MOLECULAR AND PHYSICAL CHARACTERIZATION OF THE VULNERABLE PLAQUE

NIH GUIDE, Volume 26, Number 37, November 7, 1997

RFA:  HL-98-003

P.T.

National Heart, Lung, and Blood Institute

Letter of Intent Receipt Date:  February 2,1998
Application Receipt Date:  March 11, 1998

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

PURPOSE

The purpose of this solicitation is to promote research into the
properties of the atherosclerotic vulnerable plaque, especially
those that relate to its tendency to progress to erosion or to
rupture leading to thromboembolic events, unstable angina,
myocardial infarction, and/or sudden death. A special emphasis is
placed on multidisciplinary approaches in view of the variety of
research disciplines and strategies that are needed to study the
vulnerable plaque. Of interest would be studies on pathoanatomical
and biochemical issues to identify major determinants of plaque
vulnerability to erosion or rupture; humoral and systemic factors
involved in coronary thrombosis; the physical forces associated
with plaque disruption; and methods to identify and quantify the
physicochemical features of plaque in vivo.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the
health promotion and disease prevention objectives of Healthy
People 2000, a PHS-led national activity for setting priority
areas.  This RFA is related to the priority area, heart disease and
stroke.  Potential applicants may obtain a copy of "Healthy People
2000" (Full Report:  Stock No.017-001-00474-0 or Summary Report: 
Stock No. 017-001-00473-1) through the Superintendent of Documents,
Government Printing Office, Washington, DC 20402-9325 (telephone
202-512-1800).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign, for-profit
and non-profit organizations, public and private, such as
universities, colleges, hospitals, laboratories, units of State or
local governments, and eligible agencies of the Federal government. 
Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as Principal Investigators.

All current policies and requirements that govern the research
grant programs of the NIH will apply to grants awarded under this
RFA.  Awards under this RFA to foreign institutions will be made
only for research of very unusual merit, need, and promise, and in
accordance with Public Health Service policy governing such awards. 
Cell biology, molecular biology, biochemistry, physiology,
pathology, genetics, engineering, and physical sciences are among
the disciplines and expertise that may be appropriate for this
research program.

MECHANISMS OF SUPPORT

The mechanism available for support of applications in response to
this RFA is the collaborative R01 projects.

Collaborative R01 projects:  a group of investigators must submit
collaborative R01 projects for this RFA. Collaborative groups must
consist of between two and four research R01 projects and have a
common theme. Collaborative R01 projects may be from a single
institution or several institutions, may include shared resources,
and must demonstrate synergism among the individual components.
Applicants must propose a multidisciplinary program, comprising a
basic science R01 and up to three other R01s that include clinical
studies and imaging technologies to be performed during the grant
cycle.  If core support is requested, it should be organized as a
separate R01 application and submitted as part of the
collaboration.

Specific application instructions have been modified to reflect
"MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being
examined by the NIH.  The modular grant concept establishes
specific modules in which direct costs may be requested as well as
a maximum level for requested budgets.  Only limited budgetary
information is required under this approach.  The just-in- time
concept allows applicants to submit certain information only when
there is a possibility for an award.  It is anticipated that these
changes will reduce the administrative burden for the applicants,
reviewers and Institute staff.

For this RFA, funds must be requested in $25,000 direct cost
modules.  A feature of the modular grant concept is that no
escalation is provided for future years, and all anticipated
expenses for all years of the project must be included within the
number of modules being requested.  Only limited budget information
will be required and any budget adjustments made by the Initial
Review Group will be in modules of $25,000.

A maximum of 10 modules ($250,000 direct costs) per R01 per year
may be requested, but a group of collaborative R01 applications
cannot exceed a total of 24 modules ($600,000 direct costs) per
year for all component R01s, including cores.

Instructions for completing the Biographical Sketch have also been
modified.  In addition, Other Support information and the
application Checklist page are not required as part of the initial
application.  If there is a possibility for an award, necessary
budget, Other Support and Checklist information will be requested
by NHLBI staff following the initial review.  The APPLICATION
PROCEDURES section of this RFA provides specific details of
modifications to standard PHS 398 application kit instructions.

This RFA is a one-time solicitation.  Future unsolicited competing
continuation applications will compete with all investigator-
initiated applications and be reviewed according to the customary
peer review procedures.  It is anticipated that support for this
program will begin in September 1998.  Administrative adjustments
in project period and/or amount may be required at the time of the
award.

FUNDS AVAILABLE

It is anticipated that for fiscal year 1998, approximately
$3,000,000 total costs will be available for the first year of
support for this initiative.  Award of grants pursuant to this RFA
is contingent upon receipt of such funds for this purpose.  It is
anticipated that four to six new collaborative R01 projects will be
awarded under this program.  Applicants may request up to 4 years
of support. The specific number to be funded will, however, depend
on the merit and scope of the applications received and on the
availability of funds.  Direct costs will be awarded in modules of
$25,000, less any overlap or other necessary administrative
adjustments.  Facilities and Administrative costs will be awarded
based on the negotiated rates

RESEARCH OBJECTIVES

Background

Coronary heart disease is a major cause of death and disability in
the U.S. and other industrialized societies, and accounts for
substantial health costs.  Its underlying cause is, in most cases,
the development of atherosclerotic lesions in the coronary
arteries.  The classical concepts of progression of atherosclerosis
envisaged a progressive increase of lipids and an ensuing tissue
reaction.  These processes would lead to critical narrowing of the
affected artery, yielding anginal syndromes and eventually coronary
occlusion with myocardial infarction.

However, a major shift in our understanding of how these lesions
lead to clinical disease is occurring.  Careful clinical and
pathologic observations and the flourishing of vascular biology are
substantially revising our view. Convincing new clinical data
demonstrate that non-occlusive lesions often produce acute coronary
syndromes.  It is increasingly evident that, although the lesions
of atherosclerosis may become sufficiently advanced to produce
severe obstruction of the coronary arteries, it is often the less
prominent plaque which is particularly prone to disruption,
erosion, and thrombosis.  The clinical event is frequently the
result of severe acute coronary thrombosis.

Many of the factors involved in these processes are not fully
understood.  A multidisciplinary approach is required in view of
the many scientific disciplines involved in characterizing the
physical forces associated with plaque disruption; the
physicochemical features of plaque in vivo; the pathoanatomical and
biochemical characteristics of the major determinants of the
vulnerability of the plaque to erosion or rupture; and humoral and
systemic factors involved in coronary thrombosis.

Plaque rupture, the most frequent cause of coronary thrombosis, has
been implicated in the episodic progression of coronary stenosis as
demonstrated by sequential angiography and is often associated with
unstable angina, myocardial infarction, and sudden death. 
Atherosclerotic plaques that are vulnerable to rupture have a dense
infiltrate of macrophages and, to a lesser extent, lymphocytes,
within a fibrous cap that overlies a crescentic hypocellular mass
of lipids.  The ruptured plaque results in exposure of blood to the
lipid core and other plaque components and is believed to instigate
the majority of coronary thrombi.

Pathological studies of the microanatomy of fatal coronary lesions
have shown that the physical disruption of plaques usually
furnishes the nucleus for thrombotic coronary occlusion.  Plaques
that fissure or rupture are relatively small, are usually of the
advanced or raised fibrolipid type, and have a characteristic
microanatomy.  The core of the plaque is rich in lipids and
contains extracellular matrix material separated from the lumen by
a fibrous tissue cap.  Within this cap there are smooth muscle
cells and monocyte/macrophages, particularly concentrated at the
lateral or shoulder area of the plaque.  The disruption most
commonly involves a fracture of the fibrous cap overlying the lipid
core, but may also involve a superficial erosion of the intimal
surface.  Once the lesion's integrity is breached, thrombosis
usually occurs due to contact of the blood with the thrombogenic
tissue-factor-rich lipid core and/or collagen in the
subendothelium.  Major features of plaques that have ruptured
include:  a thin fibrous cap; a large lipid pool; abundant
macrophages and T lymphocytes; a paucity of smooth muscle cells;
signs of inflammatory activation of arterial cells and infiltrating
leukocytes.

Another mechanism of plaque disruption and coronary thrombosis is
plaque erosion.  Plaque erosion may occur more commonly in younger
persons (~50 years old) particularly women, and has recently been
identified as an important cause of acute coronary syndrome. 
Eroded plaques differ from ruptured plaques in that they have a
proteoglycan-rich and smooth muscle cell-rich lesion lacking a
substantial lipid core, have less luminal narrowing, have less
calcification, and may have fewer foci of macrophages and T cells
compared with ruptured plaque.  The luminal surface is focally
eroded and lacks endothelial cells.  Acute thrombosis is found at
the plaque surface, and it usually occurs due to contact of the
blood with the thrombogenic collagen accumulated in the
subendothelium.  These events may lead to partial or complete
occlusion of the artery, resulting in unstable angina, acute
myocardial infarction or sudden death.

When the thrombus is non-occlusive and rapidly lysed or healed, it
may be clinically silent or cause an episode of ischemia at rest. 
In either case, generation of thrombin and associated products of
thrombosis, including platelet-derived factors, can evoke smooth
muscle proliferation and promote fibrosis, leading to lesion
progression and complication.

Exposure of collagen, lipids, and other substances and cells in
ruptured or eroded plaques leads to the activation of platelets and
the coagulation cascade system.  The resulting thrombus may lead to
marked reduction in myocardial perfusion and the development of an
unstable coronary syndrome, or it may become organized and
incorporated into the diseased vessel, thus contributing to the
progression of atherosclerosis.  This process may be potentially
influenced by new antithrombotic agents such as inhibitors of
thrombin, thromboxane, and serotonin receptor antagonists, and
monoclonal antibodies or peptides aimed at blocking platelet
membrane receptors or adhesive proteins.  However, much remains to
be understood regarding the thrombogenicity of plaque materials
before and after plaque rupture, the contribution of the
reorganization of a thrombus to plaque progression, and the role of
various vascular wall cells. In addition, it is not clear how, why,
or at what stage a plaque would erode.  Factors important to these
plaque transformations need to be delineated.

Force imbalances within the plaque volume or in the area of
stenosis, due, for example, to sudden changes in intraluminal
coronary pressure or tone, or bending and twisting of an artery
during each heart contraction, may be important physical factors
that influence the probability of plaque vulnerability.  Thus,
imaging technology is emerging as an important research tool. 
Several techniques have the potential for quantifying plaques in
vivo, such as intravascular ultrasonography, ultrasound imaging
from the body surface, magnetic resonance imaging, and ultra fast
computed tomography (electron beam CT).  Identification of plaque
composition and the distribution of components such as lipids,
fibrous tissues, and calcium within the plaque may be related to
its potential rupture and erosion. Ultrasound, magnetic resonance
spectroscopy, and radioisotope imaging offer some promise for
accomplishing this.

The characterization of these relatively less stenotic plaques
prone to erosion or rupture, and the recognition that they
contribute to unstable angina and myocardial infarction, has
important implications.  Early identification of potentially
vulnerable plaques may lead to changes in the indications for
patients considered for bypass surgery, angioplasty, and other
procedures, and may identify new strategies and novel approaches
for prevention and treatment of the vulnerable plaque.  This offers
a possible explanation of why cholesterol lowering therapy has a
favorable effect on clinical events as has been shown by the
results of several recent trials.

Objectives

It is proposed to support four to six collaborative projects for
research into the properties of the vulnerable atherosclerotic
plaque, especially its tendency to erode or rupture and its
thrombotic consequences.  Applications must be multidisciplinary. 
Furthermore, to accelerate the transition from bench to bed-side,
this RFA requests the use of clinical studies and of imaging
technologies to be performed during the grant cycle to achieve its
objectives. Areas of special emphasis and examples of research
topics that may be applied to humans and animal models amenable to
the development of the vulnerable plaque and which would be
responsive to this RFA may include, but are not limited to the
following:

o Studies to explore the molecular mechanisms that link the
characteristics of vulnerable plaques on cellular gene expression
of various extracellular matrix materials, and substances affecting
plaque integrity.  Also included may be studies on plaque
elastomechanics and the physical forces associated with plaque
rupture or erosion, i.e., evaluate forces internal and external to
the artery wall using experimental models, animal models, and
mathematical and computer simulations.

o Studies of inflammatory factors in the development of vulnerable
plaques and the thrombogenicity of plaque materials before and
after rupture or erosion.  These could include in vivo studies of
the exposure of plaque material to circulating blood, and
determinants of coronary thrombosis, enzymatic release,
inflammatory activation of arterial cells and infiltrating
leukocytes, abscess development, or exposure of procoagulant
activity after plaque rupture or erosion.

o Studies of plaque composition and the distribution of various
components within the plaque utilizing evolving modalities of
imaging such as magnetic resonance, ultrasound, or computed
tomography imaging.  Imaging studies over time of individuals with
plaques that are likely to rupture or erode may also be valuable
for obtaining imaging markers associated with plaque rupture or for
imaging microemboli in vivo.  Studies of vulnerable plaques in the
abdominal aorta and carotid arteries may be especially useful
because of their accessibility with non-invasive imaging techniques
and the potential for pathologic and histologic validation.

o Clinical studies that enhance understanding of the progression,
stabilization, and regression of the vulnerable plaque.  Such
studies are not to be epidemiological, but could address questions
such as what imaging parameters are associated with thromboembolic
events, what may be the significance of raised lesions, and whether
vascular remodeling is predictive of thromboembolic events.

These examples often overlap, and applicants are required to
propose multidisciplinary approaches to address more than one of
these areas.  Clinical studies and use of image technologies are
required, and should be performed during the grant cycle.

This initiative will not support grants that focus on large
epidemiological studies or clinical trials.  In addition, any
application that focuses on cerebrovascular disease or stroke
(other than vascular effects and blood flow) should be addressed to
the National Institute of Neurological Disorders and Stroke.

SPECIAL REQUIREMENTS

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. should request travel funds for
a 1 day meeting each year, most likely to be held in Bethesda,
Maryland.  Applicants should also include a statement in their
applications indicating their willingness to participate in these
meetings.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN
SUBJECTS

It is the policy of the NIH that women and members of minority
groups and their subpopulations must be included in all NIH
supported biomedical and behavioral research projects involving
human subjects, unless a clear and compelling rationale and
justification is provided that inclusion is inappropriate with
respect to the health of the subjects or the purpose of the
research.  This policy results from the NIH Revitalization Act of
1993 (Section 492B of Public Law 103-43).

All investigators proposing research involving human subjects
should read the "NIH Guidelines for Inclusion of Women and
Minorities as Subjects in Clinical Research," which have been
published in the Federal Register of March 28, 1994 (FR 59
14508-14513) and in the NIH Guide to Grants and Contracts, Volume
23, Number 11, March 18, 1994.

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

LETTER OF INTENT

Prospective applicants are asked to submit, by February 2, 1998, 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 to avoid conflict of interest in the review.

The letter of intent is to be mailed, or faxed, to:

Dr. C. James Scheirer
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7220, MSC 7924
Bethesda, MD  20892-7924
Telephone:  (301) 435-0266
FAX:  (301) 480-3541
Email:  James_Scheirer@NIH.GOV

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 5/95) is to be
used in applying for these grants, with the modifications noted
below.  These forms are available at most institutional offices of
sponsored research; 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: ASKNIH@od.nih.gov; and on the  internet at
https://grants.nih.gov/grants/funding/phs398/phs398.html.

The RFA label found in the PHS 398 application form must be affixed
to the bottom of the face page of the application. Failure to use
this label could result in delayed processing of the application
such that it may not reach the review committee in time for review. 
In addition, the RFA title [Characterization of the Vulnerable
Plaque] and number [HL-98-003] must be typed on line 2 of the face
page of the application form and the YES box must be marked.

State on the face page, Title Line (line 1), of each application
that the submission is part of a "Collaborative R01".  The
individual components and cores must be submitted as one packet
accompanied by a cover letter that lists the principal
investigators of each R01.  Include this letter with each of the
individual R01s, and in each R01 list the collaborating projects
and principal investigators on page 2, under "Performance Sites". 
In addition, the description section for each R01 within a
collaborative R01 should be the same and the applicants should
define how and why the individual participants propose to
collaborate.  Applicants should elaborate on the significance and
nature of the collaboration in an Introduction section of the
"Research Plan" of each component R01.

Sample budgets and justification page will be provided upon request
or following the submission of a letter of intent from Mr. William
Darby at the address listed below.

BUDGET INSTRUCTIONS

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:

FACE PAGE
As a reminder, Item 7 should be completed to indicated Modular
Direct Costs requested and Item 8 should reflect Total Costs
(Modular Direct plus F&A costs).

DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD
Do not complete Form Page 4 of the PHS 398 (rev 5/95).  It is not
required nor will it be accepted at the time of application.

BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT
Do not complete the categorical budget tables on page 5 of the PHS
398 (rev.  5/95) Form.  Only the requested total direct costs line
for each year must be completed based on the number of $25,000
modules being requested.  Applicants may not request a change in
the amount of each module.  A maximum of 24 modules ($600,000
direct costs) for a whole collaborative application, including
cores, per year may be requested, and a maximum of 10 modules
($250,000 direct cost) per R01 unit per year may be requested . 
Applicants may request up to 4 years of support for this RFA. 
Direct cost budgets will remain constant throughout the life of the
project (i.e. the same number of modules requested for all budget
periods).  Any necessary escalation should be considered when
determining the number of modules to be requested.  However, in the
event that the number of modules requested must change in any
future year due to the nature of the research proposed, appropriate
justification must be provided.  Total Direct Costs for the Entire
Proposed Project Period should be shown in the box provided.

BUDGET JUSTIFICATION

o Budget justifications should be provided under "Justifications"
on Form Page 5 of the PHS 398.

o List the names, role on the project and proposed percent effort
for all project personnel (salaried or unsalaried)and provide a
narrative justification for each person based on his/her role on
the project.

o Identify all consultants by name and organizational affiliation
and describe the services to be performed.

o Provide a general narrative justification for individual
categories (equipment, supplies, etc.) required to complete the
work proposed.  More detailed justifications should be provided for
high cost items.  Any large one-time purchases, such as large
equipment requests, must be accommodated within these limits.

CONSORTIUM/CONTRACTUAL COSTS

If collaborations or subcontracts are involved that require
transfer of funds from the grantee to other institutions, it is
necessary to establish formal subcontract agreements with each
collaborating institution.  A letter of intent from each
collaborating institution should be submitted with the application. 
Only the percentage of the consortium/contractual TOTAL COSTS
(direct and facilities and administrative costs) relative to the
total DIRECT COSTS of the overall project needs to be stated at
this time.  The following example should be used to indicate the
percentage cost of the consortium, "The consortium agreement
represents 27% of overall direct costs requested in the first
year."  A budget justification for the consortium should be
provided as described in the "Budget Justification" section above
(no Form Page 5 required for the consortium).  Please indicate
whether the consortium will be in place for the entire project
period and identify any future year changes in the percentage
relative to the parent grant.

If there is a possibility for an award, the applicant will be
requested to identify actual direct and indirect costs for all
years of the consortium.  Please note that total subcontract costs
need not be calculated in $25,000 modules. However, when
subcontract funds are added to the parent grant budget, the total
direct cost amount must be included in the number of $25,000
modules requested.

BIOGRAPHICAL SKETCH

A biographical sketch is required for all key personnel, following
the modified instructions below.  Do not exceed the two-page limit
for each person.

o Complete the educational block at the top of the form page;

o List current position(s) and those previous positions directly
relevant to the application;

o List selected peer-reviewed publications directly relevant to the
proposed project, with full citation;

o The applicant has the option to provide information on research
projects completed and/or research grants participated in during
the last five years that are relevant to the proposed project.

OTHER SUPPORT - Do not complete the "Other Support" pages (Form
Page 7).  Selected other support information relevant to the
proposed research may be included in the Biographical Sketch as
indicated above.  Complete Other Support information will be
requested by NHLBI staff if there is a possibility for an award.

CHECKLIST

No "Checklist" page is required as part of the initial application. 
A completed Checklist will be requested by NHLBI staff if there is
a possibility for an award.

The applicant should provide the name and phone number of the
individual to contact concerning fiscal and administrative issues
if additional information is necessary following the initial
review.

Applications not conforming to these guidelines will be considered
unresponsive to this RFA and will be returned without further
review.

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

CENTER FOR SCIENTIFIC REVIEW (formerly Division of Research Grants)
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

At the time of submission, two additional copies of the application
should be sent to Dr. C. James Scheirer, at the same address given
above in the section on LETTER OF INTENT.

Applications must be received by March 11, 1998.  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.

REVIEW CONSIDERATIONS

Upon receipt, applications will reviewed for completeness by CSR
and responsiveness by NHLBI.  Incomplete and/or unresponsive
applications will be returned to the applicant without further
consideration.  Remaining applications may be subjected to a
streamlined review process by a Special Emphasis Panel convened by
NHLBI Scientific Review Office to determine their scientific merit
relative to other applications received in response to the RFA. 
The roster of reviewers for the RFA will be available on the NHLBI
home page approximately four weeks prior to the scheduled review
date.  Applications determined to be meritorious will be evaluated
for scientific and technical merit by the review committee, be
discussed and receive a priority score.  All other applications
will not be discussed or scored.  The initial review group will
evaluate all applications as individual investigator-initiated
grant applications.  Additionally, the IRG will comment on the
overall strength and likelihood of effective collaboration of each
collaborative program.  Each R01 within a collaborative program
will receive a priority score.  Secondary review of the
applications will be conducted by the National Heart, Lung, and
Blood Advisory Council (NHLBAC).

Other review criteria and major factors to be considered in the
evaluation of the applications will include:

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?

6) Collaboration
Do the submitted collaborative R01 projects represent collaborative
research among investigators from different disciplines?  What are
the likelihood of effective collaboration among the investigators,
and the likelihood of success of the research objectives proposed?

The personnel category will be reviewed for appropriate staffing
based on the requested percent effort.  The direct costs budget
request will be reviewed for consistency with the proposed methods
and specific aims.  Any budgetary adjustments recommended by the
reviewers will be in $25,000 modules.  The duration of support will
be reviewed to determine if it is appropriate to ensure successful
completion of the requested scope of the project.

AWARD CRITERIA

Applications will receive a secondary level of review by National
Heart, Lung, and Blood Advisory Council (NHLBAC) in September 1998. 
The earliest anticipated date of award is September 1998. 
Applicants should be aware that, in addition to scientific merit,
program priorities and program balance, the total costs of the
proposed project and the availability of funds will be considered
by NHLBI staff as well as NHLBAC in making funding recommendations. 
In addition, NHLBI appreciates the value of complementary funding
from other public and private sources including foundations and
industrial concerns.  In circumstances in which applications have
similar scientific merit, but vary in cost competitiveness, NHLBI
is likely to select the more cost competitive application for
funding.

Schedule

Letter of Intent Receipt Date:     February 2, 1998
Application Receipt Date:          March 11, 1998
Date of Initial Review:            June/July 1998
Review by NHLBI Advisory Council:  September 3-4, 1998
Anticipated Award Date:            September 30,1998

INQUIRIES

Inquiries concerning this RFA are encouraged.  Potential applicants
may request sample budget pages.  The opportunity to clarify any
issues or questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues and requests for
sample budget pages to:

Momtaz Wassef, Ph.D. or Alan Berson, Ph.D.
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 10186
Bethesda, MD  20892-7956
Telephone:  (301) 435-0550 or (301) 435-0513
FAX:  (301) 480-2848 or (301) 480-1454
Email: WASSEFM@GWGATE.NHLBI.NIH.GOV or BERSONA@GWGATE.NHLBI.NIH.GOV

Direct inquiries regarding fiscal matters to:

Mr. William Darby
Grants Operations Branch
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 7128
Bethesda, MD  20892-7128
Telephone:  (301) 435-0177
FAX:  (301) 480-3310
Email:  William_Darby@NIH.GOV

AUTHORITY AND REGULATIONS

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 PHS grants' policies and Federal Regulations 42 CFR 52 and 45
CFR Part 74.  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 and contract recipients to
provide a smoke-free workplace and promote the non-use of all
tobacco products.  In addition, Public Law 103-227, the Pro-
Children Act of 1994, prohibits smoking in certain facilities (or
in some cases, any portion of a facility) in which regular or
routine education, library, day care, health care or early
childhood development services are provided to children.  This is
consistent with the PHS mission to protect and advance the physical
and mental health of the American people.

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