Full Text PA-95-014

BASIC AND CLINICAL RESEARCH ON SLEEP AND WAKEFULNESS

NIH GUIDE, Volume 23, Number 45, December 23, 1994

PA NUMBER:  PA-95-014 (This PA has been reissued, see PA-05-046)

P.T. 34

Keywords: 
  Sleep Disorders 
  Neurophysiology 
  Neuroscience 
  Etiology 
  Pathophysiology 

National Heart, Lung, and Blood Institute
National Institute on Aging
National Institute on Alcohol Abuse and Alcoholism
National Institute of Child Health and Human Development
National Institute on Drug Abuse
National Institute of Mental Health
National Institute of Neurological Disorders and Stroke
National Institute of Nursing Research

PURPOSE

Sleep disturbances affect a wide range of age groups and practically
every segment of society is profoundly affected by the absence of
healthful patterns of sleep and wakefulness.  It is now apparent that
sleep disorders, disturbances of sleep, and sleep deprivation are
major public health concerns.  Recent estimates suggest that as many
as 40 million people may suffer from chronic or intermittent
disorders of sleep.  Many of these people remain undiagnosed and
untreated, the consequences of which include reduced productivity,
lowered cognitive performance, increased likelihood of accidents,
higher risk of morbidity and mortality and decreased quality of life.

Research in sleep and sleep disorders has increased steadily over the
past decade and basic research is rapidly becoming relevant to
clinical problems.  However, despite this growth in sleep research,
the neurobiological mechanisms underlying sleep and wakefulness and
many of the clinical manifestations affected by sleep remain largely
unknown.  It is now recognized that the sleeping brain is not in an
inactive phase of existence, but rather is undergoing a complex set
of active physiological and behavioral processes.  Improved
understanding of the fundamental nature of sleep, how sleep affects
neural function, and how the central nervous system is modified by
sleep can begin to provide a means to primary prevention of sleep
disorders to reduce the economic and social impact of sleep/wake
disturbances, and to significantly improve life expectancy and
overall quality of life of all people across the lifespan.

The purpose of this broad based sleep research program announcement
is to inform the scientific community of the interests of the various
Institutes at the National Institutes of Health (NIH) and to
stimulate, foster, and coordinate a wide range of basic and clinical
studies on sleep and wakefulness as they relate to the missions of
these Institutes.  These areas include, but are not limited to:  (1)
the neuroscience and behavioral science of sleep; (2) the molecular
and cellular mechanisms of sleep and circadian rhythms across the
life span; (3) the development of sleep from fetal life through
infancy; (4) the neurobiologic role of dreaming in humans; (5) the
etiologic factors and pathophysiology of transient or persistent
insomnia; and (6) the treatment of sleep disorders.

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, Basic and Clinical Research on Sleep and Wakefulness,
is related to the fundamental research areas of the Decade of the
Brain, and to the priority areas of chronic disabling conditions,
mental health and disorders, and clinical prevention services.
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 20402-9325 (telephone 202-783-3238).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by foreign and domestic, 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.
Foreign institutions are not eligible for small research grants
(R03s), First Independent Research Support and Transition (FIRST)
(R29) awards (R29s), and research program project (P01) awards.
Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as principal investigators.

MECHANISM OF SUPPORT

The mechanisms of support will be the investigator initiated research
project grant (R01), FIRST award (R29), and small research grants
(R03).  To apply for support of a more broadly based
multidisciplinary research program, the research program project
(P01) mechanism is suggested.  Policies that govern the research
grants programs of the NIH will prevail.  Details of eligibility for
the different funding mechanisms vary.  Applicants are strongly
advised to contact the program official listed under INQUIRIES for
additional information, particularly related to P01s and other
specific application procedures.

RESEARCH OBJECTIVES

There are a number of research directions that could be pursued to
provide new insights on the underlying neurobiological mechanisms and
clinical manifestations of sleep and wakefulness.  This program
announcement seeks to stimulate and encourage ideas that can compete
successfully for support through grants-in-aid from the NIH.  The
following examples of research topics, many of which may lend
themselves to studies in humans as well as in animal models and in
vitro systems, are intended to reflect the breadth of interests of
the NIH programs.  Neurophysiological, behavioral, neuroanatomical,
pharmacological, cellular, molecular and genetic techniques or
combinations of these approaches are appropriate.  All of the areas
identified cut across Institutes and programs and should not be
viewed as restricted to only one specific Institute.  Current NIH
referral guidelines will be used to assign grant applications to the
most appropriate NIH Institute based on the scientific focus of the
application.  The National Center on Sleep Disorders Research (NCSDR)
plans to coordinate sleep related activities at the NIH.  The
following topic areas are not intended to be comprehensive or
exclusive:

Neuroscience and Behavioral Science of Sleep.

o  Elucidate neural structures and mechanisms that control states of
sleep and wakefulness.

o  Examine how neural circuits controlling sleep are modulated
through emotions and stress, ethanol use or abuse, diseases or other
disorders.

o  Obtain a better understanding of behavioral and physiological
adaptations to sleep/wake cycles, hibernation, circadian and
biological rhythms.

o  Determine neural correlates of cognition during sleep including
learning and memory.

o  Utilize neural network models and theoretical approaches to
understand the transitions between wakefulness and different stages
of sleep.

o  Determine the homeostatic regulation of brain functions through
interactions of sleep-promoting circuits in the brain.

o  Examine the role of sleep in understanding the basic neurobiology
of substance and ethanol abuse.

o  Investigate the effects of drugs on the neurochemistry and
determination of sleep onset, dreaming, awakening and transition
between sleep and wakefulness.

o  Explore possible social factors and the development of sleep in
children and adolescents as a model for acquiring behavioral control
of homeostatic processes.

Molecular and Cellular Mechanisms of Sleep and Circadian Rhythms
Across the Life Span.

o  Identify genes, genetic mechanisms and heritable determinants in
controlling sleep or circadian systems.

o  Isolate and characterize gene products that are expressed during
sleep in order to identify molecules that alter intrinsic properties
of neurons during this state of altered awareness.

o  Elucidate the mechanisms through which various stimuli, such as
light, exercise, or endogenous factors (e.g., monoamines and
melatonin) entrain sleep and circadian rhythms in mammalian and
nonmammalian species, and any other sleep regulators such as the
immune system and the suprachiasmatic nucleus.

o  Identify age related molecular, cellular and structural changes in
the aging nervous system related to sleep and circadian systems.

o  Explore interventions, such as transplants of neuronal tissue,
hormone or growth factor replacements to understand underlying
mechanisms of age related alterations of sleep and circadian rhythms.

o  Apply noninvasive brain imaging techniques such as PET and MRI to
identify changes in metabolism in specific brain areas, localize
brain regulator mechanisms, and correlates of transitions between
sleep states, dreaming and wakefulness during development and in the
sleeping brain of older people.

Development of Sleep from Fetal Life Through Infancy.

o  Determine the role of sleep and sleep state organization during
fetal and infant development.

o  Identify potentially life threatening sleep disorders and
dysfunctions which emanate specifically from chronic maternal use of
alcohol, cigarette smoking and narcotic drugs.

o  Determine possible interactions between the developing immune
system and the organization of sleep/wake state that occur in the
first few months of life.

o  Explore the mechanisms underlying prenatal development of
biological clocks and the relationship between maternal and
fetal/neonatal behaviors necessary for establishing circadian
rhythms.

Neurobiologic Role of Dreaming in Humans.

o  Investigate the biological and behavioral functions and
significance of dreams, including the role of REM sleep in mammalian
evolution and memory.

o  Examine the role of non-REM sleep dreams and whether these are a
qualitatively different type of brain activity than REM sleep dreams.
Determine perceptual and cognitive influences on dream content.

o  Determine neural correlates of, and interactions between, sexual
or other motivational systems, the content of dreams and sensory
processing.

o  Employ multidisciplinary approaches utilizing metabolic and
electrophysiologic methods to correlate events that occur during REM
sleep with dreams involving non-visual sensory modalities.

o  Develop improved and more precise methods for identifying specific
sleep stages, and the occurrence, onset and termination of dreams
independent of waking recollections.

o  Correlate patterns of neuronal activity during REM sleep with
dreams having other sensory modalities such as audition, olfaction or
temperature regulation.

o  Develop better approaches to correlate subjective passage of time
in a dream with real time duration.

Etiologic Factors and Pathophysiology of Transient or Persistent
Insomnia.

o  Investigate the role of the thalamus and other brain substrates in
mediating insomnia.

o  Determine the relationship of insomnia to other medical conditions
such as neurological, cardiovascular and psychiatric diseases.
Determine physiological mechanisms that may account for the potential
link between poor sleep, insomnia and cardiovascular disease, and
whether insomnia may be predictive for future cardiovascular events.
Examine the relationship of insomnia with other sleep disorders such
as periodic movements of sleep and restless leg syndrome.

o  Investigate the role of persistent insomnia as a risk factor for
development of depression and anxiety disorders.  Determine the
prognostic aspects of sleep for depression, alcoholism and other
disorders; and the role of various sleep stages in predicting relapse
following successful treatment of depression.  Determine the
mechanisms underlying the anti-depressant effect of sleep deprivation
and changes associated with a night of recovery sleep.

o  Examine the effects of benzodiazepines on central nervous system
acquisition or encoding of new information and the process of memory
storage and recall.

o  Utilize sleep deprived, restricted, or disrupted models to
understand the fundamental mechanisms of insomnia and effects on
daytime function.

Treatment of Sleep Disorders and Co-Morbidity with Other Conditions

o  Investigate the interactions between brainstem control of
respiration and the neural mechanisms specific to sleep and
wakefulness, and the source of the respiratory variations during
sleep.

o  Investigate underlying autonomic mechanisms and physiological
interrelations between snoring, obesity, sleep apnea, hypertension,
and the regulation of sleep.

o  Determine the cellular and molecular basis of excessive daytime
sleepiness, particularly as it relates to sleep apnea.

o  Explore the pharmacology and role of hormones in respiratory
disorders of sleep.

o  Conduct studies on the efficacy of pharmacologic, behavioral and
psychotherapeutic interventions for specific types of insomnia.

o  Investigate the risks, benefits, long term safety, and efficacy of
hypnotic agents (i.e., benzodiazepines).  Examine the long term
efficacy of hypnotic agents in treating insomnia, especially whether
the long term use renders them ineffective or if prolonged use
actively disturbs sleep.  Investigate the role of hypnotic agents on
respiratory drive and autonomic function.

o  Determine the mechanisms underlying rebound insomnia and whether
or not long term use of hypnotic agents leads to risk of physical
dependence.

o  Develop and evaluate the best outcome variables and parameters to
assess the clinical significance for insomnia therapy.

o  Understand co-morbidity of sleep disorders with neurological
disorders to include but not limited to epilepsy, stroke, and
movement disorders.

o  Examine the effects of ethanol use on respiratory function during
sleep (e.g., sleep apnea).

o  Investigate the effects of sleep deprivation and use of ethanol
and other drugs of abuse on daytime drowsiness and behavioral
performance.

o  Understand co-morbidity of sleep and mental disorders

o  Explore mechanisms of environmental causes of sleep disturbances
such as drug abuse, stressors, toxins, or artificial zeitgebers.

o  Investigate sleep disorders in underserved and understudied
populations.

o  Investigate therapies that will ameliorate or eliminate sleep
disorders due to disruptions of circadian rhythms.

o  Characterize sleep disturbances in persons with physical
disabilities that result from traumatic injuries or chronic disease
and how they influence the course of rehabilitation.

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 justifications 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
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 20, 1994 (FR 59 14508-14513) and reprinted
in the NIH Guide for Grants and Contracts, Volume 23, Number 11,
March 18, 1994.

Investigators also may obtain copies of the policy from the program
staff listed under INQUIRIES.  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. 9/91) and will be accepted at the standard application
deadlines as indicated in the application kit.  Application kits are
available at most institutional offices of sponsored research and may
be obtained from the Office of Grants Information, Division of
Research Grants, National Institutes of Health, Westwood Building,
Room 449, Bethesda, MD 20892, telephone 301/435-0714.  The title and
number of the program announcement must be typed in Section 2a on the
face page of the application.

Applications for the FIRST Award (R29) must include at least three
sealed letters of reference attached to the face page of the original
application.  FIRST Award (R29) 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 GCRC as a resource for conducting
the proposed research.  If so, a letter of agreement from either the
GCRC program director or principal investigator should be included
with the application.

The completed original application and five legible copies must be
sent or delivered to:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

REVIEW CONSIDERATIONS

Applications will be assigned on the basis of established PHS
referral guidelines.  Applications will be reviewed for scientific
and technical merit in accordance with the standard NIH peer review
procedures.  Following scientific-technical review, the applications
will receive a second-level review by the appropriate national
advisory council or board.

As part of the initial merit review, a process (triage) may be used
by the initial review group in which applications will be determined
to be competitive or non-competitive based on their scientific merit
relative to other applications received in response to the RFA.
Applications judged to be competitive will be discussed and  be
assigned a priority score.  Applications determined to be non-
competitive will be withdrawn from further consideration and the
Principal Investigator and the official signing for the applicant
organization will be notified.

Review Criteria

The following criteria will be considered when assessing the
scientific/technical merit review of a research grant application:

o  Scientific, technical, or medical significance and originality of
proposed research;

o  Appropriateness and adequacy of the experimental approach and
methodology;

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;

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 approved
applications assigned to that IC.  The following will be considered
in making funding decisions:  quality of the proposed project as
determined by peer review, availability of funds, and program
priority.

INQUIRIES

Inquiries are encouraged.  The opportunity to clarify any issues or
questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Andrew A. Monjan, Ph.D., M.P.H.
Neuroscience and Neuropsychology of Aging Program
National Institute on Aging
Gateway Building, Suite 3C307
Bethesda, MD  20892
Telephone:  (301) 496-9350
Email:  MonjanA:NIA-GW:NIH

Ellen D. Witt, Ph.D.
Division of Basic Research
National Institute on Alcohol Abuse and Alcoholism
Willco Building, Suite 402
6000 Executive Boulevard
Rockville, MD  20892
Telephone:  (301) 443-4223
Email:  ewitt@willco.niaaa.nih.gov

Marian Willinger, Ph.D.
Pregnancy and Perinatology Branch
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 4B03
Bethesda, MD  20892
Telephone:  (301) 496-5575
Email:  willingm@hd01.nichd.nih.gov

James R. Cooper, M.D.
Division of Clinical Research
National Institute on Drug Abuse
Parklawn Building, Room 10A-12
5600 Fishers Lane
Rockville, MD  20857
Telephone:  (301) 443-4877
Email:  jcooper@aoada.ssw.dhhs.gov

James P. Kiley, Ph.D.
Division of Lung Diseases
National Heart, Lung and Blood Institute
Westwood Building, Room 6A15
Bethesda, MD  20892
Telephone:  (301) 594-7443
Email:  james_kiley@nihh311.Bitnet

Richard K. Nakamura, Ph.D.
Coordinator for Sleep Research
National Institute of Mental Health
5600 Fishers Lane, Room 11-102
Rockville, MD  20857
Telephone:  (301) 443-1576
Email:  NRN@CU.NIH.GOV

Charlotte McCutchen, M.D.
Epilepsy Branch, DCDND
National Institute of Neurological Disorders and Stroke
Federal Building, Room 114
Bethesda, MD  20892
Telephone:  (301) 496-1917
Email:  c5m@cu.nih.gov

Mary Lucas Leveck, Ph.D.
Acute and Chronic Illnesses Branch
National Institute of Nursing Research
Building 45, Room 3AN-12
Bethesda, MD  20892-6300
Telephone:  (301) 594-5963
Email:  mleveck@ep.ninr.nih.gov

Direct inquiries regarding fiscal matters to:

Crystal Ferguson
Grants Management Office
National Institute on Aging
Gateway Building, Suite 2C212
7201 Wisconsin Avenue, MSC 9205
Bethesda, MD  20892-9205 (Courier Zip: 20814)
Telephone:  (301) 496-1472
Email:  Ferguson%nihniagw.bitnet@cu.nih.gov

Linda Hilley
Grants Management Branch
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard, Suite 504 MSC 7003
Bethesda, MD  20892-7003
Telephone:  (301) 443-0915
Email:  LHILLEY@willco.niaaa.nih.gov

Douglas Shawver
Office of Grants and Contracts
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 8A17
Bethesda, MD  20892
Telephone:  (301) 496-1303
Email:  SHAWVERD@HD01.NICHD>NIH>GOV

Gary Fleming
Grants Management Branch
National Institute on Drug Abuse
Parklawn Building, Room 8A-54
5600 Fishers Lane
Rockville, MD  20857
Telephone:  (301) 443-6710
Email:  gfleming@aoada.ssw.dhhs.gov

Raymond L. Zimmerman
Grants Management Branch
National Heart, Lung, and Blood Institute
Westwood Building, Room 4A17A
Bethesda, MD  20892
Telephone:  (301) 594-7420
Email:  raymond_zimmerman%nihhwb1.bitnet@cu.nih.gov

Diana Trunnell
Grants Management Branch
National Institute of Mental Health
5600 Fishers Lane, Room 7C-08
Rockville, MD  20857
Telephone:  (301) 443-3065
Email:  DT21A@NIH.GOV

Karen Shields
Grants Management Branch
National Institute of Neurological Disorders and Stroke
Federal Building, Room 1004
Bethesda, MD  20892-9190
Telephone:  (301) 496-9231

Sally A. Nichols
Grants Management Officer
National Institute of Nursing Research
Building 45, Room 3AN-32
Bethesda, MD  20892-6301
Telephone:  (301) 594-7498
Email:  USN@CU.NIH.GOV

AUTHORITY AND REGULATIONS

This project is described in the Catalog of Federal Domestic
Assistance No. 93.837.  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
recipients to provide a smoke-free workplace and promote the non-use
of all tobacco products.  This is consistent with the PHS mission to
protect and advance the physical and mental health of the American
people.

.


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