Full Text HL-96-015
 
MOLECULAR BIOLOGY AND GENETICS OF SLEEP AND SLEEP DISORDERS
 
NIH GUIDE, Volume 25, Number 29, August 30, 1996
 
RFA:  HL-96-015
 
P.T. 34

Keywords: 
  Sleep Disorders 
  Biology, Molecular 
  Genetics 

 
National Heart, Lung, and Blood Institute
National Institute on Mental Health
National Institute on Child Health and Human Development
 
Letter of Intent Receipt Date:  January 6, 1997
Application Receipt Date:  March 13, 1997
 
THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS AND
INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS
AND MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA.
 
PURPOSE
 
The purpose of this initiative is to advance our understanding of the
molecular and genetic basis of sleep and sleep disorders.
Specifically, the program is designed to stimulate studies on basic
molecular correlates of sleep, cellular mechanisms responsible for
restorative processes during sleep, the interactions between sleep
and circadian systems controlling sleep and wakefulness at a
molecular level, the genetic basis of sleep disorders, and the
molecular neurobiology of sleep and 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 request
for applications (RFA), Molecular Biology and Genetics of Sleep and
Sleep Disorders, is related to the priority areas of heart disease
and stroke, chronic disabling conditions, mental health and
disorders, maternal and infant health, 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
202-512-1800).
 
ELIGIBILITY REQUIREMENTS
 
Applications may be submitted by 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
may not apply.  However, subcontracts to foreign institutions maybe
allowed if justified.  Ethnic minority individuals, women, and
persons with disabilities are encouraged to apply as principal
investigators.
 
Collaborations and consortia promoting the cross-fertilization of
ideas are strongly  encouraged.  In such cases, each participant's
contribution should be identified and well-integrated into the
overall experimental design.
 
MECHANISM OF SUPPORT
 
This RFA will use the NIH individual research project grant (R01)
mechanism of support.  Awards will be made and managed by the
National Heart, Lung, and Blood Institute (NHLBI) and/or the National
Institute of Mental Health (NIMH) and/or the National Institute on
Child Health and Human Development (NICHD).  Policies that govern the
research grants programs of the NIH will prevail.  However, specific
application instructions have been modified to reflect "MODULAR
GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the
NIH.  The modular grant concept establishes specific modules in which
direct costs may be requested as well as a maximum level for
requested budgets. Only limited budgetary information is required
under this approach.  The just-in-time concept allows applicants to
submit certain information only when there is a possibility for an
award.  It is anticipated that these changes will reduce the
administrative burden for the applicants, applicant institutions,
reviewers, and Institute staff.
 
For this RFA, funds must be requested in $25,000 direct cost modules
and a maximum of 9 modules ($225,000 direct costs) per year may be
requested.  A feature of the modular grant concept is that no
escalation is provided for future years, and all anticipated expenses
for all years of the project must be included within the number of
modules being requested. Only limited budget information will be
required and any budget adjustments made by the Initial Review Group
will be in modules of $25,000.  Instructions for completing the
Biographical Sketch have also been modified.  In addition, Other
Support information and the application Checklist page are not
required as part of the initial application.  If there is a
possibility for an award, necessary budget, Other Support and
Checklist information will be requested by staff at NHLBI and/or NIMH
and/or NICHD following the initial review.  The APPLICATION
PROCEDURES section of this RFA provides specific details of these
modifications to standard PHS 398 application kit instructions.
 
This RFA is a one time solicitation.  Future unsolicited competing
continuation applications will compete with all investigator
initiated applications and be reviewed according to customary peer
review procedures.
 
FUNDS AVAILABLE
 
It is anticipated that during fiscal year 1997, support will be
available for total costs of approximately $2,000,000 from the NHLBI,
$800,000 from NIMH, and $400,000 from NICHD for the first year of
this initiative.  Award of grants pursuant to this RFA is contingent
upon receipt of such funds for this purpose.  It is anticipated that
approximately 12 to 15 grants will be awarded under this program.
Applicants may request up to four years of support.  The specific
number to be funded will, however, depend on the merit and scope of
the applications received and on the availability of funds.  Direct
costs will be awarded in modules of $25,000, less any overlap or
other necessary administrative adjustments.  Indirect costs will be
awarded based on the negotiated rates.
 
RESEARCH OBJECTIVES
 
Background
 
Sleep related problems represent a significant health concern for
millions of Americans and all age groups.  The impact of sleep
disturbances on society includes reduced productivity, lowered
cognitive performance, increased likelihood of accidents, decreased
quality of life, and higher risk of morbidity and mortality.  Sleep
disturbances are important markers of affective disorders and
possibly are a contributing factor in the pathogenesis of Sudden
Infant Death Syndrome.
 
Although recent scientific progress has provided a strong foundation
for advancing our basic scientific understanding of this important
clinical problem,  neurobiological mechanisms underlying normal and
disordered sleep remain largely unknown.  Physiological, metabolic,
and behavioral processes during sleep contribute to the normal
function and maturation of the nervous system.  Improved
understanding of how sleep modifies the nervous system at a molecular
level is critical to develop new approaches for the primary
prevention and treatment of sleep disorders.
 
Research Scope
 
Little is currently known about the molecular events involved in
sleep regulation or the restorative processes that occur in neurons
and/or glia during sleep.  Consequently, there are a number of
directions that could be pursued by applicants responding to this
RFA.  The topics that follow serve as examples and are not a
comprehensive or exclusive list of the areas supported by this
initiative.  Applicants are encouraged to propose other topics
consistent with the goals of this program.  An essential requirement
of this RFA is that the framework for proposed studies include
molecular or genetic approaches.
 
A current hypothesis is that sleep-promoting compounds accumulate
during wakefulness and are dissipated during sleep.  Although a
number of candidate compounds have been proposed, the study of these
compounds needs to be extended to a molecular level.  For instance,
we need to know whether molecular events leading to the formation of
sleep promoting molecules or their receptors are regulated by the
sleep/wake cycle and how this regulation is achieved in relevant
brain regions.
 
Defining the basic role of sleep in health and disease represents a
significant, unmet biological challenge.  One theory is that sleep
has a restorative role such as replenishing the energy stores of glia
or contributing to the reorganization of synaptic connections.
Molecular studies to test these hypotheses are strongly encouraged.
A related question is whether molecular changes in brain function
accompany sleep deprivation.  Sleep deprivation may have long-term
effects through changes in gene expression (e.g. IL-1beta, TNF, and
prostaglandins) and neuronal plasticity.  Where are these genes
regulated (cell type, location) and what signals account for changes
in transcriptional regulation? Studies are also needed to identify
the role of specific sleep regulating molecules that provoke the
development of major affective disorders or are linked to
cardiorespiratory or  thermoregulatory function.
 
Animal models are needed to study the development and maintenance of
neuronal circuitry controlling sleep (e.g. synaptogenesis, neural
plasticity) using molecular techniques.  The mouse provides an
especially useful vehicle for studying homeostatic control of sleep
because techniques are available to precisely manipulate gene
expression in this species.  The role of specific genes in sleep
disorders could be investigated using knock-out, knock-in, and other
recently developed transgenic techniques in mouse models.
 
Current definitions of sleep are based primarily on criteria derived
from the mammalian electroencephalogram and hence limit the study of
sleep to mammalian species.  However, the genome of nonmammalian
species (e.g., Drosophila, C. Elegans) is more easily manipulated and
presents the opportunity to develop model systems in which the basic
control mechanisms governing activity cycles and their effects on
neurobiological processes can be investigated.  The development of
new approaches enabling the neurobiological significance of sleep to
be studied in nonmammalian species is encouraged.
 
There are significant changes to the sleep process that occur across
the life span.  The neurobiological basis for such changes and
especially the role of sleep regulating molecules in development and
aging requires investigation.   Animal models containing specific
gene deletions may have unique value for studying the molecular basis
for altered patterns of sleep and rhythmicity associated with
development or traumatic experiences.  Studies are also needed to
determine whether neurodegenerative mechanisms (e.g., apoptosis) or
molecular defects in neuroendocrine regulation are factors in the
pathogenesis of sleep disorders with age.
 
Genetic factors are implicated in many sleep disorders, e.g.,
narcolepsy, restless legs syndrome (RLS) and obstructive sleep apnea
(OSA).  Narcolepsy is associated with an HLA subtype and close
relatives of individuals with narcolepsy have a much greater risk of
having the disorder.  Studies are needed in human narcolepsy to
advance our understanding of fundamental sleep mechanisms and open
new areas of investigation.  Narcolepsy in a canine model of the
disorder is transmitted as a single autosomal recessive trait.
However, genetic studies in the canine model have been hampered by
the lack of information on the canine genome.  On the other hand, a
large base of genetic information is available in mice.  The
development of a mouse model of narcolepsy would advance markedly
studies of this disease and create new opportunities to investigate
the genetic basis for sleep disorders.  In this regard, genetic
factors are also thought to contribute significantly to restless leg
syndrome (RLS) and obstructive sleep apnea (OSA) since multiple
family members are frequently affected when one of these disorders is
present.  In the case of OSA, familial risk seems to be associated
with certain facial bony structures suggesting that the genes
determining that structure are involved.  A close familial
association may also exist with respect to primary insomnia.  Studies
contributing a more precise definition of the genetic basis for these
and other sleep disorders including elements associated with
behavioral and mental disorders and genetic disorders affecting
arousal and cardiorespiratory or thermoregulatory function during
sleep and infancy will be responsive.
 
SPECIAL REQUIREMENTS
 
The primary focus of proposed studies must be on the molecular or
genetic basis of sleep and sleep disorders.  Studies of the circadian
system must be tightly coupled to mechanisms of sleep control.
Psychobiological, neurophysiological, anatomical, or polysomnographic
studies which do not include molecular or genetic approaches to
understanding sleep will be considered unresponsive to this RFA.
Pharmacological studies that investigate the efficacy of sleep
promoting agents but not the underlying molecular mechanisms will
also not be acceptable.  Studies proposing the use of nonmammalian
species should clearly establish the relationship of these models to
the goals set forth in this RFA.  Applicants are encouraged to
contact the program officials listed under INQUIRIES for further
information.
 
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 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 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 28, 1994, (F 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 of the policy from these sources or
from the program staff listed under INQUIRIES.  Program staff may
also provide additional relevant information concerning the policy.
 
LETTER OF INTENT
 
Prospective applicants are asked to submit, by January 6, 1997, a
letter of intent that includes a descriptive title of the proposed
research, the name, address, and telephone number of the Principal
Investigator, the identities of other key personnel, participating
institutions, and the number and title of the RFA in response to
which the application may be submitted.
 
Although a letter of intent is not required, is not binding, and does
not enter into the review of subsequent applications, the information
that it contains allows NIH staff to estimate the potential review
workload and to avoid conflict of interest in the review.  The letter
of intent is to be faxed or sent to Dr. C. James Scheirer, at the
address listed under INQUIRIES.
 
APPLICATION PROCEDURES
 
Applications are to be submitted on the grant application form PHS
398 (rev. 5/95).  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 301/435-0714,
email:  ASKNIH@odrockm1.od.nih.gov.
 
The RFA label available in the PHS 398 application form must be
affixed to the bottom of the face page of the application.  Failure
to use this label could result in delayed processing of the
application such that it may not reach the review committee in time
for review.  In addition, to identify the application as a response
to this RFA, check "YES" in item 2 of page 1 of the application and
enter the title "Molecular Biology and Genetics of Sleep and Sleep
Disorders, HL-96-015".
 
The following modifications are made to the standard PHS 398
application instructions:
 
BUDGET INSTRUCTIONS
 
The total direct costs must be requested in accordance with the
program guidelines and modifications made to the standard PHS 398
application instructions as described below:
 
o  DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD -  Do not complete
Form Page 4 of the PHS 398 (rev 5/95).  It is not required nor will
it be accepted at the time of application.
 
o  BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT -  Do not
complete the categorical budget tables on Form page 5 of the PHS 398
(rev. 5/95). Only the requested total direct costs line for each year
must be completed based on the number of $25,000 modules being
requested.  Applicants may not request a change in the amount of each
module.  A maximum of 9 modules ($225,000 direct costs) per year may
be requested and each applicant may request up to four years of
support for this RFA.  Direct cost budget remain constant throughout
the life of the project (i.e., the same number of modules requested
for all budget periods).  Any necessary escalation should be
considered when determining the number of modules to be requested.
However, in the event that the number of modules requested must
change in any future year due to the nature of the research proposed,
appropriate justification must be provided.  Total Direct Costs for
the Entire Proposed Project Period should be shown in the box
provided.
 
o  BUDGET JUSTIFICATION
- Budget justifications should be provided under "Justifications" on
Form Page 5 of the PHS 398.
- List the names, role on the project and proposed percent effort for
all project personnel (salaried or unsalaried) and provide a
narrative justification for each person based on his/her role on the
project.
- Identify all consultants by name and organizational affiliation and
describe the services to be performed.
-Provide a general narrative justification for individual categories
(equipment, supplies, etc.) required to complete the work proposed.
More detailed justifications should be provided for high cost items.
Any large one-time purchases, such as large equipment requests, must
be accommodated within these limits.
 
o  CONSORTIUM/CONTRACTUAL COSTS - If collaborations or subcontracts
are involved that require transfer of funds from the grantee to other
institutions, it is necessary to establish formal subcontract
agreements with each collaborating institution.  A letter of intent
from each collaborating institution should be submitted with the
application.  Only the percentage of the consortium/contractual TOTAL
COSTS (direct and indirect) relative to the total DIRECT COSTS of the
overall project needs to be stated at this time. The following
example should be used to indicate the percentage cost of the
consortium, "The consortium agreement represents 27% of overall
$175,000 direct costs requested in the first year".  A budget
justification for the consortium should be provided as described in
the "Budget Justification" section above (no Form Page 5 required for
the consortium).  Please indicate whether the consortium will be in
place for the entire project period and identify any future year
changes in the percentage relative to the parent grant.
 
If there is a possibility for an award, the applicant will be
requested to identify actual direct and indirect costs for all years
of the consortium. Please note that total subcontract costs need not
be calculated in $25,000 modules.  However, when subcontract funds
are added to the parent grant budget, the total direct cost amount
must be included in the number of $25,000 modules requested.
 
o  BIOGRAPHICAL SKETCH - Biographical sketches are required for key
personnel, following the modified instructions below.  Do not exceed
the two-page limit for each person.
- Complete the educational block at the top of the form page;
- List current position(s) and those previous positions directly
relevant to the application;
- List selected peer-reviewed publications directly relevant to the
proposed project, with full citation;
- The applicant has the option to provide information on research
projects completed and/or research grants participated in during the
last five years that are relevant to the proposed project.
 
o  OTHER SUPPORT - Do not complete the "Other Support" pages (Form
Page 7).  Selected other support information relevant to the proposed
research may be included in the Biographical Sketch as indicated
above. Complete Other Support information will be requested by the
staff of NHLBI or collaborating Institutes if there is a possibility
for an award.
 
o  CHECKLIST - No "Checklist" page is required as part of the initial
application.  A completed Checklist will be requested by the staff of
NHLBI or collaborating Institutes if there is a possibility for an
award.
 
o  The applicant should provide the name and phone number of the
individual to contact concerning fiscal and administrative issues if
additional information is necessary following the initial review.
 
Applications not conforming to these guidelines will be considered
unresponsive to this RFA and will be returned without further review.
 
Submit a signed, typewritten original of the application and three
signed, photocopies, in one package to:
 
DIVISION OF RESEARCH GRANTS
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)
 
At the time of submission, two additional copies of the application
must be sent to Dr. C. James Scheirer, at the address listed under
INQUIRIES.
 
Applications must be received by March 13, 1997.  If an application
is received after this date, it will be returned to the applicant
without review.  The Division of Research Grants (DRG) will not
accept any application in response to this RFA that is essentially
the same as one currently pending initial review, unless the
applicant withdraws the pending application.  The DRG will also not
accept any application that is essentially the same as one already
reviewed.  This does not preclude the submission of substantial
revisions of applications already reviewed, but such applications
must include an introduction addressing the previous critique.
 
o  A sample budget is available upon request from Mr. Raymond
Zimmerman at the number listed under INQUIRIES.
 
REVIEW CONSIDERATIONS
 
Upon receipt, applications will be reviewed for completeness by the
DRG and responsiveness to this RFA by the collaborating institutes.
Incomplete and/or non-responsive applications will be returned to the
applicant without further consideration.  Applications will be
evaluated for scientific and technical merit by an appropriate peer
review group convened by the Division of Extramural Affairs, NHLBI.
 
As part of the initial merit review, all applications will receive a
written critique and undergo a review in which only those
applications deemed to have the highest scientific merit of the
applications under review (usually two to three times the number of
applications that the NHLBI and participating Institutes anticipate
being able to fund under the program) will be discussed, assigned a
priority score, and receive a second level review by the National
Heart, Lung, and Blood Advisory Council and the Advisory Council of
NIMH and/or NICHD.
 
The following criteria will be considered when assessing the
scientific and technical merit 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. Applications that couple basic sleep
with molecular biology or genetics expertise are strongly encouraged.
 
o  Availability of the resources necessary to perform the research.
 
The personnel category will be reviewed for appropriate staffing
based on the requested percent effort.  The direct costs budget
request will be reviewed for consistency with the proposed methods
and specific aims. Any budgetary adjustments recommended by the
reviewers will be in $25,000 modules.  The duration of support will
be reviewed to determine if it is appropriate to ensure successful
completion of the requested scope of the project.
 
AWARD CRITERIA
 
The anticipated date of award is September 30, 1997.  Factors that
will be taken into consideration in making awards include the
scientific merit of the proposed program as evidenced by the priority
score and the availability of funds.  Subject to the availability of
necessary funds and consonant with the priorities of this RFA, the
NHLBI, NIMH, and/or NICHD will provide funds for a project period up
to four years.
 
INQUIRIES
 
Inquiries concerning this RFA are encouraged.  The opportunity to
clarify any issues or questions from potential applicants is welcome.
 
Direct inquiries regarding programmatic issues to:
 
James P. Kiley, Ph.D.
National Center on Sleep Disorders Research
National Heart, Lung, Blood Institute
6701 Rockledge Drive, Suite 7024, MSC-7920
Bethesda, MD  20892-7920
Telephone:  (301) 435-0199
FAX:  (301) 480-3451
Email:  Kileyj@nih.gov
 
Israel I. Lederhendler, Ph.D.
Coordinator for Sleep Research
National Institute of Mental Health
5600 Fishers Lane, Room 11-102
Rockville, MD  20857
Telephone:  (301) 443-1576
FAX:  (301) 443-4822
Email:  ilu@helix.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
 
Direct inquiries regarding review matters to:
 
C. James Scheirer, Ph.D.
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7220, MSC 7924
Bethesda, MD  20892-7924
Telephone:  (301) 435-0266
FAX:  (301) 480-3541
Email:  ScheireJ@nih.gov
 
Direct inquiries regarding fiscal matters to:
 
Raymond L. Zimmerman
Grants Operations Branch
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7154
Bethesda, MD  20892-7926
Telephone:  (301) 435-0171
FAX:  (301) 480-3310
Email:  ZimmermR@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
 
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
 
AUTHORITY AND REGULATIONS
 
This program is described in the Catalog of Federal Domestic
Assistance No. 93.838.  Grants are made under the authorization of
the Public Health Service Act, Title III, Section 301 (Public Law
78-410, as amended by Public Law 99-158, 42 US 241 and 285) and
administered under PHS grants policies and Federal Regulations 42 CFR
52 and 45 CFR Part 74. This program is subject to the
intergovernmental review requirements of Executive Order 12372 or to
a review by a Health Systems Agency.
 
The PHS strongly encourages all grant and contract recipients to
provide a smoke-free workplace 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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