Release Date:  November 29, 1999

RFA:  HL-00-004

National Heart, Lung, and Blood Institute

Letter of Intent Receipt Date: January 24, 2000
Application Receipt Date: February 23, 2000



The purpose of this initiative is to improve our understanding of how 
intermittent hypoxia contributes to the pathophysiology of cardiopulmonary, 
vascular, hematological, and sleep disorders. Specific objectives are to 
determine the basic molecular and genomic mechanisms involved in cellular 
responses to brief intermittent hypoxic episodes including mechanisms 
responsible for the detection and signaling of oxygen level changes, and the 
mechanisms that mediate adaptive changes in metabolism, oxygen sensing, and 
gene expression. For the purpose of this announcement, intermittent hypoxia is 
defined as repetitive hypoxic episodes lasting up to two minutes.


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), 
Oxygen Sensing During Intermittent Hypoxia, is related to one or more of the 
priority areas. Potential applicants may obtain a copy of "Healthy People 
2000" at http://odphp.osophs.dhhs.gov/pubs/hp2000.


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 

Multiple applications from the same institution will not be considered for 
support under this program unless each application is submitted by a different 
principal investigator, and is self-contained and independent of other 
applications from that institution. Overlap in the scientific scope of 
applications from the same institution will not be accepted. This does not 
preclude cooperation among participants after awards are made. If more than 
one application is envisioned from an institution, the investigators are 
encouraged to discuss their plans with one of the program administrators 
listed under INQUIRIES. 


This RFA will use the National Institutes of Health (NIH) research project 
grant (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 according to the customary peer review procedures. The 
anticipated award date is September 30, 2000.

Specific application instructions have been modified to reflect "MODULAR 
GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH. 
Complete and detailed instructions and information on Modular Grant 
applications can be found at 


The NHLBI intends to commit $3.6 million in FY 2000 to fund up to 14-16 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 of up to $175,000 (7 modules) 
per year, excluding facilities and administrative (F&A) costs on consortium 
arrangements. Because the nature and scope of the research proposed in each 
application may vary, it is anticipated that the size of each award will also 
vary. Although the financial plans of the National Heart, Lung, and Blood 
Institute provide support for this program, awards pursuant to this RFA are 
contingent upon the availability of funds, and the scope and merit of 
applications received.



Recent progress in understanding the molecular bases of oxygen sensing 
mechanisms provides a strong foundation for studying cellular responses to 
intermittent hypoxia and characterizing its cumulative effects. Studies of 
oxygen sensing and signaling mechanisms based on models of continuous hypoxia 
may not be applicable to understanding physiological or pathological responses 
during intermittent hypoxic episodes such as in sleep apnea, central 
hypoventilation syndrome, apnea of prematurity, and vascular occlusion 
associated with sickle cell disease. Episodes of intermittent systemic or 
local hypoxia affect metabolic pathways, induce angiogenesis, and affect 
inflammatory responses. The inability of cells to detect and adapt rapidly to 
changes in oxygen may underlie various vascular, pulmonary, coronary, 
cerebral, and sleep disease states. Hypoxia has also been shown to modulate 
the activity of gene regulators, growth factors, and reactive oxygen species 
that serve as intermediary signals in the cellular response to oxygen level 
changes. Furthermore, cyclic reductions in blood oxygen saturation of 30-50% 
during sleep apnea are associated with blunted chemosensitivity, and increased 
risk of hypertension, myocardial infarction, cerebrovascular disease, and 
neurocognitive deficits.

Research Scope

New approaches and paradigms are needed to investigate the effects of 
intermittent oxygen depletion and reoxygenation in a wide variety of tissues 
and cell types. Little is known of the function of heme-containing compounds, 
membrane conductances, calcium homeostasis, and other elements in the 
metabolic and signaling cascade mediating chemotransduction during 
intermittent hypoxia. The function of the red blood cell and other blood 
components as oxygen-sensing units also needs to be characterized. 
Hypoxia-induced free intracellular calcium level changes have been closely 
related to alterations in mitochondrial function, signal transduction, 
transmitter secretion, and the regulation of gene expression. A number of 
genes have been identified whose transcription is markedly stimulated when 
cells continuously lack oxygen. Characterization of the effects of 
intermittent hypoxia on gene expression through oxygen sensitive protein 
kinases and other regulators of transcription is needed to better understand 
the mechanisms by which cells adapt and respond to changes in oxygen levels. 
The role of reactive oxygen species during intermittent hypoxia also needs to 
be investigated since much of the remaining oxygen may go to the production of 
intermediates that influence the signaling pathways between nucleus and 
mitochondria, mitochondrial function, blood vessel tone, and cell survival. 
Transgenic technologies that alter gene expression in specific tissues or in 
response to pharmacological stimulation could be used to address these issues.

Clarification of the molecular events during intermittent hypoxia will help 
elucidate hypoxia-related pathology in a wide range of tissues. One 
fundamental question relates to the role of intermittent cycles of hypoxia and 
reoxygenation in disease. For example, sleep apnea is associated with 
congestive heart failure and reduced survival. We need to know whether 
intermittent hypoxia during heart failure exacerbates tissue injury through 
changes in vascular smooth muscle function, vascular permeability, or 
apoptotic cardiac cell death.  Intermittent hypoxia may contribute to vascular 
or pulmonary inflammation.  Developing biomarkers and imaging techniques that 
identify or assess these inflammatory changes should help in the early 
detection of disease. Hypoxia responsive genes are widely expressed during 
embryogenesis, regulate  proliferation or  differentiation of cells, and 
affect the development of critical systems such as glucose metabolism, 
hematopoiesis, and blood vessel development. There is a need for studies that 
characterize developmental effects of intermittent hypoxia on heart, lung, 
vascular, and blood tissues, and the maturation of central pathways regulating 
the function of these tissues. 

This RFA is designed to stimulate molecular, genomic, and biophysical 
approaches to studying the effects of intermittent hypoxia on gene expression, 
cellular signaling pathways, and oxygen sensing in a variety of tissues. 
Listed below are examples of studies that would be responsive to this program. 
These are only illustrative examples and applicants are encouraged to propose 
other topics consistent with the goals of this program. Not all areas need to 
be addressed in a single application. 

o Elucidation of the signal transduction, gene regulating, and mitochondrial 
mechanisms that mediate oxygen sensing during intermittent hypoxia in central 
and peripheral tissues, and of the time course and oxygen level threshold for 
adaptive changes in cellular, local, or systemic responses.

o Elucidation of the role of intermittent hypoxia in tissue injury produced by 
alterations in mitochondrial electron transport, mitochondrial genome damage, 
or oxidant and excitotoxic stress contributing to heart, lung, blood, or sleep 

o Development and use of noninvasive approaches and biomarkers for tissue-
specific mapping of changes in gene expression and the cellular injury 
produced by intermittent hypoxia, and to identify and assess oxidative injury 
and vascular inflammation in brain and other tissues at early time points in 
sleep apnea patients. 

o Development and use of animal models to elucidate the cellular mechanisms 
mediating effects of intermittent hypoxia on autonomic control of heart rate, 
cerebral blood flow, respiration, or the daily rhythm of cytokine-immune and 
endocrine function.

o Identification and characterization of cellular mechanisms that may regulate 
vascular tone in response to intermittent hypoxia such as the nitric oxide 
synthase system and the microsomal electron transporting systems associated 
with P450 enzymes.

o Identification and characterization of intermittent hypoxia effects on 
angiogenesis, the structure and permeability of the blood brain barrier, or 
the microvasculature of organ systems in newborns and adults.

o Identification and characterization of mechanisms through which intermittent 
hypoxia contributes to either atherosclerotic or  hypertensive diseases.

o Elucidation of the pathophysiological role of intermittent hypoxia during 
vascular occlusion in sickle cell disease.

o Identification and characterization of molecular events that follow 
intermittent, localized hypoxia in individuals with thrombosis. 

o Characterization of intermittent hypoxic effects on interactions between the 
hemostatic system and endothelium including changes in leukocyte adhesion.

o Elucidation of the role of intermittent hypoxia and abnormal oxygen sensing 
in polycythemia vera.

o Elucidation of molecular effects of intermittent hypoxia on hematopoiesis, 
including megakaryocyte development and platelet production.

o Identification and characterization of oxygen sensing mechanisms in red 
blood cells that are responsive to intermittent hypoxia.


In order to be considered responsive to this announcement, applications must 
propose hypothesis-driven studies that address the molecular effects of brief 
intermittent systemic or local hypoxia (repetitive hypoxic episodes lasting up 
to two minutes) as it occurs in diseases like sleep apnea and sickle cell 
microvascular occlusions. If in vitro models are proposed, they must test the 
effects of intermittent hypoxia as defined in this announcement. Research 
should be linked to understanding the role of intermittent hypoxia in 
disorders affecting the heart, vasculature, lung, blood, or sleep. Studies to 
elucidate the effects of a single hypoxic episode, chronic hypoxia, or 
ischemia are not responsive to this RFA. Applications focused solely on the 
development of methodology without plans for addressing the goals of this RFA 
will not be accepted. Studies needed to develop biomarkers or to overcome 
barriers such as the development of instrumentation should be integrated into 
the proposed research program.

Collaborations and consortia promoting interdisciplinary approaches between 
scientists studying the molecular biology of the carotid body and arterial 
oxygen sensing, genetics, vascular and sickle cell disease, immunology, and 
developmental biology are strongly encouraged. In such cases, each 
participant's contribution should be identified and well-integrated into the 
overall experimental design.

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 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 information.


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).

All investigators proposing research involving human subjects should read the 
"NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical 
Research," which was published in the Federal Register of March 28, 1994 (FR 
59 14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No. 
11, March 18, 1994, available on the web at: 


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 
address: https://grants.nih.gov/grants/guide/notice-files/not98-024.html.

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.


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 IC staff to 
estimate the potential review workload and avoid conflict of interest in the 

The letter of intent is to be sent to Dr. C. James Scheirer listed under 
INQUIRIES by the letter of intent receipt date listed in the heading of this 
RFA, January 24, 2000.


The research grant application form PHS 398 (rev. 4/98) is to be used in 
applying for these grants. These forms are available at most institutional 
offices of sponsored research and from the Division of Extramural Outreach and 
Information Resources, National Institutes of Health, 6701 Rockledge Drive, 
MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: 
GrantsInfo@nih.gov and on the internet at 

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 Institute 
staff. The research grant application form PHS 398 (rev. 4/98) is to be used 
in applying for these grants, with the modifications noted below.


Modular Grant applications will request direct costs in $25,000 modules, up to 
a total direct cost request of $175,000 (7 modules) per year excluding F&A 
costs on consortium arrangements. The total direct costs must be requested in 
accordance with the program guidelines and the modifications made to the 
standard PHS 398 application instructions described below:

PHS 398

o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in 
$25,000 increments up to a maximum of $175,000) and Total Costs [Modular Total 
Direct plus F&A costs] for the initial budget period Items 8a and 8b should be 
completed indicating the Direct and Total Costs for the entire proposed period 
of support.

of the PHS 398. It is not required and will not be accepted with the 

categorical budget table on Form Page 5 of the PHS 398. It is not required and 
will not be accepted with the application.

o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative 
page. (See https://grants.nih.gov/grants/funding/modular/modular.htm for sample 
pages.) At the top of the page, enter the total direct costs requested for 
each year. This is not a Form page.

o Under Personnel, List key project personnel, including their names, percent 
of effort, and roles on the project. No individual salary information should 
be provided. However, the applicant should use the NIH appropriation language 
salary cap and the NIH policy for graduate student compensation in developing 
the budget request.

For Consortium/Contractual costs, provide an estimate of total costs (direct 
plus F&A costs) for each year, each rounded to the nearest $1,000. List the 
individuals/ organizations with whom consortium or contractual arrangements 
have been made, the percent effort of key personnel, and the role on the 
project. Indicate whether the collaborating institution is foreign or 
domestic. The total cost for a consortium/contractual arrangement is included 
in the overall requested modular direct cost amount. Include the Letter of 
Intent to establish a consortium.

Provide an additional narrative budget justification for any variation in the 
number of modules requested.

o BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by 
reviewers in the assessment of each individual's qualifications for a specific 
role in the proposed project, as well as to evaluate the overall 
qualifications of the research team. A biographical sketch is required for all 
key personnel, following the instructions below. No more than three pages may 
be used for each person. A sample biographical sketch may be viewed at: 

- Complete the educational block at the top of the form page;
- List position(s) and any honors;
- Provide information, including overall goals and responsibilities, on 
research projects ongoing or completed during the last three years.
- List selected peer-reviewed publications, with full citations;

o CHECKLIST - This page should be completed and submitted with the 
application. If the F&A rate agreement has been established, indicate the type 
of agreement and the date. All appropriate exclusions must be applied in the 
calculation of the F&A costs for the initial budget period and all future 
budget years.

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. 

The RFA label available in the PHS 398 (rev. 4/98) application form must have 
the RFA number typed on it and be affixed to the bottom of the application 
face page. 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.

A sample RFA label available at: 
https://grants.nih.gov/grants/funding/phs398/label-bk.pdf 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 must be 
sent to Dr. C. James Scheirer 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 review.

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.


Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by the NHLBI. Incomplete and/or non-responsive applications 
will be returned to the applicant without further consideration or submitted 
for review in competition with unsolicited applications at the next review 

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, a process will be used by the initial review group in 
which applications 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 Heart, Lung, 
and Blood Advisory Council.

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 

(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 support?

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:    January 24, 2000
Application Receipt Date:         February 23, 2000
Peer Review:                      June/July, 2000
Council Review:                   September 7-8, 2000
Anticipated Award Date:           September 30, 2000


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

o scientific merit (as determined by peer review)

o availability of funds

o program balance.


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:

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

Greg Evans, Ph.D.
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 10152 (MSC 7950)
Bethesda, MD 20892-7950
Telephone:  (301) 435-0055
FAX:  (301) 480-0868
Email: EvansG@nih.gov 

Stephen Goldman, Ph.D.
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 10192 (MSC 7956)
Bethesda, MD 20892-7956
Telephone:  (301) 435-0565
FAX:  (301)
Email: GoldmanS@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 Dr.,Room 7220 (MSC 7924)
Bethesda, MD 20892-7924
Telephone: (301) 435-0266
Fax: (301) 480-3460
Email: js110j@nih.gov 

Direct inquiries regarding fiscal matters to:

Raymond Zimmerman
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
E-mail: ZimmermR@nih.gov 


This program 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 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 

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