CARDIOVASCULAR, LUNG, AND BLOOD IMMUNOBIOLOGY IN HEALTH AND DISEASE

Release Date:  January 2, 2001

RFA:  RFA-HL-01-003

National Heart, Lung, and Blood Institute
 (http://www.nhlbi.nih.gov/)

Letter of Intent Receipt Date:  March 1, 2001
Application Receipt Date:       March 29, 2001

THIS RFA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS.  IT INCLUDES
DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED
WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA.

PURPOSE

The National Heart, Lung, and Blood Institute (NHLBI) invites research grant 
applications to conduct studies on the immunobiology of health and disease in
the cardiovascular, pulmonary, OR blood systems.

The intent of this Request for Applications (RFA) is to stimulate research
that will increase fundamental knowledge of the cellular and molecular
components and mechanisms and signaling processes that regulate the immune
system in cardiovascular, pulmonary, and blood tissues and are important in
healthy tissue maintenance, damaged tissue repair, or disease pathogenesis.
Toward this goal, this initiative strongly encourages scientific
collaborations among investigators with interest in cardiovascular, pulmonary
or blood systems with investigators who study inflammation and immunology. 

ALTHOUGH IMMUNOBIOLOGY IS A COMMON THREAD, THE INTERESTS WITHIN EACH AREA
(CARDIOVASCULAR, PULMONARY, AND BLOOD)ARE DIFFERENT.  THEREFORE, APPLICANTS
SHOULD PAY CLOSE ATTENTION TO THE CARDIOVASCULAR, PULMONARY, OR BLOOD SECTION
OF THIS RFA THAT IS RELEVANT TO THEIR APPLICATION.  PRIOR TO SUBMITTING AN
APPLICATION, APPLICANTS ARE STRONGLY ENCOURAGED TO DISCUSS THEIR PLANNED
APPLICATION WITH APPROPRIATE PROGRAM STAFF LISTED IN THE INQUIRIES SECTION
BELOW. IT IS SUFFICIENT FOR APPLICATIONS TO FOCUS ON ONE OF THE THREE AREAS
(e.g., CARDIOVASCULAR, PULMONARY, BLOOD) AND SUCH APPLICATIONS WILL BE
CONSIDERED RESPONSIVE TO THIS RFA.  FINAL AWARD DECISIONS WILL INCLUDE A
CONSIDERATION OF PROGRAMMATIC BALANCE.

HEALTHY PEOPLE 2010

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),
"Immunobiology of Cardiovascular, Pulmonary, and Blood Systems in Health and
Disease," is related to one or more of the priority areas.  Potential
applicants may obtain a copy of "Healthy People 2010" at
http://www.health.gov/healthypeople/.

ELIGIBILITY REQUIREMENTS

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.  Awards under this RFA to foreign
institutions will be made only for research of very unusual merit, need, and
promise, and in accordance with PHS policy governing such awards. 
Racial/ethnic minority individuals, women, and persons with disabilities are
encouraged to apply as Principal Investigators.

MECHANISM OF SUPPORT

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 4 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, 2001.

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
http://grants.nih.gov/grants/funding/modular/modular.htm

FUNDS AVAILABLE

The NHLBI intends to commit approximately $5,600,000 in FY 2001 to fund 15 to
17 new grants in response to this RFA. An applicant may request a project
period of up to 4 years and a budget for direct costs of up to $250,000 per
year or 10 modules of $25,000 each. Because the nature and scope of the
research proposed may vary, it is anticipated that the size of each award will
also vary. Although the financial plans of the NHLBI provide support for this
program, awards pursuant to this RFA are contingent upon the availability of
funds and the receipt of a sufficient number of meritorious applications.

RESEARCH OBJECTIVES

Background

Cardiovascular disease is a major cause of death and disability in the United
States.  Known risk factors do not fully account for its widespread
prevalence.  New experimental findings suggest that the immune response
contributes to the wide range and complexity of pathogenesis that has been
observed in diseases of the heart and vasculature.  Close proximity of cells
of the immune and inflammatory systems with cells that comprise the blood
vessel provide a unique environment for the influence of one on the function
or structure of the other.  Lymphoid cell infiltration is an early event in
the development of atherosclerosis and immunoregulatory molecules are
expressed by vascular cells in coronary and peripheral arterial diseases and
at sites of myocardial reperfusion injury.  Interruption of immune signaling
mitigates atherosclerosis and several recent lines of evidence implicate the
immune system in plaque vulnerability which can contribute to acute ischemic
coronary syndromes.  Distinct subpopulations of T lymphocytes have been
identified in patients with unstable angina and other cardiovascular
syndromes.  In addition, interest in the role of immune signaling in vascular
remodeling associated with disease pathogenesis is emerging.

The intense inflammatory reaction following reperfusion of the infarcted
myocardium or cardiopulmonary bypass (CPB) has been implicated as a factor in
extension of injury.  However, inflammation is also critical to tissue repair.
CPB also induces a systemic inflammatory response that causes substantial
clinical morbidity.  Both the trauma of surgery and reperfusion injury
contribute to the inflammation.   A better understanding of the cell types and
cytokines that participate in these evolving processes is essential in order
to differentiate factors responsible for injury from those critical for
healing.  

Pulmonary immunology is an understudied area of lung research that offers
unique opportunities to define not only lung homeostasis but also activation
pathways which lead to disordered inflammatory and immune responses and their
contribution to a variety of idiopathic or progressive and chronic lung
diseases.  Moreover, the respiratory system faces unique immunologic demands
and provides a unique environment in which immunologic and inflammatory
responses take place.  The lung appears to have adapted novel pathways of
immune control in order to process foreign antigens in a manner which does not
interfere with its primary biological functions.  Very little has been done to
characterize the pulmonary immune system per se, which is a key element to
further our understanding of lung homeostasis and disease.  Understanding the
mechanisms that keep the pulmonary immune system and the associated
inflammatory response in check and yet prepared to respond quickly to
potentially deadly or disease-causing materials is important to developing
knowledge-based approaches to intervening in many pulmonary diseases. 

Alterations in the pulmonary immune system are likely to occur as a
consequence of disrupted or aberrant lung development; and, such alterations
can adversely affect development of normal lung structure and function. 
Evidence is accumulating that, even in utero, unmodulated inflammatory events
can disrupt the course of normal lung development.  Thus, understanding the
process of normal lung development and maturation of pulmonary immune
components is critical to evaluation of the influence of inflammatory
cytokines and growth factors on the course of normal lung development.  Such
information should help to uncover mechanisms by which pulmonary immune system
dysfunction at crucial developmental junctures may pre-dispose individuals to
chronic lung diseases of early onset (e.g., bronchopulmonary dysplasia,
asthma), and those which develop later in life (e.g., adult respiratory
distress syndrome and interstitial pulmonary fibrosis. 

In recent years it has become clear that the immune system has a significant
impact on many key systems of the blood, including those that regulate
hemostasis and oxygen transport.  The immune system may contribute to the
pathogenesis of many hematologic diseases, and to adverse or beneficial
outcomes of their treatment.  A growing body of evidence suggests that the
pathogenesis of some vascular blood diseases is dependent on inflammatory
processes initiated by immune mediators.  Sickle cell disease (SCD) is an
example where the role that inflammation plays in pathogenesis has yet to be
adequately tested. The immune system also may contribute significantly to
pathogenesis in disorders of hemostasis (e.g. thrombosis, and coagulation
disorders). Inflammation may contribute to thrombosis through the selectin
family of receptors, the complement system, or inflammatory cytokines secreted
by activated macrophages and lymphocytes.  There is also evidence that
inflammatory processes may be dependent on key blood proteins involved in
thrombosis, coagulation, and fibrinolysis. The immune system is involved in
immune thrombocytopenias, where new approaches to studying the pathogenic
effects of autoantibodies may lead to the development of new therapeutics and
improved criteria for the classification of patients. 

Other

This RFA is intended to solicit applications to investigate components, 
molecular mechanisms, and signaling processes that are involved in and
regulate the immune and inflammatory systems; and, are important in
cardiovascular, pulmonary, or blood disease pathogenesis or maintaining
healthy tissue in these systems.  Multidisciplinary studies that bring
together investigators with expertise in immunology, inflammation, and
molecular and cellular biology with investigators with expertise in the
cardiovascular, pulmonary, or hematologic system are encouraged, as are those
that address basic areas that have the potential to lead to development of new
treatments.

Some research topics that will be responsive to this program are listed below. 
These are only examples; applicants are encouraged to propose other topics 
that address the overall goals of this initiative and consistent with the
SPECIAL REQUIREMENTS section below.

APPLICANTS ARE STRONGLY ENCOURAGED TO CONTACT PROGRAM STAFF LISTED IN THE
INQUIRIES SECTION BELOW BEFORE DEVELOPING AN APPLICATION.


For Heart and Vascular-related Applications:

o  Identify immune pathways, immunoregulatory mechanisms, inflammatory cells
and molecules, and immune signaling involved in atherogenesis, accelerated
atherosclerosis, acute ischemic coronary syndromes, plaque vulnerability,
myocardial reperfusion injury, and vascular remodeling and subsequent changes
in vascular tone and permeability.  Of particular interest are studies that
identify which features of the immune response are protective, cause disease,
or exacerbate injury.  Studies that define the transition from innate to
adaptive immunity and the importance of the transition in heart and vascular
diseases are needed.  

o  Determine how immune pathways and processes such as antigen recognition and
co-stimulation, clonal expansion or ablation of lymphocyte subpopulations, and
alterations in cytokine profiles relate to acute and chronic coronary
syndromes.  Characterization of determinants of atheroantigenicity and
neoepitope formation resulting from oxidative modification of lipoproteins,
phospholipids, or fatty acids, as well as the significance of antibodies to
lipid oxidation products is an important element.  Similarly, understanding
the relevance of heat shock proteins in atherogenesis, the nature of their
interactions with products of lipid metabolism, and how and whether they
contribute to the immunogenicity of such products is of interest.

o  Identify the cell types and cytokines that play a role in the inflammatory
response following reperfusion or cardiopulmonary bypass, specifically
defining the regulatory mechanisms and the role of adhesion molecules in
initiating, perpetuating, or down-regulating reperfusion-type injuries and
identifying compensatory, healing components from the injurious components of
the response.

For Pulmonary-related Applications:

o  Characterize the mechanisms regulating lung innate immunity, immune
tolerance, homeostasis and the interactions between lung immunity and
inflamation.  Such investigations would explore how the lung determines if up-
regulation of inflammation and an immune response are appropriate for the
foreign material that has entered the lung.  In addition, investigations would
attempt to identify the specific inflammatory and immune cells and mediators
or lung architecture that contribute to pathways that permit or initiate an
appropriate vigorous response or prevent an inappropriate over-expression. 
Elucidation of mechanisms involved in the down-regulation and prevention of
lung-specific immune responses may be particularly important.  A component of
such control may include how antigens are actively processed in the lung and
whether there are fundamental differences in the way antigens are processed
and presented in the lung.  Another element that might affect the response is
the local milieu - the difference of responses in the mucosa of the upper
airway compared to alveoli or the interstitium.  Related to the milieu is the
influence of the physical location of the lymphoid tissue - nasal-associated
lymphoid tissue (NALT), bronchiole-associated-lymphoid tissue (BALT), and
draining lymph nodes - on the response.

o  Delineate the maturation of the immune system in the lung and learn: a) how
it relates to pulmonary defense mechanisms against microbial pathogens or
foreign antigens in utero, in early life, and during childhood and b) how
pathogens or antigens, and the response to them, modify lung repair and growth
in neonates, children, and adults.  Research in the area of immune system
development in the fetus and infant should offer considerable insight into how
the pulmonary immune system learns to encounter foreign material without an
inflammatory response.

For Blood-related Applications:

o  Investigate the contribution of inflammation and the immune response to 
clinical manifestations seen in sickle cell disease, particularly inflammation 
that may be initiated by early cell-cell interactions between sickle red blood 
cells, neutrophils, monocytes, endothelial cells, or platelets in the blood. 
It is also important to know the value of white blood cell counts, and blood
flow  in assessment of patient status during the inflammatory events. It would
be useful to know the effect of anti-inflammatory agents on disease phenotype
in human patients, or in animal models, especially on the rate of vaso-
occlusive crises.  In addition, more information is needed on the role of
specific endothelial adhesion molecules (e.g. selectins), cytokine receptors,
and chemokines in vaso-occlusive crises, perhaps through the use of animal
models of the disease, which also have been engineered to be deficient in the
molecules listed.  Related investigations of the role of selectins, the
complement system, and hemostatic and fibrinolytic factors (including
activated protein C) in inflammation, thrombosis and sepsis are also
important.  Similarly, there is a need to explore the role of inflammation,
cytokines, and selectins in venous inflammation and thromboembolic disease,
with a possible goal of designing new therapeutic inhibitors.

o  Develop novel approaches to identify clinically relevant platelet-reactive
antibodies in ITP, TTP, and systemic lupus erythematosis, study the von
Willebrand factor-cleaving protease in TTP and hemolytic uremic syndrome,
study the role of phospholipid antibodies and annexin in thrombosis associated
with SLE, and study drug-induced autoimmune disorders (e.g. heparin-induced
thrombocytopenia) using new approaches such as the Fc gamma receptor.

SPECIAL REQUIREMENTS

In order to be considered responsive, applications need not address 
immunobiology of all three areas - cardiovascular, pulmonary, blood.  
Applications can address immunobiology in only one of the three areas -
cardiovascular, pulmonary, or blood.  However, the proposed research should
focus on the immune and inflammation systems and not on a specific disease
with incidental inclusion of the immune and inflammation systems. Applications
using in vitro, cellular, or animal models or humans, to study the
cardiovascular, pulmonary or hematologic immune and inflammatory systems will
be considered responsive.  Studies that address development of the pulmonary
immune system or responses to blood transfusions also will be responsive.

Characteristics of applications that will be considered nonresponsive include: 

o  Applications that propose descriptive studies and do not contain
hypothesis-driven studies.  

o  Applications that primarily focus on disease pathology in the absence of a
major examination of the fundamental aspects of the cardiovascular, pulmonary,
or hematologic immune system. 

o  Transplant-associated coronary artery disease; lung transplantation and
lung transplant rejection, xenotransplantation, and stem cell transplantation

o  Applications concerned with autoimmune diseases of the heart, bacterial or
viral myocarditis, and hyperacute rejection of cardiac xenografts.  

o  Studies of modification of the cardiopulmonary bypass circuit, e.g.,
coating with heparin.  

o  Applications that propose research related to optimization of
non-myeloablative methods of stem cell transplantation to induce
allochimerism. 

o  Large clinical studies or epidemiologic studies.

Grantees' Meeting

Upon initiation of the program, the NHLBI will sponsor periodic meetings to
encourage exchange of information among investigators who participate in this
program.  Travel funds for a one day meeting each year, most likely to be held
in Bethesda, Maryland, should be included in the modules.  Applicants should
also include a statement in their application indicating their willingness to
participate in these meetings and to interact openly with other study
participants so as to provide the greatest promise for scientific advances
from the approved research scope of the awards.

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 are 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
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
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html); a
complete copy of the updated Guidelines are available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm:  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.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

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: http://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.

URLS IN NIH GRANT APPLICATIONS OR APPENDICES

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.

LETTER OF INTENT

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 faxed or mailed to Dr. Deborah Beebe at the
address listed under INQUIRES, by March 1.

APPLICATION PROCEDURES

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.

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.

The RFA label available in the PHS 398 (rev. 4/98) 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:
http://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:

CENTER FOR SCIENTIFIC REVIEW
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. Deborah Beebe, at the listing 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.

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS

BUDGET INSTRUCTIONS

Modular Grant applications will request direct costs in $25,000 modules, up to
a maximum of 10 modules or total direct cost request of $250,000 per year.  An
R01 grant  application may include research activities that involve
institutions other than the sponsoring organization, creating a consortium
effort.  The consortium costs should be included in the direct cost limit
($250,000).  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:

o  FACE PAGE:  Items 7a and 7b should be completed, indicating Direct Costs
(in $25,000 modules up to a maximum of $250,000) 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. 

o  DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page
4-DD of the PHS 398 (rev 4/98).  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 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 http://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 all 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 facilities and administrative) for each year, each rounded to the nearest 
$1,000.  For this RFA, the consortium costs (direct and F&A) should be
included in the $250,000 direct cost limit.  List the
individuals/organizations with whom consortium or contractual arrangements
have been made, the percent effort of all personnel, and the role on the
project.  Indicate whether the collaborative institution is foreign or
domestic.  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 modified instructions below.  No more than
three pages may be used for each person.  A sample biographical sketch may be
viewed at: http://grants.nih.gov/grants/funding/modular/modular.htm

- 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 citation;

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.

REVIEW CONSIDERATIONS

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 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 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 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.  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.

Schedule

Letter of Intent Receipt Date:    March 1, 2001
Application Receipt Date:         March 29, 2001
Peer Review Date:                 June/July 2001
Council Review:                   September 6-7, 2001
Earliest Anticipated Start Date:  September 2001

AWARD CRITERIA

Factors that will be considered in making awards include: a) the scientific
merit of the proposed program as determined by peer review; b) the multi
disciplinary nature of the proposed studies; c) meeting the special 
requirements stated in this RFA; d) relevance to the overall programmatic
balance and priorities of the NHLBI; and e) the availability of funds.

INQUIRIES

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:

David Robinson, Ph.D. (heart- and vascular-related applications)
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Diseases
6701 Rockledge Drive, Room 9158, MSC 7940
Bethesda, MD 20892-7952
Telephone:  (301) 435-0477
FAX:  (301) 480-7971
Email:  dr14j@nih.gov

or

Robert A. Musson, Ph.D. (pulmonary-related applications)
Division of Lung Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 10018, MSC 7952
Bethesda, MD  20892-7952
Telephone:  (301) 435-0222
FAX:  (301) 480-3557
Email:  rmusson@nih.gov

or

Greg Evans, Ph.D. (hematologic-related applications)
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room10152, MSC 7950
Bethesda, Maryland 20892-7950
Telephone:  (301) 435-0055
FAX:  (301) 480-0868
E-Mail: evansg@nih.gov

Direct inquiries regarding review issues, send letter of intent, and 2 copies
of the application to:

Deborah Beebe, Ph.D.
Chief, Review Branch
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Rm 7178, MSC 7924
Bethesda,  MD 20892-7924 (20817 for express mail)
Phone: (301) 435-0270
FAX: (301) 480-3541
E-Mail: beebed@nhlbi.nih.gov

Direct inquiries regarding fiscal matters to:

Robert Pike
Grants Operations Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7154, MSC 7926
Bethesda, MD 20892-7926
Telephone:  (301) 594-9529
FAX:  (301) 480-3310
E-mail: piker@nih.gov 

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.838.  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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