ABDOMINAL AORTIC ANEURYSM:  PATHOGENESIS

Release Date:  December 11, 1998

RFA:  HL-99-007

P.T.

National Heart, Lung, and Blood Institute

Letter of Intent Receipt Date:  January 15, 1999
Application Receipt Date:  March 22, 1999

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

PURPOSE

The objective of this solicitation is to support research into the
characteristics of the abdominal aortic aneurysm (AAA), especially research that
relates to its initiation, progression, and rupture leading to thromboembolic
events and/or sudden death.  The goals of the program are to advance our
understanding of the etiology, and pathobiology of AAA at the molecular level
through the modern methods and approaches of molecular medicine.  This program
requires investigators to engage in interdisciplinary and collaborative research
through the R01 mechanism, which is focused on studies of human subjects and/or
human materials as well as basic studies clearly related to the etiology,
pathophysiology, and clinical progression (stabilization or regression),
management and prevention of AAA.  Cell biology, molecular biology, biochemistry,
physiology, pathology, and  genetics are among the disciplines and expertise that
may be appropriate for this research program.

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 Request for Applications (RFA),
Abdominal Aortic Aneurysm:  Pathogenesis, 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.

MECHANISM OF SUPPORT

The mechanism of support for applications in response to this RFA is the
collaborative Research Project (R01) grant.  Applicants should propose a
multidisciplinary program, comprising basic and clinical science studies. 
Investigators are encouraged to establish collaborations to complement their
basic or clinical projects to meet the objectives of  this RFA.  Collaborative
groups may consist of either two or three research R01 projects consisting of
basic science and clinical studies, and have a common theme.  Collaborative R01
projects may be from a single institution or several institutions, may include
shared resources, and should demonstrate synergism among the individual
components.  If core support is requested, it should be organized as a separate
R01 application and submitted as part of the collaboration, but its funding will
be part of one of the research R01s.  Although applicants are required to submit
collaborative applications, the Institute may choose to fund individual R01s
outside the collaborative arrangement owing to their special scientific merit and
programmatic needs and balance.

Specific application instructions have been modified to reflect "MODULAR GRANT"
and "JUST-IN-TIME" streamlining efforts being introduced 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. However, a group of collaborative R01 applications may request up to
a total of 20 modules ($500,000 direct cost), 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 1999.  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 1999, approximately $2,500,000 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 six to eight R01s will be funded either as part
of collaborative projects or as individual R01s.  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 (F&A)
costs will be awarded based on the negotiated rates.

RESEARCH OBJECTIVES

Background

Abdominal Aortic Aneurysm (AAA) is an increasingly common vascular disease with
life-threatening implications.  Incidence of AAA is estimated to range from 2-9
percent of the elderly population in industrialized nations.  The incidence of
this condition is expected to accelerate with the aging of the general
population.  Because most aortic aneurysms are asymptomatic prior to rupture,
many remain unsuspected and undetected.  It is estimated that less than 10
percent of patients with ruptured AAA survive emergency interventions.  There is
no proven effective  pharmacological intervention for intact AAA, and surgical
repair is the predominant mode of treatment at substantial financial costs.

The majority of aneurysms detected are less than 4.5 cm in diameter; a size
considered too small to warrant surgical repair.  However, it is recognized that
the natural history of small aneurysms is one of gradual expansion.  Predicting
the rate of progression for individual patients is uncertain at best and further
complicated by the fact that not all aortic aneurysms expand.  Those that do
expand, do so in an irregular and unpredictable fashion.  Moreover, even a small
AAA can rupture.  Because there are no proven medical interventions effectively
limiting the growth of aortic aneurysms, patients with a small AAA are generally
followed with repeated measurements of aneurysm diameter.  Surgical repair is
reserved for those aneurysms reaching at least 5.0 cm in diameter. Thus, patients
with a small AAA pose both diagnostic and therapeutic dilemma subjected either
to surgical repair or to an increasing risk of aneurysm rupture within several
years of diagnosis.

Classical descriptions have attributed the development of AAA to atherosclerosis,
but the underlying cause of aneurysms remains unknown.  Based on documented
associations between AAA and various clinical risk factors, the etiology of AAA
is currently thought to arise through a complex interaction among various risk
factors including atherosclerosis, aging, gender, cigarette smoking, and
hemodynamic factors, as well as through an undefined genetic component.  Male
gender is considered a risk factor for AAA, with some studies showing male:female
ratios as high as 9:1.  The possibility that there might be a relative biological
resistance to aneurysm development in women remains an intriguing but unexamined
hypothesis.  For reasons that are not yet clear, there also appears to be a
predilection for aortic aneurysms in Caucasians compared to other populations.

Severe intimal atherosclerosis is almost invariably found in AAA at the time of
surgery or postmortem examination, and patients with atherosclerosis in other
circulatory beds have an increased prevalence of AAA.  However, there are
compelling reasons to believe that aortic atherosclerosis is neither sufficient,
nor even necessary, for aneurysm development.  Indeed, some evidence has
suggested that arterial wall remodeling associated with the regression of
atherosclerotic plaques might be linked to aneurysm development.

A relationship between arterial anomalies such as arteriomegaly and the
occurrence of aneurysms both within the abdominal aorta and in other arteries,
particularly the popliteal and femoral arteries, has long been recognized.  It
is not known if this represents a genetic predisposition to aneurysms or an
environmentally-triggered association.  Moreover, we do not understand why
aneurysms tend to develop in these distinct locations compared to other sites in
the arterial tree.  Likewise, it is unclear why aneurysms are extremely rare in
the carotid or external iliac arteries, despite a high frequency of
atherosclerosis in these locations.

A familial tendency to develop aneurysms is well documented in 15-20 percent of
patients with AAA.  Although this suggests an inherited predisposition to AAA in
some patients, the genetic basis for this predisposition is unknown.  Genetic
mutations in fibrillin-1 and type III procollagen have been found to be
responsible for aneurysm development in a small number of patients, but the
majority of AAA appears to arise through degenerative processes affecting
otherwise normal tissue.  Attempts to define the genetic component(s) underlying
AAA have used a variety of strategies, including both linkage analysis and
candidate gene approaches; nonetheless, a consensus on the patterns of
inheritance or specific linkages that might be associated with AAA has yet to
emerge.  These efforts continue to be frustrated by a chronic multifactorial
disease that predominantly affects the elderly population, underscoring the need
for more fundamental knowledge before an exact cause of aneurysm disease can be
defined.

Much of the current information on the pathophysiology of AAA has come from
studies on end-stage human AAA tissues obtained at surgery or postmortem
examination.  The extent to which these tissues might reflect earlier stages of
disease is unclear.  However, investigations in a limited number of animal models
of aortic aneurysms has made advances leading to increased recognition that
chronic inflammation, increased expression of endogenous proteinases, degradation
of structural matrix proteins, and medial smooth muscle cell depletion all play
prominent roles in the process of aneurysmal degeneration.  These systems have
included genetically- or pharmacologically-induced alterations in connective
tissue proteins, localized immune rejection, or the response to
enzymatically-induced injury to the aortic wall.  None of these models accurately
reproduces all aspects of the condition as it occurs in humans.  However, recent
experimental investigations have revealed the potential of different therapeutic
interventions, including the use of anti-inflammatory agents and matrix
metalloproteinase inhibitors, to suppress aneurysmal degeneration in vivo.

The histopathology of aneurysm tissues is characterized by pronounced changes
affecting all three layers of the aortic wall.  In addition to severe intimal
atherosclerosis and a variable amount of laminated mural thrombus, the most
striking morphological change in AAA is destruction of the medial elastic
lamellae.  Recent studies have demonstrated that the inflammatory response is
associated with alterations in the balance between matrix-degrading proteinases
and their inhibitors, particularly members of the matrix metalloproteinase and
plasminogen activator families.  Other data suggest that AAA may be associated
with an (auto)immune process targeting certain components of the aortic wall. 
A variety of inflammatory cytokines, chemoattractants, and peptide growth factors
are shown to be produced in aneurysm tissues. Additional studies provide evidence
of apoptosis and cellular senescence.  Taken together, the spectrum of changes
observed in AAA appears to reflect an accelerated but ineffectual wound healing
response to chronic injury, which is largely localized to the outer aortic wall. 
Additional investigations are needed to clarify the cellular and molecular nature
of this process and its component mechanisms.

A number of clinical factors are known to be associated with rapid rates of
aneurysm expansion. These factors include the original size of the aneurysm, the
amount of laminated mural thrombus, the presence of uncontrolled hypertension,
severe chronic obstructive pulmonary disease, persistent cigarette smoking, and
aneurysms associated with a familial pattern.  The biological mechanisms by which
these various factors might influence the rate or extent of aneurysm expansion
are not well understood.  Nonetheless, it is a reasonable assumption that a
better understanding of the etiology, pathophysiology, and natural history of AAA
has the potential to foster new approaches to therapy.

Objectives

It is proposed to support six to eight R01s either as part of collaborative
projects or as individual R01 projects for research into the characteristics of
the abdominal aortic aneurysm (AAA), especially research that relates to its
initiation, progression, and rupture leading to thromboembolic events and/or
sudden death.  Applications must be multidisciplinary.  Furthermore, to
accelerate the transition from bench to bed-side, this RFA request applicants to
propose basic as well as clinical studies during the grant cycle to achieve its
objectives. The Institute strongly encourages P.I.s to establish collaborations
to augment their basic or clinical proposals to meet the objectives of the RFA.
The funding decision will be influenced by the scientific merit of the individual
applications, the degree of collaboration between the investigators,  the
approaches taken to meet the objectives of the RFA, and the programmatic balance
and needs of NHLBI. The Institute may fund collaborative groups or individual
applications dealing with either basic or clinical science.

Proposed Research

Current needs for basic research on AAA encompass a broad spectrum of potential
areas of investigation.  Previous models of AAA have focused on the mechanical
aspects of aneurysms and, consequently, surgical solutions have dominated the
therapeutic approach to this problem. However, with increasing recognition of the
prevalence of small AAA's and the unfavorable natural history of these lesions,
it is apparent that a broader base of interdisciplinary attention is needed. 
This will necessarily include physicians specializing in cardiology and vascular
medicine, as well as scientists focusing on aspects of vascular biology.  It is
expected that rapid progress on the problem will be stimulated by attracting
investigators with expertise in a variety of disciplines to studies focused on
AAA to integrate approaches involving vascular physiology, tissue-specific
pathology, vascular cell biology, molecular analysis of gene expression, clinical
investigations, and genetics.  More careful characterization and creative
utilization of human tissue resources would expedite this effort, as would the
development of more representative animal models of AAA.  A more detailed
analysis of factors influencing the evolution of aneurysm disease in different
clinical settings, particularly those exploring new avenues for clinical
management of small AAA's is also likely to generate new testable hypotheses. 
Using the collaborative  R01 mechanism, responses to this initiative requires
collaborations between basic and clinical investigations to better understand the
etiology, pathophysiology,  and natural history of abdominal aortic aneurysms.

The cause of aortic aneurysms is unknown, yet a number of risk factors have been
identified through their clinical association with AAA.  It remains to be
determined if one or more of these factors can be considered to be causally
related to aneurysm development.  Appropriate topics for investigation under this
RFA would include, but not be limited to, the following:

o  Studies to further define the familial nature of AAA and to identify the
genetic basis for an inherited predisposition to aneurysmal degeneration.

o  Mechanisms that underlie the evolution of aneurysm disease.  A noticeable gap
exists in defining cellular and molecular factors involved in the initiation and
progression of AAA, as well as those factors that might reflect patient-specific
susceptibility to rapid aneurysm expansion.

o  Studies designed to clarify the cause and consequences of chronic inflammation
within the outer aortic wall, to elucidate the molecular signals and cellular
processes initiating mononuclear cell infiltration of the aortic media, to
identify factors that promote persistence of the chronic inflammatory response,
and to determine which features of the inflammatory response distinguish AAA from
intimal (occlusive) atherosclerosis and/or non-aneurysmal arthritides.

o  Studies to elucidate the role of medial neovascularization in aneurysm
disease, and how this process interacts with other components of the chronic
inflammatory response in aortic tissues.

o  Studies to examine the mechanisms that promote and/or limit matrix protein
repair in aneurysmal tissues, and studies to explore the factors regulating
tissue calcification during aneurysmal degeneration and how calcification might
be related to other processes involved in aneurysmal degeneration.

o  Studies employing novel use of human tissue resources and animal models of
aneurysm disease to elucidate the cellular and molecular mechanisms of the
disease.

o  Studies to better define the factors regulating the clinical progression (or
regression) of small AAA's and how new therapeutic strategies might be developed
to influence these processes. In particular, investigation is needed to examine
the potential of new mechanism-based interventions to suppress disease
progression in vivo.

o  Studies to define the mechanisms by which hypertension, smoking, aneurysm
size, and mural thrombus might affect the progression of aneurysmal degeneration;
and studies to examine the potential of different medical and pharmacologic
interventions to suppress the expansion of small AAA's in patients.

These examples often overlap, and applicants should consider proposing
multidisciplinary approaches to address more than one of these areas.
Collaboration between investigators performing clinical studies and basic science
research is required to be responsive to the RFA.

EXCLUSIONS

This RFA is intended to support multidiscplinary collaborative R01 research
programs studying the pathogenesis of aortic aneurysms and must propose basic and
clinical studies.  Applications that focus mainly on the kinetics and function
of enzymes involved in the degradation of matrix proteins, or on large
epidemiological studies or large clinical trials will be considered unresponsive
to this initiative.

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.  Applicants should include travel funds for a 1 day meeting each year,
most likely to be held in Bethesda, Maryland in the requested modules. 
Applicants should 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.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

Applications received in response to this RFA are expected to focus on scientific
issues related to Abdominal Aortic Aneurysm and to Cardiovascular related aspects
of disease.  In describing the plan to recruit human subjects, investigators may
cite a focus on Abdominal Aortic Aneurysm or on Cardiovascular related aspects
of disease as the justification for why children will be excluded.  In this
regard applicants may use Justification 1, the research topic to be studied is
irrelevant to children, from the policy announcement.

LETTER OF INTENT

Prospective applicants are asked to submit, by January 15, 1999, 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 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. 4/98) 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, 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 found in the PHS 398 (rev. 4/98) 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 (Abdominal
Aortic Aneurysm) and number (HL-99-007) 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 package 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 Ms. Marie Willet 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:

DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD

Do not complete Form Page 4 of the PHS 398 (rev 4/98).  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.
4/98) 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 20 modules
($500,00 direct costs) for the entire collaborative package, 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 F&A)
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
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. C. James Scheirer, at the address listed under LETTER OF INTENT.

Applications must be received by March 22, 1999 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 be reviewed for completeness by the CSR, and
responsiveness by NHLBI.  Incomplete and/or non-responsive applications will be
returned to the applicant without further consideration.  Applications that are
completed and responsive to the RFA will be evaluated for scientific and
technical merit 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.
Secondary review of the applications will be conducted by the National Heart,
Lung, and Blood Advisory Council (NHLBAC).

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 an)?

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 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 initial review group will evaluate all applications as individual
investigator-initiated grant applications.  Additionally, the IRG will consider
in their evaluation the overall strength and likelihood of effective
collaboration of each collaborative program. Each R01 will receive a priority
score.

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

Funding decisions will be influenced by the scientific merit of the individual
applications, the degree of collaboration between the investigators, the
approaches taken to meet the objectives of the RFA, and the programmatic balance
and needs of NHLBI.

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.  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:     January 15, 1999
Application Receipt Date:          March 22, 1999
Review by NHLBI Advisory Council:  September 16-17, 1999
Anticipated Award Date:            September 30, 1999

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 to:

Momtaz Wassef, 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
FAX:  (301) 480-2848
Email:  WASSEFM@GWGATE.NHLBI.NIH.GOV

Direct inquiries regarding fiscal matters to:

Ms. Marie Willet
Grants Operations Branch
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 7156
Bethesda, MD  20892-7926
Telephone:  (301) 435-0144
FAX:  (301) 480-3310
Email:  willetm@gwgate.nhlbi.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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