Full Text PA-96-070
 
CHRONIC FATIGUE SYNDROME PATHOPHYSIOLOGY
 
NIH GUIDE, Volume 25, Number 28, August 16, 1996
 
PA NUMBER:  PA-96-070
 
P.T. 34

Keywords: 
  Chronic Fatigue 
  Biomedical Research, Multidiscipl 

 
National Institute of Allergy and Infectious Diseases
National Institute of Arthritis and Musculoskeletal and Skin Diseases
National Institute of Mental Health
National Heart, Lung, and Blood Institute
National Institute of Environmental Health Sciences
National Institute of Nursing Research
National Institute of Diabetes and Digestive and Kidney Diseases
Office for Research on Women's Health
 
PURPOSE
 
The National Institute of Allergy and Infectious Diseases (NIAID),
National Institute of Arthritis and Musculoskeletal and Skin Diseases
(NIAMS), National Institute of Mental Health (NIMH), National Heart,
Lung, and Blood Institute (NHLBI), National Institute of
Environmental Health Sciences (NIEHS), National Institute of Diabetes
and Digestive and Kidney Diseases (NIDDK), National Institute of
Nursing Research (NINR), and the Office for Research on Women's
Health (ORWH) invite submission of investigator-initiated research
grant applications to support research on the pathophysiology of
chronic fatigue syndrome (CFS).  Applications are encouraged that
address new hypotheses and research gap areas or that are small
studies that explore new ideas.
 
HEALTHY PEOPLE 2000
 
The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000,"
a PHS-led national activity for setting priority areas.  This program
announcement, Chronic Fatigue Syndrome Pathophysiology, is related to
the priority area of chronic disabling diseases.  Potential
applicants may obtain a copy of "Healthy People 2000" (Full Report:
Stock No. 017-001-00474-0 or Summary Report:  Stock No.
017-001-00473-1) through the Superintendent of Documents, Government
Printing Office, Washington, DC 20402-0325 (telephone 202-512-1800).
 
ELIGIBILITY REQUIREMENTS
 
Applications may be submitted by domestic and foreign, for-profit and
non-profit organizations, public and private, such as universities,
colleges, hospitals, laboratories, units of State and local
governments, and eligible agencies of the Federal government.
Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as Principal Investigators.
Foreign institutions are not eligible for the First Independent
Research Support and Transition (FIRST) award (R29).
 
MECHANISM OF SUPPORT
 
Traditional research project grant (R01) and FIRST award (R29)
applications may be submitted in response to this program
announcement.  The R01 mechanism can be used to support small
studies.  Funds and time requested should be appropriate for the
research proposed.  Several Institutes use specialized mechanisms
such as the small research grant (R03); if you believe that your
project is appropriate for such a mechanism, consult the individuals
listed in the INQUIRIES section.
 
RESEARCH OBJECTIVES
 
Background
 
Chronic fatigue syndrome (CFS) is a multisystem syndrome
characterized by months of debilitating fatigue frequently associated
with myalgia, headache, sore throat, low grade fever, cognitive
complaints, gastrointestinal symptoms, and tender lymph nodes.  The
cause(s) and pathogenic mechanism(s) of the illness remain unknown.
The range of symptoms and comparisons of CFS patients with healthy
persons and with other chronically ill persons suggest subtle
perturbations in multiple physiological pathways. However, no single
marker or physiological alteration has been identified that can be
used to diagnose the syndrome. CFS is diagnosed three to four times
more frequently in women than in men and about 10 times more often in
white Americans than in other American population groups.
 
Research Objectives and Experimental Approaches
 
Well-designed studies are needed to provide a better understanding of
CFS pathogenesis with the goal of developing diagnostic and
intervention strategies.  Studies should include appropriate sample
sizes and test biologically rational hypotheses.  Selection criteria
and procedures for CFS cases and comparison groups should be
carefully delineated and appropriate for the hypothesis under study.
Factors which may explain or have an impact on CFS pathogenesis and
areas needing additional research include, but are not limited to:
 
o  low levels of cortisol and corticotropin-releasing hormone in CFS
patients in the absence of documented adrenal-hypothalamic axis
dysfunction attributable to other causes
 
o  overlapping symptomatology with neurally-mediated hypotension
 
o  role of cardiovascular regulatory centers in the brain stem,
hypothalamus, and higher cortical regions in the loss of the normal
control of blood pressure, heart rate, and contractility in CFS
patients.
 
o  dysfunctions in the baroreceptor, ventricular mechanoreceptor, and
other cardiovascular reflex pathways in the chronic fatigue syndrome
and in acute and chronic episodes of hypotension and syncope observed
in CFS patients.
 
o  development of novel cardiovascular pharmacological and
non-pharmacological interventions for treatment of CFS patients.
 
o  development of novel and objective cardiovascular markers for the
diagnosis of CFS.
 
o  interaction of cytokines with physiological systems other than the
immune system as effectors of CFS pathogenesis
 
o  increased frequency of sleep disturbances (hypersomnia or
insomnia)
 
o  overlapping symptomatology with fibromyalgia
 
o  role of neuroendocrine and neuroimmune functions in CFS
pathogenesis
 
o  hormonal effects, including in pregnancy, on illness severity
and/or symptomatic improvement
 
o  low tolerance to physical exertion manifested by prolonged
generalized fatigue after very moderate exercise
 
o  potential role of viruses or other infectious agents as markers of
disease pathogenesis or as co-factors in pathophysiological
processes.
 
o  lymphocyte patterns suggestive of immune activation (e.g.,
alterations in T-cell subsets number and function, altered cytokine
levels and function)
 
o  increased frequency of psychiatric diagnoses in CFS patients
(except those that would exclude an individual from the CFS case
definition)
 
o  increased frequency of atopy in CFS patients compared with the
U.S. population as a whole
 
o  role of environmental agents as etiological or pathophysiological
factors
 
o  gender specific factors in etiology and disease progression
 
o  highly active lifestyle prior to onset of CFS
 
o  epidemiology, natural history and pathophysiology of CFS in less
studied populations such as children, adolescents, minorities, men
 
o  demographic risk factors (gender, age, race, socioeconomic class)
 
Applications for small studies that explore new ideas are also
encouraged and could provide the basis for submission of a subsequent
larger grant application.
 
Study Design and Methodological Issues
 
Multidisciplinary studies and collaboration among investigators with
expertise in appropriate disciplines are encouraged.  When
investigators are at different institutions, individual R01
applications may include consortium arrangements.
 
Collaborative arrangements with on-going studies that provide patient
populations, specimens and data are encouraged.  Such arrangements
should be clearly delineated in the application.
 
The methodologies and personnel involved in
statistical/epidemiological analyses should be described in the
application and evident in the study design.  The hypothesis(es) to
be tested should be clearly stated.  The constructs and measurements
to be used operationally to obtain statistically and biologically
meaningful results should be clearly defined and enumerated.
 
The value of studies of patients or their specimens will be directly
related to the care exercised in selection and initial
characterization of cases and controls.  A detailed description of
case recruitment procedures, the criteria to be used for case
definition and the manner in which the criteria are to be applied
must be included.  Similar care should be given to descriptions of
enrollment of comparison groups.  Investigators are encouraged to use
the CFS case definition as presented in Fukuda, et. al., Annals of
Internal Medicine:  121, 953-9, 1994.  If other case definitions are
proposed, they should be clearly defined and the rationale for their
choice clearly delineated.
 
Applications to estimate the frequency of physiological or behavioral
variables or responses, or to address other quantitative aspects in
relevant populations should pay particular attention to sample sizes
required to attain the degree of precision sought or needed for
statistically and biologically meaningful results.  The reliability
and validity of markers chosen for measurement should be
demonstrated.   Applications attempting to examine interrelationships
among two or more separate factors are encouraged to the extent that
the types and numbers of subjects are sufficient for such
comparisons.
 
The measurement of many markers, including immunological,
virological, physiological and psychological markers, are dependent
on the measurement system chosen and its execution.  Thus, it is very
important that applicants clearly define the methodologies to be
used, the rationale for choosing that methodology and for validating
results as well as methods of collection, processing, and storage of
samples and data.  When conflicting results have been reported in the
literature, applicants should provide possible explanations for such
variability and indicate how their approach might resolve the issue.
 
INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN
SUBJECTS
 
It is the policy of the NIH that women and members of minority groups
and their subpopulations must be included in all NIH supported
biomedical and behavioral research projects involving human subjects,
unless a clear and compelling rationale and justification is provided
that inclusion is inappropriate with respect to the health of the
subjects or the purpose of the research.  This new policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43) and supersedes and strengthens the previous policies
(Concerning the Inclusion of Women in Study Populations, and
Concerning the Inclusion of Minorities in Study Populations) which
have been in effect since 1990.  The new policy contains some new
provisions that are substantially different from the 1990 policies.
 
All investigators proposing research involving human subjects should
read the "NIH Guidelines For Inclusion of Women and Minorities as
Subjects in Clinical Research", which have been published in the
Federal Register of March 28, 1994 (FR 59 14508-14513), and reprinted
in the NIH GUIDE FOR GRANTS AND CONTRACTS of March 18, 1994, Volume
23, Number 11.
 
Investigators may obtain copies from these sources or from the
program staff or contact persons listed below.  Program staff may
also provide additional relevant information concerning the policy.
 
APPLICATION PROCEDURES
 
Applications are to be submitted on the grant application form PHS
398 (rev. 5/95) and will be accepted on the standard application
deadlines as indicated in the application kit.  Applications kits are
available at most institutional offices of sponsored research and may
be obtained from the Grants Information Office, Office of Extramural
Outreach and Information Resources, National Institutes of Health,
6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone
301/710-0267, email:  ASKNIH@odrockm1.od.nih.gov.
 
Each application must be identified by checking "YES" on line 2 of
the PHS face page, and the number and title of this program
announcement must be typed in section 2.
 
The completed original and five legible, single-sided copies of the
application must be sent or delivered to:
 
DIVISION OF RESEARCH GRANTS
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD 20817 (for courier/overnight service)
 
FIRST (R29) award applications must include at least three sealed
letters of reference attached to the face page of the original
application.  FIRST (R29) award applications submitted without the
required number of reference letters will be considered incomplete
and will be returned without review.
 
Applicants from institutions that have a General Clinical Research
Center (GCRC) funded by the NIH National Center for Research
Resources may wish to identify the Center as a resource for
conducting the proposed research.  If so, a letter of agreement from
the GCRC Program Director must be included in the application
material.
 
REVIEW CONSIDERATIONS
 
Applications will be assigned on the basis of established PHS
referral guidelines.  Applications will be reviewed for scientific
and technical merit by study sections of the Division of Research
Grants, NIH, in accordance with the standard NIH peer review
procedures.  Following scientific/technical review, the applications
will receive secondary review by the appropriate national advisory
council.
 
Review Criteria
 
o  scientific, technical, or medical significance and originality of
proposed research;
 
o  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;
 
o  qualifications and research experience of the Principal
Investigator and staff, particularly, but not exclusively, in the
area of the proposed research;
 
o  availability of the resources necessary to perform the research;
 
o  appropriateness of the proposed budget and duration in relation to
the proposed research;
 
o  adequacy of plans to include both genders and minorities and their
subgroups as appropriate for the scientific goals of the research.
Plans for the recruitment and retention of subjects will also be
evaluated.
 
The initial review group will also examine the provisions for the
protection of human and animal subjects and the safety of the
research environment.
 
AWARD CRITERIA
 
Applications will compete for available funds with all other
favorably recommended applications assigned to an Institute or
Center.  The following will be considered when making funding
decisions:  quality of the proposed project as determined by peer
review, program balance among research areas of the announcement, and
availability of funds.
 
INQUIRIES
 
Written and telephone inquiries are encouraged.  The opportunity to
clarify any issues from potential applicants is welcome.
 
Direct inquiries regarding programmatic issues to:
 
Catherine Laughlin, Ph.D.
Division of Microbiology and Infectious Diseases
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 3A16 - MSC 7630
Bethesda, MD  20892-7630
Telephone:  (301) 496-7453
FAX:  (301) 402-0659
Email:  c128r@nih.gov
 
Susana A. Serrate-Sztein, Ph.D.
Arthritis Branch
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Natcher Building, Room 5AS37G
Bethesda, MD  20892
Telephone:  (301) 594-5032
FAX:  (301) 480-4543
Email:  szteins@ep.niams.nih.gov
 
Fred Altman, Ph.D.
Basic Prevention and Behavioral Medicine Research Branch
National Institute of Mental Health
Parklawn Building, Room 10-104
Rockville, MD  20857
Telephone:  (301) 443-4337
FAX:  (301) 443-4045
Email:  fa2w@nih.gov
 
Paul Velletri, Ph.D.
Division of Heart and Vascular Diseases
National Heart, Lung and Blood Institute
6701 Rockledge Drive, Suite 10193 - MSC 7956
Bethesda, MD  20892-7956
Telephone:  (301) 435-0560
FAX:  (301) 480-2849
Email:  p4v@cu.nih.gov
 
June Lunney, Ph.D. RN
Division of Extramural Programs
National Institute of Nursing Research
Building 45, Room 3AN12
Bethesda, MD  20892-6300
Telephone:  (301) 594-6908
FAX:  (301)480-8260
Email:  Jlunney@ep.ninr.nih.gov
 
Philip F. Smith, Ph.D.
Division of Diabetes, Endocrinology, and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8816
FAX:  (301) 480-3503
Email:  phil_smith@nih.gov
 
Annette G. Kirshner, Ph.D.
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
104 Alexander Drive, Box 12233, MD 3-03
Research Triangle Park, NC  27709
Telephone:  (919) 541-0488
FAX:  (919) 541-2843
Email:  kirshner@niehs.nih.gov
 
Direct inquiries regarding fiscal matters to:
 
Ms. Victoria Putprush
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
6003 Executive Boulevard, Room 4B35 - MSC 7610
Bethesda, MD  20892-7610
Telephone:  (301) 496-7075
FAX:  (301) 480-3780
Email:  vp8g@nih.gov
 
Ms. Carol Fitzpatrick
Grants Management Branch
National Institute of Arthritis and Musculoskeletal and Skin Diseases
45 Center Drive, Room 5AS-43K - MSC 6500
Bethesda, MD  20892-6500
Telephone:  (301) 594-3535
FAX:  (301) 480-5450
Email:  fitzpatc@ep.niams.nih.gov
 
Mr. Bruce Ringler
Grants Management Branch
National Institute of Mental Health
5600 Fishers Lane, Room 7C08
Rockville, MD  20857
Telephone:  (301) 443-3065
FAX:  (301) 443-6885
Email:  bringler%nimh@ngmsmtp.samhsa.gov
 
Mr. Jeff Carow
Grants Management Office
National Institute of Nursing Research
Building 45, Room 3AN32
Bethesda, MD  20892-6100
Telephone:  (301) 594-5974
FAX:  (301) 480-8256
Email:  Jcarow@ep.ninr.nih.gov
 
Ms. Donita Marconi
Division of Extamural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8860
Email:  dm150h@nih.gov
 
Mr. David L. Mineo
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
104 Alexander Drive, Box 12233, MD 2-01
Research Triangle Park, NC  27709
Telephone:  (919) 541-1373
FAX:  (919) 541-2860
Email:  mineo@niehs.nih.gov
 
AUTHORITY AND REGULATIONS
 
This program is described in the Catalog of Federal Domestic
Assistance No. 93.856, Microbiology and Infectious Disease Research;
No. 93.846, Arthritis, Musculoskeletal, and Skin Diseases Research;
No.93.837, Heart and Vascular Diseases Research; No. 93.361, Nursing
Research; No. 93.242, Mental Health Research; No. 93.847 Diabetes,
Endocrinology, and Metabolic Diseases Research; and Nos. 93.113,
93.115 Environmental Health Research.  Awards are made under
authorization of the Public Health Service Act, Title IV, Part A
(Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and
285) and administered under PHS grants policies and Federal
Regulations 42 CFR 52 and 45 CFR Part 74.  This program is not
subject to the intergovernmental review requirements of Executive
Order 12372 or Health Systems Agency review.
 
The Public Health Service (PHS) strongly encourages all grant and
contract recipients to provide a smoke-free work place and promote
the non-use of all tobacco products.  In addition, Public Law
103-227, the Pro-Children Act of 1994, prohibits smoking in certain
facilities (or in some cases, any portion of a facility) in which
regular or routine education, library, day care, health care or early
childhood development services are provided to children.  This is
consistent with the PHS mission to protect and advance the physical
and mental health of the American people.
 
.

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