Release Date:  September 7, 2001

RFA:  RFA-HL-02-003

National Heart, Lung, and Blood Institute
National Institute of Neurological Disorders and Stroke

Letter of Intent Receipt Date:  January 10, 2002
Application Receipt Date:       February 12, 2002



This RFA supports novel basic research designed to elucidate effects of 
whole-body ischemia and subsequent blood flow restoration on cardiovascular 
and neurological function.  The ultimate goal is to provide a rational basis 
for development of effective new therapeutic strategies to restore heart 
function and preserve neurological function after cardiopulmonary arrest.


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), 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 


This RFA will use the National Institutes of Health (NIH) research 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 and be reviewed according to the customary 
peer review procedures.  The anticipated award date is September 30, 2002.

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 


The NHLBI intends to commit $3 million total costs in FY2002 to award up to 8 
new grants submitted in response to this announcement.  NINDS will contribute 
up to $1 million  total costs in FY2002 for award of up to 3 new grants.  An 
applicant may request a project period of up to four years and a budget for 
direct costs of up to $250,000 (10 modules) per year, including facilities and 
administrative (F&A) costs on consortium arrangements.  Because the nature and 
scope of the research proposed may vary, the amount of each award should also 
be expected to vary.  Although the financial plans of the National Heart, 
Lung, and Blood Institute and the National Institute of Neurological Disorders 
and Stroke provide support for this program, awards pursuant to this RFA are 
contingent upon the availability of funds in each fiscal year, and receipt of 
a sufficient number of meritorious applications.



Chances of survival following cardiac arrest are poor.  Although the average 
time from arrest to defibrillation by trained medical personnel in large 
American cities have decreased dramatically to as short as 16 minutes, the 
survival rate following out-of-hospital arrest continues to be less than five 
percent.  Thus, despite marked decreases in the time before initiation of 
medical aid to arrest victims, there remains tremendous need for development 
of new, effective interventions to restore blood flow to vital body organs 
including the heart and brain following cardiopulmonary arrest.  New 
interventions should, in addition to restoring the heart beat, minimize and 
prevent irreversible cardiac and cerebral damage due to oxygen deprivation 
that may be exacerbated by restoration of blood flow throughout the body.  Any 
advances in therapy for cardiopulmonary arrest require an improved basic 
science understanding of the pathophysiology of whole-body ischemia and 
subsequent reperfusion injury.

Cardiac arrest, and the resulting whole-body ischemia, creates a unique state 
that affects many distant, otherwise healthy organs, including perturbations 
in systemic blood pH and compromised  cerebral, renal, and pulmonary function, 
as well as a multitude of other poorly understood pathophysiologic 
alterations.  Such changes may have a significant impact on cardiovascular and 
neurologic functions, particularly once blood flow is restored.  The global 
changes to the internal milieu and distinct organ systems are difficult to 
mimic in isolated organ paradigms and other in vitro preparations.  
Understanding of the molecular, cellular, and biochemical interactions 
initiated within the heart, brain, and the other essential organs of these 
organs by whole-body ischemia should ultimately lead to amelioration and 
prevention of irreversible damage and allow successful cardiopulmonary 

Recently, several concepts drawn from fundamental investigations, 
cardiothoracic surgical experiences, and cardiac arrest studies, provide 
directions for the development of new therapeutic strategies to improve 
cardiac and neurological outcomes after cardiac resuscitation and to restore 
function following cardiopulmonary arrest, whole-body ischemia, and 
restoration of blood flow throughout the entire body.  These new directions 
include reducing:  (1) cardiac metabolic demands to allow additional time for 
the arrest victim to receive in-hospital medical treatment to restore heart 
function, (2) reducing the effects of cardiac ischemia and reperfusion injury, 
and (3) optimizing cardiac defibrillation effectiveness.  The effects of these 
procedures on subsequent cardiovascular and brain function, including stroke, 
hemorrhage or neurocognitive consequences, in survivors have yet to be 
evaluated.  These new research avenues were the basis for discussion during 
the Post-Resuscitation and Initial Utility in Life Saving Efforts (PULSE) 
workshop, sponsored in part by the NHLBI in the summer of 2000 and summarized 
in the published Workshop Executive Summary Report (Circulation 
One strategy to improve cardiopulmonary resuscitation outcomes might include 
induction of a temporary hypo-metabolic state of "hibernation" to both halt 
progression of arrest-initiated pathological processes and to prolong the time 
for additional medical interventions to restore cardiac and brain circulation 
and function.  Hypothermia, for instance, slows destructive enzymatic 
reactions, suppresses the destructive effects of free radicals, and alters 
lipoprotein membrane complianceB all organ-protective effects.  Understanding 
the arrest-induced metabolic perturbations and their consequence in the 
setting of reduced metabolic demands could lead to the development of 
biochemical or pharmacologic methods to dramatically reduce ischemic and 
reperfusion damage induced by cardiopulmonary arrest.

Interventions that ameliorate reperfusion injury following resuscitation 
represent another possible strategy to improve resuscitation of cardiovascular 
and neurologic function following arrest.  Cardiac surgical experience 
suggests that extracorporal control of reperfusion protects against myocardial 
damage during whole-body ischemia and reperfusion.  Experimental data also 
suggests that certain drug combinations mitigate ischemia/reperfusion damage 
and mimic the protective effects of ischemic preconditioning.  Such drug 
combinations might include:  antioxidants, drugs that block the 
leukocyte-endothelial cell cascade, antibodies to neutrophil adhesion 
molecules, and agents that modify ion channel, exchanger, and pump activities. 
The effectiveness of such methods to control cardiac reperfusion and drug 
combinations to curtail myocardial, cerebrovascular, or neuronal 
ischemia/reperfusion injury need to be examined in appropriate models of 
whole-body ischemia.

Another approach to improving cardiopulmonary resuscitation outcomes could be 
to limit the apoptotic process following whole-body ischemia and restoration 
of whole body blood flow.  In models of acute myocardial ischemia, caspase 
inhibitor administration prior to ischemia decreases myocyte apoptosis and 
infarct size.  Transgenic mice with cardiac overexpression of a protein that 
inhibits cytochrome c release and subsequent caspase activation exhibit less 
myocyte apoptosis and smaller myocardial infarcts following 
ischemia-reperfusion.  Inhibition of cardiocyte apoptosis, therefore, may 
provide a novel approach for reducing both cardiac ischemic damage and 
myocardial reperfusion injury.  Similarly, research on the roles of the 
various caspases in focal and global cerebral ischemia indicates that this 
enzyme cascade can activate both cell death and survival mechanisms in 
neurons.  Further research on the involvement of caspases in cells of the 
cerebrovascular/neuronal unit is needed. 

New, improved methods to restore and preserve heart rhythm following 
cardiopulmonary arrest would result from improved understanding of the effects 
of whole-body ischemia and restoration of blood flow to the entire body.  
Although rapid defibrillation is standard care for cardiac arrest, successful 
defibrillation rates rapidly decrease as the period of myocardial ischemia 
following arrest increases.  In addition, cardiac surgeons note that dilated 
hearts are difficult to defibrillate; the question arises as to whether 
biomechanical factors also play an important role in determining 
defibrillation success or failure following arrest.  Understanding 
interactions between whole-body ischemia, optimal defibrillation thresholds, 
and restoration of blood flow to the body appear critical to successful 
defibrillation and cardiac resuscitation.

Research Scope

Novel approaches to better understand the effects of whole-body ischemia and 
restoration of whole-body circulation on cardiovascular performance and 
neurological involvement, and the application of these findings to development 
of effective new strategies to improve cardiopulmonary resuscitation are 
sought.  New research collaborations are encouraged.  Some examples of 
research that might address the effects of whole-body ischemia on 
cardiovascular and neurologic functions and how they may be ameliorated to 
reduce or prevent ischemia/reperfusion injury during resuscitation from 
cardiopulmonary arrest include:  

o  characterization of the molecular, biochemical, and physiologic alterations 
in heart and brain function initiated by whole-body ischemia and how they may 
be affected by restoration of whole-body blood flow, 

o  development of interventions to inhibit or limit the detrimental effect of 
whole body ischemia, such as the rapid induction of hypometabolic states, on 
restoration of heart and brain function  in the setting of whole-body 

o  development of models of whole-body ischemia and whole-body blood flow 
restoration to mimic the effects of cardiopulmonary arrest and allow testing 
of the effectiveness of promising experimental interventions to effectively 
restore heart and brain function, 

o  studies to evaluate experimental treatments that may have differential 
effects on heart and brain outcomes following whole body ischemia and 
restoration of blood flow,

o  development of effective defibrillation techniques in the setting of 
whole-body ischemia and restoration of blood flow to the entire body, and 

o  utilization of genetically altered animal models to elucidate the 
integrated role of specific gene products and signaling systems in determining 
the cardiovascular and neurologic responses to whole-body ischemia and 


For applications to be considered responsive to this RFA, proposed studies 
need to address the effects of whole body ischemia / reperfusion on 
cardiopulmonary or neural function.  Studies that focus on the effects of 
cardiac or cerebral ischemia / reperfusion (i.e., regional or focal organ 
ischemia / reperfusion) alone will not be considered responsive and will be 
returned to the applicant without further consideration.  In addition to 
yearly progress reports, the Principal Investigators of grants funded under 
this RFA will be expected to participate in yearly grantee meetings to present 
findings of the research supported and suggest future research directions.  
Funds for travel to such meetings must be incorporated in the standard NIH 
travel allowance for principal investigators.


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 this RFA.  
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. Beebe at the address listed under 
INQUIRIES by January 10, 2002.


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 beginning on page 
13 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 RFA label is also available at:

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 

Principal investigators should not sent 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 within three weeks after 
submitting the application, contact Dr. Deborah Beebe at the address listed 
under Inquiries.

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.

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 applicants 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 Heart, Lung, and Blood Advisory Council and the 
National Advisory Neurological Disorders and Stroke 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 
their 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.  Because of the nature of this RFA, and application must be judged to 
be innovative to deserve a high priority score.

(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 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.  If the proposed research includes studies in human subjects, plans 
for the recruitment and retention of subjects will also be evaluated.

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 10, 2002
Application Receipt Date:         February 12, 2002
Peer Review Date:                 June/July 2002
Council Review:                   September 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  program priorities.

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:

David A. Lathrop, Ph.D.
Division of Heart And Vascular Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 9186 (MSC 7940)
Bethesda, MD  20892-7940 (20817 for Courier)
Telephone:  (301) 435-0504
FAX:  (301) 480-1454

Mariana Gerschenson, Ph.D.
Division of Heart And Vascular Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 9180 (MSC 7940)
Bethesda, MD  20892-7934 (20817 for Courier)
Telephone:  (301) 435-0515 
FAX:  (301) 480-1336 

Mary Ellen Michel, Ph.D.
National Institute of Neurological Disorders and Stroke
Neuroscience Center, Room 2222, MSC 9525
6001 Executive Boulevard
Rockville, MD  20892-9525 (20852 for Courier)
Telephone:  (301) 496-1447
FAX:  (301) 480-1080

Send letter of intent and 2 copies of the application and direct inquiries 
regarding review matters to:

Deborah P. Beebe, Ph.D.
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Dr., Room 7178 (MSC 7924)
Bethesda, MD  20892-7924 (20817 for Courier)
Telephone:  (301) 435-0270
Fax:  (301) 480-3541

Direct inquiries regarding fiscal matters to:

Ms. Teneshia Alston
Grants Operations Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7156, MSC 7926
Bethesda, Maryland  20892-7926
Telephone:  (301) 496-6740
FAX:  (301) 480-3310


This program is described in the Catalog of Federal Domestic Assistance No. 
93.837 and 93.853.  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 people.

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