
Mast cells, antidepressants and chronic fatigue syndrome
Abstract: DESCRIPTION (provided by applicant): Chronic fatigue syndrome (CFS) is characterized by fatigue, malaise, sleep and autonomic disturbances; it is considered a neuroimmune disorder with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, precipitated by stress and associated with high disability. CFS often occurs with comorbid diseases such as fibromyalgia, irritable bowel syndrome (IBS), interstitial cystitis (1C) and migraines, all of which also worsen by stress. There are no reliable animal models for CFS. Mast cells have emerged as a major regulator of neuroimmune endocrine processes affected by stress and have been implicated in all comorbid diseases associated with CFS. We have shown that: (a) mast cells have functional associations with nerve endings; (b) acute stress activates mast cells, an action blocked by pretreatment with corticotropin-releasing hormone (CRH) neutralizing antiserum, (c) stress increases blood-brain-barrier (BBB) permeability, which is inhibited by the CRH-receptor-1 (CRH-R1) antagonist Antalarmin and does not develop in mast cell deficient W/W mice, (d) human mast cells express CRH receptors, activation of which leads to selective release of vascular endothelial growth factor (VEGF), (e) some of the stimulatory effects of CRH on mast cells are mediated by neurotensin (NT), which has been shown to regulate the HPA axis. Tricyclic antidepressants are helpful in CFS and in the other comorbid diseases, but this mechanism of action is unknown. Our preliminary results show that the tricyclic antidepressant amitriptyline can inhibit rat mast cell secretion and intracellular calcium ion levels. Hypothesis: CRH, or the structurally related urocortin (Ucn), secreted by stress activates diencephalic mast cells, either alone or together with other neuropeptides such as NT leading to release of molecules that contribute to the central pathogenesis of CFS, and secretion of which can be inhibited by tricyclic antidepressants. We will investigate: Aim 1. The dose-response (0.1-100 uM) and time-course (0.5,1,6, 24 h) effects of three different classes of antidepressants, (a) the tricyclic (amitriptyline, imipramine), (b) the selective serotonin uptake inhibitors (fluoxetine, sertraline) and (c) bupropion on secretion of histamine, IL-1, IL-6, IL-8, IL-13, TNF, tryptase and VEGF from normal human umbilical cord-derived cultured mast cells (hCBMCs) derived from CD34+ progenitors triggered by IL-1, CRH or Ucn (100 nM). Aim 2. The effect of those antidepressants shown to be effective in Aim 1 for their ability to inhibit "brain mast cells" developed by culturing human umbilical cord matrix stem cells (hCMSCs) that are CD34- in the presence of 10 nM IL-4 and nerve growth factor (NGF), stimulated as in Aim 1 q NT (0.1-100 mM). Results from these studies will further our understanding of molecules released in response to stress hormones and which antidepressants may be useful in inhibiting these effects. Future studies will build on these findings to develop in vitro and in vivo models of CFS and lead to clinical trials with select antidepressants or other molecules that inhibit brain mast cells.
Thesaurus Terms:
There are no thesaurus terms on file for this project.
Institution:
TUFTS UNIVERSITY BOSTON
136 HARRISON AVENUEBOSTON, MA 02111
Fiscal Year:
2006
Department:
PHARMACOL & EXPER THERAPEUTICS
Project Start:
20-SEP-2006
Project End:
31-AUG-2008
ICD:
NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
IRG:
ZRG1
1. Grant Number:
1R21AA016636-01
PI Name:
FLETCHER, MARY A.
PI Email:
PI Title:
DIRECTOR AND PROFESSOR OF MEDICINE, MICR
Project Title:
Neuropeptide Y and dipeptidyl-peptidase IV (CD26) in chronic fatigue syndrome
Abstract: DESCRIPTION (provided by applicant): According to the Centers for Disease Control (CDC) case definition, Chronic Fatigue Syndrome (CFS) is an illness of severe fatigue with defined associated symptoms that cannot be ascribed to any other pathologic condition. Although studies on CFS have increased in recent years, no unanimity of opinion regarding etiology has emerged. Several etiologies have been proposed, immunological, neuroendocrine, and autonomic, and yet no physiological mechanism has been consistently and uniquely related to CFS. It is probable that CFS encompasses sub-populations that share a common symptom profile yet are mediated by different factors. Neuropeptides such as neuropeptide Y (NPY) have long been proposed to play a role in the pathogenesis of inflammatory diseases. NPY is a 36 amino acid neuropeptide, which participates in the regulation of a large number of physiological and pathophysiological processes in the cardiorespiratory system, immune system, nervous system and endocrine system. In the periphery, NPY is concentrated in the sympathetic nerve endings and is released alone or with catecholamines. NPY receptors are present most cells of the immune system, including NK cells. NPY suppresses natural killer cell function (NKCC). Given the potential for adverse effects with a constant stimulus, down regulation mechanisms are essential for neuropeptides, including NPY. One regulator of NPY is dipeptidyl peptidase IV (CD26). Preliminary data from our lab indicate that CD26 concentrations on lymphocytes are abnormally low. The role of NPY in CFS is undefined. Our goal is to improve the understanding of CFS pathophysiology and to develop biomarkers useful in diagnosis, in defining subsets and in therapeutic trials. In this study, we will study one aspect of the neuroimmune relationship in CFS. Specific Aim 1 is to determine the extent to which patients, or a subset of patients who meet the CFS case definition have elevated NPY, as compared to healthy, sedentary controls. Specific Aim 2 is to determine the relationship of NPY to the cell surface concentration of (CD26) in patients with CFS as compared to controls. Specific Aim 3 is to define the relationship of NPY and CD26 to NKCC in CFS. Specific Aim 4 is to determine the relationship of NPY and CD26 to clinical severity in CFS patients.
Thesaurus Terms:
There are no thesaurus terms on file for this project.
Institution:
UNIVERSITY OF MIAMI-MEDICAL1507 Levante Avenue
CORAL GABLES, FL 33124
Fiscal Year:
2006
Department:
MEDICINE
Project Start:
30-SEP-2006
Project End:
31-AUG-2008
ICD:
NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
IRG:
ZRG1
1. Grant Number:
1R01ES015382-01
PI Name:
BARANIUK, JAMES N.
PI Email:
PI Title:
ASSOCIATE PROFESSOR OF MEDICINE
Project Title:
Proteomics of Cerebrospinal Fluid in Chronic Fatigue Syndrome
Abstract: DESCRIPTION (provided by applicant): HYPOTHESIS: Central nervous system dysfunction is a central pathogenic mechanism in the CFS spectrum of illnesses. Cerebrospinal fluid provides a "window" into potential dysfunctional regulatory, innate immune, and neurological pathways. Neurons, glial cells, epithelial choroid plexus and leptomeningeal cells may be sources of CFS-related proteins. Despite the diverse clinical syndromes, the CFS-related proteome is the same, suggesting a unified pathogenesis. DATA: We have performed tandem mass spectrometry (MS-MS) on cerebrospinal fluid from CFS and healthy control subjects. Traditional and support vector machine (SVM) learning statistical analyses identified nearly identical CFS-related proteomes. A specific pattern of proteins (biosignature) predicted CFS with a significant odds ratio of 34.5 and concordance of 80%. Amyloidogenic proteins, antiproteases, Ig lambda, heme and Fe scavengers, and regulatory prohormones were associated with CFS. This is the first predictive model of CFS to be defined solely from objective data. PLAN: Recruit a new set of CFS and HC subjects (n=50 per group, "cohort 4") to a cross-sectional "training-test" study design. (A) Perform qualitative MS-MS to identify proteins in all samples of cohort 4. Train the SVM algorithm with cohort 4, then test the output "classifier" on an independent set of 42 samples (cohort 3). Determine the prediction accuracy, sensitivity and specificity of the SVM classifier. (B) Perform quantitative MS-MS on pooled CFS and pooled control samples by labeling one with O16 and the other with O18. Mix the samples and identify peptides (and their parent proteins) with O16/O18 ratios that are significantly higher or lower in CFS than controls. (C) These CFS-related proteins will be measured using novel, high sensitivity, luciferase- fusion protein competition immunoassays. Significant concentrations differences between CFS and control and between the 2 cohorts will define protein biomarkers and their sensitivity, specificity and predictive accuracy. (D) Subjective psychometric and other input variables will be tested by SVM learning to define a highly predictive model of CFS. The subjective results and objective proteomic results will also be analyzed to determine if the biomarkers are highly correlated with fatigue, systemic hyperalgesia, or other components of the CFS spectrum of illness. These methods and biomarkers may be of diagnostic value. They will be useful for assessing longitudinal changes in disease severity, phenotype, or the effects of treatment.
Thesaurus Terms:
biomarker, cerebrospinal fluid, chronic fatigue syndrome, fibromyalgia, proteomics
blood brain barrier, functional ability, protein quantitation /detection
bioinformatics, clinical research, human subject, liquid chromatography, mass spectrometry, questionnaire, radiotracer
Institution:
GEORGETOWN UNIVERSITY37TH AND O STS NW
WASHINGTON, DC 20057
Fiscal Year:
2006
Department:
MEDICINE
Project Start:
14-JUL-2006
Project End:
30-APR-2010
ICD:
NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
IRG:
ZRG1
1. Grant Number:
1R01NS055672-01
PI Name:
ANTONI, MICHAEL H.
PI Email:
PI Title:
Project Title:
Cognitive Behavioral Stress Management for Chronic Fatigue Syndrome
Abstract: DESCRIPTION (provided by applicant): This is a 4-year study that uses a 10-week telephone based cognitive behavioral stress management intervention (T-CBSM) to illuminate neuroimmune mechanisms underlying the effects of stress and stress management on physical health status and immune regulation in individuals with chronic fatigue syndrome (CFS) relative to participants receiving a health promotion telephone (T-HP) intervention. CFS is characterized by physical symptoms which bring about severe limitations in lifestyle behaviors and vocational activities. Associated symptoms include debilitating fatigue, low grade fever, lymph node pain and tenderness, cognitive difficulties, and mood changes. There is growing evidence that CFS patients may also show abnormalities in HPA axis functioning and on several indices of immune functioning. Chronic stress is also associated with a flattened diurnal secretion pattern for cortisol. An inability to maintain regulation in the HPA axis may contribute to the pathophysiology of CFS via diminished control of pro-inflammatory cytokines and associated physical symptoms related to chronic immune activation and inflammation. Given the debilitating nature of CFS, we propose to deliver the T-CBSM intervention through a telecommunications system (i.e. Telecare) designed to enhance access to formal and informal care for a population that may have difficulty accessing traditional psychotherapeutic settings. In our prior work with individuals with CFS, we have shown that individuals in a structured group CBSM intervention report significantly improved quality of life, perceived stress, fatigue, memory, muscle pain, and post-exertional malaise compared to individuals in the control condition. The Telecare system has been successful in delivering a supportive intervention for older caregivers of dementia patients. This study is novel in expanding our prior work to individuals with CFS who have reported difficulty participating in structured groups due to physical burden. The study design is a 2 X 3 randomized experimental design with group (T-CBSM, n=60 vs. T-HP, n=60) as the between-group factor, and time (Pre-intervention, Post-intervention and 6 month follow-up) as the within-group factor. Our primary objective is to evaluate the extent to which a T-CBSM intervention Aimed at building skills in anxiety reduction, distress tolerance, stressor appraisals, and adaptive coping strategies may improve physical health status and immune regulation in CFS by modulating neuroimmune interactions.
Thesaurus Terms:
There are no thesaurus terms on file for this project.
Institution:
UNIVERSITY OF MIAMI CORAL GABLES
1204 DICKINSON DR
CORAL GABLES, FL 33134
Fiscal Year:
2006
Department:
PSYCHOLOGY
Project Start:
05-SEP-2006
Project End:
31-JUL-2010
ICD:
NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
IRG:
ZRG1
1. Grant Number:
1R01NS055670-01
PI Name:
BIAGGIONI, ITALO
PI Email:
PI Title:
PROFESSOR
Project Title:
Autonomic Nervous System in Chronic Fatigue Syndrome
Abstract: DESCRIPTION (provided by applicant): The overall goal of this application is to determine the role of the autonomic nervous system in the abnormalities associated with Chronic Fatigue Syndrome. We propose to test the hypothesis that the sympathetic nervous system contributes to the cardiovascular and inflammatory abnormalities present in the Chronic Fatigue Syndrome (CFS) and, in particular in the subset of patients characterized by postural tachycardia (POTS). CFS and POTS are seen mostly in otherwise normal young women, and are the cause of significant disability. Our preliminary indicates a decrease in plasma volume in patients with POTS, which can contribute to, and be the consequence of, sympathetic activation. Our preliminary studies also indicate an interaction between the sympathetic nervous system and nitric oxide mechanisms; this may also create a negative feedback mechanism whereby a decrease nitric oxide results in sympathetic activation, and increased sympathetic activity results in impaired nitric oxide mechanisms. We have developed a paradigm that will allow us to define selectively the contribution of endothelial nitric oxide to blood pressure regulation and will apply this approach to patients with CFS and POTS. In addition, our preliminary studies indicate that sympathetic activity is associated with inflammatory processes. In particular, C-reactive protein are increased in patients with POTS and, conversely, decreased in patients with low sympathetic tone due to pure autonomic unsuccessful undertaking. We propose to measure validated indices of sympathetic activity, inflammation and oxidative stress in patients with CFS and POTS, and compare them to appropriate control groups, including patients with CFS without POTS, POTS without CFS, and normal controls. If our hypothesis is correct, and sympathetic activity contributes to the pathophysiology of CFS, then chronic inhibition of sympathetic tone will result in improvement of symptoms, cardiovascular alterations, volume defects, and inflammatory abnormalities present in CFS.
Thesaurus Terms:
There are no thesaurus terms on file for this project.
Institution:
VANDERBILT UNIVERSITYMedical Center
NASHVILLE, TN 372036869
Fiscal Year:
2006
Department:
MEDICINE
Project Start:
15-SEP-2006
Project End:
31-AUG-2010
ICD:
NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
IRG:
ZRG1