Release Date:  September 27, 2001

RFA:  RFA-HL-01-009

National Heart, Lung, and Blood Institute
National Institute on Drug Abuse

Letter of Intent Receipt Date:  December 14, 2001
Application Receipt Date:       January 24, 2002



One goal of this Request for Applications (RFA) is to elucidate 
characteristics of sleep physiology, sleep disorders, and pathophysiological 
mechanisms mediating the interrelationship between sleep disturbance and 
heart, lung, and blood diseases.  The specific objectives of this program are 
to identify measurable characteristics of sleep potentially useful for the 
investigation of heart, lung, blood, and sleep disorder pathogenesis; for 
diagnosis of these disorders, for therapeutic stratification of patients; and 
for assessing treatment efficacy. Another goal of this RFA is to identify 
markers of sleep disturbances produced by the use of psychoactive substances. 
Useful biomarkers might reflect the risk, presence, or severity of sleep 
abnormalities, and the relationship of sleep to progression or exacerbations 
of disease.  A variety of techniques might be employed, ranging from proteomic 
analysis of tissue to functional imaging of brain, heart, vasculature, or 
lungs.  The focus of this RFA is on novel biomarkers of sleep that can be 
determined by minimally invasive means and have the potential to facilitate 
basic and clinical studies of heart, lung, blood, and sleep disorders.  


The Public Health Service (PHS) is committed to achieving the health promotion 
and disease prevention objectives of "Healthy People 2010," a PHS-led national 
activity for setting priority areas.  This Request for Applications (RFA), 
Interrelationship Between Sleep and Heart, Lung, and Blood Diseases, is 
related to one or more of the priority areas.  Potential applicants may obtain 
a copy of "Healthy People 2010" at


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 


Specific application instructions have been modified to reflect "MODULAR 
GRANT" and "JUST-IN-TIME" streamlining efforts that have been adopted by the 
NIH. Complete and detailed instructions and information on Modular Grant 
applications have been incorporated into the PHS 398 (rev. 5/2001).  
Additional information on Modular Grants can be found at

This RFA will use the National Institutes of Health (NIH) R01 award mechanism. 
Responsibility for the planning, direction, and execution of the proposed 
project will be solely that of the applicant.  The total project period for an 
application submitted in response to this RFA may not exceed four years.  This 
RFA is a one-time solicitation.  Future unsolicited competing continuation 
applications will compete with all investigator-initiated applications and be 
reviewed according to the customary peer review procedures.  The earliest 
anticipated award date is September 30, 2002.


The National Heart, Lung, and Blood Institute (NHLBI) intends to commit 
approximately $3.1 million, and the National Institute on Drug Abuse (NIDA) 
intends to commit $375,000 in FY 2002 to fund seven to nine new grants in 
response to this RFA. An applicant may request a project period of up to four 
years and a budget for direct costs not to exceed $250,000 per year (10 
modules of $25,000 per year). Because the nature and scope of the research 
proposed may vary, it is anticipated that the size of each award will also 
vary. The financial plans of the NHLBI and the NIDA provide support for this 
program, however, awards pursuant to this RFA are contingent upon the 
availability of funds and the receipt of a sufficient number of meritorious 
applications. Although the National Institute of Mental Health (NIMH, will not participate in this RFA, NIMH has a shared 
interest in some topics covered by this RFA. NIMH will continue to fund these 
areas through the regular investigator-initiated mechanisms.



Sleep related problems represent a severe health concern for millions of 
Americans and all age groups.  Sleep disturbances reduce productivity and 
quality of life; increase the likelihood of workplace, home, and vehicular 
accidents; and are associated with a higher risk of morbidity and mortality.  
Sleep has a fundamental physiological role in neural, metabolic, 
immunological, and behavioral processes associated with normal health and 
maturation.  However, relatively few biological functions of sleep have been 
elucidated.  Sleep abnormalities such as excessive sleepiness, disturbed 
sleep, and inability to sleep occur in close association with a variety of 
diseases.  Mutually exacerbating effects of sleep abnormalities and primary 
illness may be a significant barrier to recovery.   While sleep abnormalities 
and excessive daytime sleepiness are recognized as an important clinical 
symptom of many illnesses, the role of sleep abnormalities in the 
pathophysiology of disease has not been widely studied.  Polysomnographic and 
behavioral methods, used to assess sleep pattern abnormalities, need to be 
supplemented by additional biological correlates to investigate mechanisms 
underlying specific risks to health.  The identification of measurable 
characteristics of sleep and its interrelationship with other physiological 
systems is needed to facilitate epidemiological and clinical studies, provide 
improved diagnostic tools, and stimulate the development of innovative 

Sleep disordered breathing ranging from chronic snoring to repeated 
interruptions in breathing (sleep apnea) is a common sleep disorder.  Several 
lines of converging evidence associate sleep disordered breathing with a broad 
array of metabolic, vascular, hematological, and genetic markers associated 
with increased cardiovascular disease and stroke risk.  Sleep apnea produces a 
lightening in sleep state, abrupt increases in blood pressure, and may be a 
secondary cause of hypertension.  Vascular response to bradykinin, a 
vasodilator, is blunted in sleep apnea patients, and the level of a potent 
vasoconstrictor peptide, endothelin-1, appears to be elevated.  Another factor 
contributing to increased vascular morbidity in sleep apnea patients may be 
elevated levels of fibrinogen, a liver protein enhancing thrombosis and 
atherosclerosis.  Ischemic stroke patients with sleep apnea exhibit elevated 
plasma fibrinogen levels suggesting that inflammation or hypercoagulation may 
contribute to the increased risk of stroke in sleep apnea.  Apolipoprotein E 
epsilon4 (apoE epsilon4), a genetic marker previously linked to cardiovascular 
disease risk, is associated with a two fold increased risk of sleep apnea, and 
an increase in the severity of apnea symptoms.  The association between apoE 
epsilon4 marker, cardiovascular diseases, and sleep apnea suggests a possible 
common pathophysiological pathway involving lipid metabolism.  Leptin, an 
anti-obesity hormone produced by adipose tissue, is significantly higher in 
obese subjects with sleep apnea.  Animal studies suggest that obesity-related 
leptin resistance may contribute to sleep apnea pathophysiology by depressing 
respiration and chemosensitivity.  

A variety of cardiopulmonary and other diseases including those associated 
with psychoactive drugs are affected by and affect the quality of sleep.  
Intermittent sleep disturbances (arousals) alter cerebral blood flow and cause 
abnormalities in the circadian secretion of hormones that diminish resilience 
to stress and the ability to regulate blood glucose.  Diabetes is associated 
with disturbed sleep, and partial sleep deprivation of otherwise healthy 
adults increases insulin resistance.  Findings from the NHLBI Cardiovascular 
Health Study indicate that there is a strong association between daytime 
sleepiness and cardiovascular disease-related morbidity and mortality, 
myocardial infarction, and congestive heart failure.  Accumulating evidence 
suggests that enhancing sleep quality in patients with heart failure reduces 
sympathetic outflow and helps to preserve myocardial function.  Thrombotic 
events are more likely to occur during sleep or awakening, and are believed to 
be a major cause of stroke and heart attack.  The level of circulating cell 
subtypes in blood varies with sleep and sleep deprivation.  Asthma may worsen 
during sleep for various reasons and the majority of asthma deaths occur 
during normal sleeping hours.  Bronchitis, emphysema, and interstitial lung 
disease also impede sleep.  Infection and inflammation induce symptoms of 
excessive daytime sleepiness and fatigue.  The use of psychoactive drugs is 
associated with abnormalities in sleep pattern.  Recovering addicts often 
experience persistent sleep disturbances that contribute to the risk of 

Research Scope

Recent advances in understanding how sleep is regulated and coupled to other 
physiological systems have provided a foundation on which to further develop 
our understanding of potential pathophysiological relationships.  Research is 
needed to identify measurable characteristics of sleep and related biomarkers 
that are significant in relation to cardiopulmonary and hematological disease 
pathophysiology, sleep disorders, and sleep deprivation in children and 
adults.  Identification of measurable sleep characteristics that change during 
illness should allow interrelationships between sleep and disease to be 
studied by a broad community of cardiovascular, pulmonary, hematological, and 
sleep researchers.  Such characteristics could potentially serve as indicators 
of disease risk, severity, progression, prognosis, and response to treatment. 
 Identifying pathophysiologic indicators associated with excessive daytime 
sleepiness, nonrestorative or poor sleep during acute or chronic disease 
conditions will provide the groundwork to determine how disease causes sleep 
abnormalities and vice versa.  Listed below are examples of studies that would 
be responsive to this program.  These are only illustrative examples and 
applicants are encouraged to consider other topics consistent with the goals 
of this program. Not all areas need to be addressed in a single application. 

Identify measurable characteristics of sleep that 

o Facilitate studies of the function of sleep, the interrelationship between 
sleep and other physiological systems, and the integration of epidemiologic 
and clinical information;

o Reflect early pathophysiological consequences of excessive daytime 
sleepiness due to abnormalities in sleep timing, pattern, or duration.

o Predict the risk, progression, or prognosis of sleep, heart, lung, and blood 

o Reflect individual susceptibility to excessive daytime sleepiness and to 
sleep abnormalities

o Are useful for the diagnosis or prevention of sleep related morbidity and 
for assessing the progression of sleep disorders and the effectiveness of 

o Are associated with insomnia and other sleep disturbances produced by the 
use of psychoactive substances.


For the purpose of this RFA, a biomarker is defined as a qualitatitive or 
quantitative indicator of biological, physical, anatomical, chemical, or 
cellular changes contributing to the understanding of disease pathogenesis or 
risk. Among the approaches this definition permits are the following:

o  Proteomic analyses,
o  Gene expression profiles,
o  Neurophysiological analyses,
o  Identification of genetic markers,
o  Cellular and biochemical profiles of tissues or biological fluids, and
o  Functional imaging technologies such as magnetic resonance, positron 
emission tomography, or magnetoencephalography.

In order to be considered responsive to this announcement, applications must 
propose hypothesis-driven studies that focus on elucidating measurable 
characteristics of sleep physiology, sleep disorders, or pathophysiological 
mechanisms mediating the interrelationship between sleep disturbance and 
cardiovascular, pulmonary, immunological, or hematological health.  Studies to 
identify genetic markers of this interrelationship will also be responsive.   
Biomarkers that can be determined by minimally invasive means and have the 
potential to facilitate epidemiological studies of cardiovascular, pulmonary, 
hematological, and sleep disorders are encouraged.  Studies proposing the use 
of nonmammalian species or in vitro preparations should clearly establish the 
relationship of these models to the goals set forth in this RFA.  

Collaborations and consortia promoting interdisciplinary approaches between 
scientists studying sleep medicine, cardiology, pulmonology, hematology, 
neuroimmunobiology, infectious disease, endocrinology, genetics, and 
neurophysiology are strongly encouraged.  In such cases, each participant's 
contribution should be identified and well-integrated into the overall 
experimental design.

The elucidation of environmental factors producing sleep abnormalities such as 
shift work, rapid time zone changes, cultural and socioeconomic factors will 
not be supported under this RFA.  Studies of alcohol abuse, pain syndromes, 
cancer, mental disorders, and the relationship of sleep to behavioral 
endpoints such as workplace performance would also be unresponsive to this 
RFA.  Applications focused on the development of methodology, large clinical 
studies, or the establishment of large epidemiological cohorts that collect 
data for future studies are not within the scope of this program.  

Upon initiation of the program, periodic meetings will be organized to 
encourage the exchange of information among investigators who participate in 
this program. Travel funds for the principal investigator to attend a two-day 
meeting each year, most likely to be held in Bethesda, Maryland, must be 
included in the module calculation.  Applicants must include a statement 
indicating their willingness to participate in these meetings.  Applicants are 
encouraged to contact the program officials listed under INQUIRIES for further 


It is the policy of the NIH that women and members of minority groups and 
their sub-populations must be included in all NIH-supported biomedical and 
behavioral research projects involving human subjects, unless a clear and 
compelling rationale and justification are provided indicating 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). 

All investigators proposing research involving human subjects should read the 
UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in 
Clinical Research," published in the NIH Guide for Grants and Contracts on 
August 2, 2000
a complete copy of the updated Guidelines are available at  The 
revisions relate to NIH defined Phase III clinical trials and require: a) all 
applications or proposals and/or protocols to provide a description of plans 
to conduct analyses, as appropriate, to address differences by sex/gender 
and/or racial/ethnic groups, including subgroups if applicable; and b) all 
investigators to report accrual, and to conduct and report analyses, as 
appropriate, by sex/gender and/or racial/ethnic group differences.


It is the policy of NIH that children (i.e., individuals under the age of 21) 
must be included in all human subjects research, conducted or supported by the 
NIH, unless there are scientific and ethical reasons not to include them.  
This policy applies to all initial (Type 1) applications submitted for receipt 
dates after October 1, 1998.

All investigators proposing research involving human subjects should read the 
"NIH Policy and Guidelines" on the Inclusion of Children as Participants in 
Research Involving Human Subjects that was published in the NIH Guide for 
Grants and Contracts, March 6, 1998, and is available at the following URL 

Investigators also may obtain copies of these policies from the program staff 
listed under INQUIRIES.  Program staff may also provide additional relevant 
information concerning the policy.


NIH policy requires education on the protection of human subject participants 
for all investigators submitting NIH proposals for research involving human 
subjects.  This policy announcement is found in the NIH Guide for Grants and 
Contracts Announcement dated June 5, 2000, at the following website:


All applications and proposals for NIH funding must be self-contained within 
specified page limitations.  Unless otherwise specified in an NIH 
solicitation, internet addresses (URLs) should not be used to provide 
information necessary to the review because reviewers are under no obligation 
to view the Internet sites.  Reviewers are cautioned that their anonymity may 
be compromised when they directly access an Internet site.


The Office of Management and Budget (OMB) Circular A-110 has been revised to 
provide public access to research data through the Freedom of Information Act 
(FOIA) under some circumstances.  Data that are (1) first produced in a 
project that is supported in whole or in part with Federal funds and (2) cited 
publicly and officially by a Federal agency in support of an action that has 
the force and effect of law (i.e., a regulation) may be accessed through FOIA. 
 It is important for applicants to understand the basic scope of this 
amendment.  NIH has provided guidance at:

Applicants may wish to place data collected under this RFA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time.  If so, the application should 
include a description of the archiving plan in the study design and include 
information about this in the budget justification section of the application. 
In addition, applicants should think about how to structure informed consent 
statements and other human subjects procedures given the potential for wider 
use of data collected under this award.


Prospective applicants are asked to submit 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 
and 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 
a subsequent application, the information that it contains allows NHLBI staff 
to estimate the potential review workload and plan the review.

The letter of intent is to be sent to Dr. Deborah Beebe (see address listed 
under Inquiries below) by the letter of intent receipt date listed.


The PHS 398 research grant application instructions and forms (rev. 5/2001) at are to be used in 
applying for these grants. This version of the PHS 398 is available in an 
interactive, searchable PDF format.  For further assistance contact 
GrantsInfo, Telephone 301/710-0267, Email:


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, reviewers and NIH staff. 
The research grant application form PHS 398 (rev. 5/2001) at is to be 
used in applying for these grants, with modular budget instructions provided 
in Section C of the application instructions.  

The RFA label available in the PHS 398 (rev. 5/2001) application form must be 
affixed to the bottom of the face page of the application.  Type the RFA 
number on the label.  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, the RFA title and number must be typed on 
line 2 of the face page of the application form and the YES box must be 
marked.  The sample RFA label available at: has been modified to 
allow for this change.  Please note this is in pdf format.

Submit a signed, typewritten original of the application, including the 
Checklist, and three signed, photocopies, in one package to:

BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

At the time of submission, two additional copies of the application as well as 
all five collated sets of Appendix material must be sent to Dr. Deborah Beebe 
at the address listed under Inquiries.  Applications must be received by the 
application receipt date listed in the heading of this RFA. If an application 
is received after that date, it will be returned to the applicant without 
The Center for Scientific Review (CSR) 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 
CSR will 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.

Principal investigators should not send supplementary material without first 
contacting the Scientific Review Administrator (SRA).  The SRA will be 
identified in the letter sent to you indicating that your application has been 
received.  If you have not yet received such a letter, contact Dr. Deborah 
Beebe at the address listed under Inquiries.


Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by the NHLBI. If the application is not responsive to the RFA, 
NHLBI staff may contact the applicant to determine whether to return the 
application to the applicant or submit it for review in the regular 
competition for unsolicited applications at the next review cycle.

Applications that are complete and responsive to the RFA will be evaluated for 
scientific and technical merit by an appropriate peer review group convened by 
the NHLBI in accordance with the review criteria stated below.  As part of the 
initial merit review, all applications will receive a written critique and 
undergo a process in which only those applications deemed to have the highest 
scientific merit, generally the top half of the applications under review, 
will be discussed, assigned a priority score, and receive a second level 
review by the National Advisory Councils of the NHLBI and/or NIDA.

Review Criteria

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  In 
the written comments reviewers will be asked to discuss the following aspects 
of the application in order to judge the likelihood that the proposed research 
will have a substantial impact on the pursuit of these goals.  Each of these 
criteria will be addressed and considered in assigning the overall score, 
weighting them as appropriate for each application.  Note that the application 
does not need to be strong in all categories to be judged likely to have major 
scientific impact and thus deserve a high priority score.  For example, an 
investigator may propose to carry out important work that by its nature is not 
innovative but is essential to move a field forward.

(1) Significance:  Does this study address an important problem? If the aims 
of the application are achieved, how will scientific knowledge be advanced?  
What will be the effect of these studies on the concepts or methods that drive 
this field?

(2) Approach:  Are the conceptual framework, design, methods, and analyses 
adequately developed, well-integrated, and appropriate to the aims of the 
project?  Does the applicant acknowledge potential problem areas and consider 
alternative tactics?

(3) Innovation:  Does the project employ novel concepts, approaches or method? 
Are the aims original and innovative?  Does the project challenge existing 
paradigms or develop new methodologies or technologies?

(4) Investigator:  Is the investigator appropriately trained and well suited 
to carry out this work?  Is the work proposed appropriate to the experience 
level of the principal investigator and other researchers (if any)?

(5) Environment:  Does the scientific environment in which the work will be 
done contribute to the probability of success?  Do the proposed experiments 
take advantage of unique features of the scientific environment or employ 
useful collaborative arrangements?  Is there evidence of institutional 

In addition to the above criteria, in accordance with NIH policy, all 
applications will also be reviewed with respect to the following:

o  The adequacy of plans to include both genders, minorities and their 
subgroups, and children as appropriate for the scientific goals of the 
research.  Plans for the recruitment and retention of subjects will also be 

o  The reasonableness of the proposed budget and duration in relation to the 
proposed research.

o  The adequacy of the proposed protection for humans, animals or the 
environment, to the extent they may be adversely affected by the project  
proposed in the application.


Letter of Intent Receipt Date:    December 14, 2001
Application Receipt Date:         January 24, 2002
Peer Review Date:                 April, 2002
Council Review:                   August, 2002
Earliest Anticipated Start Date:  September 30, 2002


Award criteria that will be used to make award decisions include:

o  scientific merit (as determined by peer review)
o  availability of funds
o  programmatic priorities.


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

Direct inquiries regarding programmatic issues to:

Michael Twery, Ph.D.
Division of Lung Diseases
National Heart, Lung, and Blood Institute
Rockledge 2, Suite 10018
6701 Rockledge Drive, MSC 7952
Bethesda, MD  20892-7952
Telephone:  (301) 435-0202
FAX:  (301) 480-3557

Harold Gordon, Ph.D.
Division of Treatment Research and Development
National Institute on Drug Abuse
Neuroscience Center, Room 4233
6001 Executive Boulevard, MSC 9559
Rockville, MD  20892-9559
Telephone:  (301) 443-4877
FAX:  (301) 443-6814

Direct inquiries regarding review issues to:

Deborah Beebe, Ph.D.
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Dr.,Room 7178 (MSC 7924)
Bethesda, MD  20892-7924
Telephone:  (301) 435-0270
Fax:  (301) 480-3541

Direct inquiries regarding fiscal matters to:

Robert Vinson
Grants Operations Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7154, MSC 7926
Bethesda, Maryland  20892-7926
Telephone:  (301) 435-0171
FAX:  (301) 480-3310


This program is described in the Catalog of Federal Domestic Assistance No. 
93.233, 93.837, 93.838, and 93.839.  Awards are made under authorization of 
Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 
and 284) and administered under NIH grants policies and Federal Regulations 42 
CFR 52 and 45 CFR Parts 74 and 92.  This program is not subject to the 
intergovernmental review requirements of Executive Order 12372 or Health 
Systems Agency review.

The PHS strongly encourages all grant 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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