Full Text HL-97-003
 
PEDIATRIC CARDIOVASCULAR DISEASE
 
NIH GUIDE, Volume 26, Number 3, January 31, 1997
 
RFA:  HL-97-003
 
P.T. 34

Keywords: 
  Cardiovascular Diseases 
  Children (Patients) 
  Adolescents 

 
National Heart, Lung, and Blood Institute
 
Letter of Intent Receipt Date:  June 30, 1997
Application Receipt Date:  December 11, 1997
 
PURPOSE
 
This solicitation invites grant applications to enter a single open
competition for Specialized Centers of Research (SCOR) in pediatric
cardiovascular disease.  This program is open to all investigators,
including those who are participating in the current program and
those who are not. The objective of this initiative is to foster
interdisciplinary studies of the etiology, pathophysiology and
diagnosis of congenital and acquired cardiovascular disease in
children in a context that will lead to more effective methods of
treatment and prevention.  To this end, investigators must present
applications that encompass both basic and clinical science, and
include studies of patients. Those studies must be designed to comply
with NIH policies regarding gender and ethnicity unless exceptions
can be scientifically justified.
 
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,
Pediatric Cardiovascular Disease, is related to the priority areas of
maternal and infant health, heart disease and stroke, diabetes and
chronic disabling diseases, and immunization and infectious diseases.
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 for-profit and non-profit
institutions, public and private, such as universities, colleges,
hospitals, and laboratories.
 
The principal investigator should be an established research
scientist with the ability to ensure quality control and the
experience to administer effectively and integrate all components of
the program.  A minimum time commitment of 25 percent is expected for
this individual.  The principal investigator must also be the project
leader of one of the component research projects.  If, through peer
review, this project is not recommended for further consideration,
the overall SCOR application will not be considered further.  If this
project is judged by peer review to be of low scientific merit, it
will markedly reduce the overall scientific merit ranking assigned to
the entire application by the review committee.  Project leaders must
agree to commit at least 20 percent effort to each project for which
they are responsible.
 
MECHANISM OF SUPPORT
 
This RFA will use the National Institutes of Health (NIH) specialized
center of research grant mechanism (P50).  Responsibility for
planning 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 five years.  The anticipated date of award is
January 1, 1999.
 
Upon initiation of the program, there will be required communications
between SCORs, usually in the setting of a meeting of SCOR
participants.  Therefore, in the preparation of the budget,
applicants should request travel funds for this purpose in fiscal
years 1999, 2000, 2001, and 2002 of the budget.  Applicants should
include a statement in their applications indicating their
willingness to participate in these meetings.
 
FUNDS AVAILABLE
 
New applications may request up to $1,140,000 direct costs, not
including indirect costs for collaborating institutions, in the first
year, with a maximum increase of no more than three percent in each
future year requested in the application.  Competing renewal
applications may request no more than 10 percent above the direct
costs awarded in the final budget period or $1,140,000, whichever is
greater.  It is anticipated to support three SCOR grants for a five
year project period at an estimated first year total cost of $3.22
million.
 
Award of grants pursuant to this RFA is contingent upon receipt of
funds for this purpose.  Designated funding levels are subject to
change at any time prior to final award, due to unforeseen budgetary,
administrative, and/or scientific developments.
 
Equipment is included in the budget limitation.  However, requests
for expensive special equipment that cause an application to exceed
this limit may be permitted on a case-by-case basis following staff
consultation.  Such equipment requires justification.  Final
decisions will depend on the nature of the justification and the
availability of funds.
 
RESEARCH OBJECTIVES
 
Background
 
According to the recent report of the American Heart Association Task
Force on Children and Youth, cardiovascular disease affects more than
600,000 infants, children and youths in the United States.  This
number includes patients with congenital cardiovascular malformations
(CCVM), inherited progressive disorders such as Marfan's syndrome and
hypertrophic cardiomyopathy, cardiac dysrhythmias and conduction
disorders, and acquired diseases such as Kawasaki disease and
rheumatic heart disease.
 
Recent studies in flies, fish, frogs and mice have identified a large
number of genes that are involved in cardiac and vascular
morphogenesis, although for the most part the gene products and their
functions have yet to be identified.  In parallel with these
discoveries, progress has been made in understanding the etiology of
congenital heart disease with the important discovery that, contrary
to earlier hypotheses, there is a relatively high incidence of
inherited heart defects and many of these are single gene defects.
However, as with animal studies, the gene products and their
functions have yet to be elucidated.  Thus, the field is now poised
for fruitful collaborations between basic and clinical investigators
who seek knowledge of how mutated or deleted genes perturb normal
development.  A goal of the SCOR program is to forge between
experimental embryologists and clinical scientists a link that will
rapidly increase knowledge of possible causes of CCVM and lead to new
treatment and prevention strategies.
 
For a number of different cell types, significant progress has been
made in understanding the molecular control of the life and death of
a cell.  However, the genes involved in proliferation of cardiac
myocytes, their differentiation, withdrawal from the cell cycle, and
programmed cell death remain to be elucidated.  Furthermore, it is
not known whether manipulation of gene expression could cause cardiac
myocytes to re-enter the cell cycle or avoid apoptosis. Such research
could provide an important foundation toward repair and regeneration
of cardiac muscle in patients with myocardial cell deficiency as in
hypoplastic left heart syndrome or cell loss resulting from disease.
The potential for gene therapy for cardiac muscle defects and disease
would be increased by such studies.
 
The clinical health of the myocardium is determined by genetic and
environmental factors.  Adverse effects of these factors could result
in dysfunction of myocytes, fibroblasts and endocardial endothelium.
Injury may result from toxic agents, infections, inflammatory cells
and neurohormonal influences.  Little is understood of the effects of
such factors and the possibilities of etiology-specific prevention
strategies and therapeutics have yet to be explored.
 
Immunologic rejection is a major cause of death and morbidity in
pediatric cardiac transplantation.  Immunologic factors may also be
crucial in the pathogenesis of coronary vascular disease following
transplantation.  Studies to define mechanisms of these events in
pediatric patients and to alter their occurrence by therapeutic
interventions will be crucial in improving outcome.
 
Arrhythmias are a substantial cause of mortality and morbidity in
pediatric patients.  Recently, molecular genetic studies of familial
arrhythmias have been fruitful. Several genetic loci causing the long
QT syndrome have been mapped and mutations in cardiac sodium and
potassium channels defined.  The mechanisms by which these mutations
are arrhythmogenic need to be elucidated.  Other familial rhythm
disorders (WPW syndrome and RV dysplasia) are being studied by
similar techniques.  The etiologies and treatments of sporadic and
post-operative arrhythmias remain as inviting challenges for
investigation.  Furthermore, little is known about the genes that
control the initiation of the heart beat and development of
conduction system or how the products of those genes control function
of the heart.
 
Recent success in the in utero repair of lung defects, congenital
diaphragmatic hernia and resection of congenital cystic adenomatoid
malformations gives good reason to expect that similar results could
be obtained for serious congenital cardiovascular malformations.
Moreover, second trimester clinical fetal surgery has shown that
tissue hypoplasia can be reversed if correction is made early.  If
the goal of early intervention is to be achieved, considerable effort
must be placed on the detection of malformations earlier in fetal
development than the current limit of 18 to 22 weeks of gestation for
diagnosis of congenital heart defects by echocardiography .  Early
and accurate visualization of cardiac defects, for instance by
ultrasound or MRI, would allow the option of in utero intervention,
either by surgery or percutaneously delivered catheters, or perhaps
ultimately by local delivery of constructs or genetically altered
cells.  Fetal somatic gene therapy with local delivery of vectors
expressing essential genes or genetically altered cells may
eventually prove to be the least traumatic way to alter aberrant
cardiovascular development.  In the meantime, refinement of current
imaging techniques and miniaturization of interventional catheters
for use in fetal therapy is essential.
 
There is increasing evidence that a spectrum of congenital
cardiovascular malformations and alterations in myocardial growth and
function may be the result of maternal-fetal interactions.  Important
environmental influences include maternal diabetes, maternal systemic
lupus erythematosus, maternal toxemia/placental insufficiency,
cocaine addiction, HIV, alcoholism, and poor nutrition.  Very little
is known about the physiological effects of altered hemodynamics and
changes in the hormonal, immune, and growth factor environment on the
developing embryo and fetus.
 
These topics are for illustrative purposes only.  Applicants are
expected to develop programs based on their knowledge of the field,
their expertise and availability of patients.
 
Basic and Clinical Research
 
The overall concept of a SCOR program focuses on scientific issues
related to diseases relevant to the mission of the NHLBI.  It is
essential, therefore, that all applications include both basic and
clinical research projects.  In the ideal SCOR, the basic research
derives from, or is otherwise intimately linked to, the clinical
research proposed by the investigators.  Interactions between basic
and clinical scientists are expected to strengthen the research,
enhance transfer of fundamental research findings to the clinical
setting, and identify new research directions.  Plans for transfer of
findings from basic to clinical studies should be described.
 
Each SCOR grant application and award must include research involving
human/patient subjects.  Support may be provided for human biomedical
studies of etiology, pathogenesis, prevention and prevention
strategies, diagnostic approaches, and treatment of diseases,
disorders or conditions.  Small population-based studies, where the
research can be completed within five years, may also be proposed.
In addition, basic research projects must be included that relate to
the clinical focus.  A SCOR may also contain one or more core units
that support the research projects.
 
SPECIAL REQUIREMENTS
 
Exclusions
 
This RFA is intended to support Specialized Centers of Research
grants.
 
A SCOR provides the opportunity for investigators to engage in
interdisciplinary and collaborative research which is focused on a
specific disease or an area within a disease category.  It is
required that SCOR applications include studies of human subjects
and/or human materials as well as basic studies clearly related to a
disease area.  The foundation of the clinical component should be
strongly linked to the basic science projects; the basic science
studies should be driven by the needs of the clinical projects.
Thus, a SCOR has a central theme to which all research projects
pertain.  In addition, a SCOR may include CORE units to provide
services to the various research projects and to support the
organizational and administrative aspects of the program.
 
Applications that include only basic or only clinical research will
not be responsive to this RFA.  In addition, clinical research
projects focused on large epidemiological studies or large clinical
trials will be considered unresponsive to this RFA.  Awards will not
be made to foreign institutions.  However, under exceptional
circumstances, a foreign component critical to a project may be
included as a part of that project.
 
In addition, to encourage women and underrepresented minority
investigators to work within a SCOR project, to facilitate
recruitment of new scientists to this area of research, and to foster
cutting edge and innovative research directions, each SCOR program
may support up to two investigators by utilizing up to $50,000 direct
costs per year per investigator to fund pilot and feasibility
projects.  This will allow underrepresented minority investigators to
acquire skills and data to make them more competitive in seeking
independent research support (e.g. R01, R29).  These funds will not
be supplements, but rather specific dollars identified in the SCOR
budget and restricted to be used for this purpose.  The recipients
would be chosen based on a proposal written by a SCOR investigator
and reviewed by an internal review committee at the parent
institution.
 
Applicants should be aware that applications for supplemental funds
will be accepted only under unusual and well defined circumstances.
For example, the NHLBI may provide supplements to Centers to continue
a project not funded for the entire project period.  NHLBI staff must
be consulted prior to submission of an application for supplemental
funds.  Supplemental grants for these purposes will not be awarded
for the first 18 months or the last 12 months of a total project
period.
 
Length of SCOR Programs
 
The National Heart, Lung, and Blood Advisory Council, at its meeting
in September 1992, recommended that each NHLBI SCOR program be
limited to ten years of support.  Exceptions to this policy will be
made only if a thorough evaluation of needs and opportunities,
conducted by a committee composed of non-federal experts, determines
that there are extraordinarily important reasons to continue a
specific SCOR program.
 
Thus, under this policy, a given SCOR grant is awarded for a
five-year project period following an open competition. Only one
five-year competing renewal is permitted, for a total of ten years of
support, unless the SCOR program is recommended for extension.
 
The NHLBI comprehensive evaluation of the SCOR program in Pediatric
Cardiovascular Disease will be conducted during the second project
period according to the following schedule:
 
Project Period (Second Competition)  FY 1999 to FY 2003
 
Letters to SCOR Directors regarding  FY 2001 (mid-way through year 02
 SCOR evaluation Plans                        of 2nd project period)
 
SCOR Evaluation Meeting              FY 2001 (Late in year
 
Notification of SCOR Directors       FY 2002 (mid-way through year 03
 of NHLBI decision period                     2nd project period)
 
Number of Applications
 
The NHLBI does not limit the number of SCOR applications in a given
SCOR program from one institution provided there is a different SCOR
principal investigator for each application and each application is
self-contained and independent of the other(s).  This does not
preclude cooperation among participants of SCORs after awards are
made.  Scientific overlap among applications will not be accepted.
If more than one application is envisioned from an institution, the
institution is encouraged to discuss its plans with the NHLBI SCOR
program administrator.
 
Consortium Arrangements
 
If a grant application includes research activities that involve
institutions other than the grantee institution, the program is
considered a consortium effort.  Such activities may be included in a
SCOR grant application, but it is imperative that a consortium
application be prepared so that the programmatic, fiscal, and
administrative considerations are explained fully.  The published
policy governing consortia is available in the business offices of
institutions that are eligible to receive Federal grants-in-aid.
Consult the latest published policy governing consortia before
developing the application.  If clarification of the policy is
needed, contact Mr. William Darby, Section Chief, Grants Operation
Branch, NHLBI, (301) 435-0177.  Applicants should exercise great
diligence in preserving the interactions of the participants and the
integration of the consortium project(s) with those of the parent
institution, because synergism and cohesiveness can be diminished
when projects are located outside the group at the parent
institution.  Indirect costs paid as part of a consortium agreement
are excluded from the limit on the amount of direct costs that can be
requested.  At least 50 percent of the projects and cores and their
associated costs must be at the parent institution.
 
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 reprinted
in the NIH Guide for Grants and Contract, Volume 23, Number 11, March
18, 1994.
 
LETTER OF INTENT
 
Prospective applicants are asked to submit, by June 30, 1997 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 subsequent applications, the information that it contains is
helpful in planning for the review of applications.
 
The letter of intent is to be sent to:
 
Dr. 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
 
Upon receipt of the letter of intent, applicants will be contacted by
program staff to discuss their proposed applications and to provide
guidance to applicants not familiar with the SCOR concept.
 
APPLICATIONS PROCEDURES
 
The research grant application form PHS 398 (rev. 5/95) is to be used
in applying for these grants.  Applications kits are available at
most institutional offices of sponsored research and may be obtained
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@odrockm1.od.nih.gov.
 
In addition potential applicants should contact Dr. Constance
Weinstein, at the address listed under INQUIRIES, to obtain
supplemental instructions for modifying the forms to accommodate a
SCOR application.  Applicants must follow these instructions for
their application to be considered responsive.
 
Applicants from institutions that have a General Clinical Research
Center (GCRC) funded by the NIH National Center for Research
Resources may wish to identify the GCRC as a resource for conducting
the proposed research.  If so, a letter of agreement from either the
GCRC program director or principal investigator should be included
with the application.
 
The RFA label available 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, to identify the application as a response
to this RFA, check "YES", enter the title, "Specialized Center of
Research: Pediatric Cardiovascular Disease," and the RFA number
HL-97-003 on Line 2 of the face page of the application.
 
Send or deliver a signed, typewritten original of the application,
including the checklist, and three signed photocopies, in one package
to:
 
DIVISION OF RESEARCH GRANTS
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, SUITE 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for courier/express service)
 
Send two additional copies of the application to Dr. James Scheirer,
Review Branch, at the address listed under LETTER OF INTENT.  It is
important to send these two copies at the same time as the original
and three copies are sent to the Division of Research Grants,
otherwise the NHLBI cannot guarantee that the application will be
reviewed in competition for this RFA.
 
Applications must be received by December 11, 1997.  If an
application is received after that date, it will be returned to the
applicant.  The Division of Research Grants (DRG) will not accept any
application in response to this RFA that is essentially the same as
one currently pending initial review, or 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 DRG
and for 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 a peer group convened
by the NHLBI in accordance with the review criteria stated below.  As
part of the initial merit review, a process may be used by the
initial review group in which applications will be determined to be
competitive or non-competitive based on their scientific merit
relative to other applications received in response to the RFA.
Applications judged to be competitive will be discussed and be
assigned a priority score.  Applications determined to be
non-competitive will be withdrawn from further consideration and the
principal investigator/program director and the official signing for
the applicant organization will be notified.  Neither site visits nor
reverse site visits are planned as a part of the review process,
therefore each application must be complete on submission.
 
Rosters of NHLBI reviewers are listed on the NHLBI Homepage at
http://www.nhlbi.nih.gov/meet/sep/devlop.asc.
 
The review criteria for this RFA are:
 
o  the scientific merit of each proposed project in the application,
including originality, feasibility of the approach, and adequacy of
the experimental design;
 
o  the integration of the clinical and fundamental research into a
coherent enterprise with adequate plans for interaction and
communication of information and concepts among the collaborating
investigators;
 
o  the technical merit and justification of each core unit;
 
o  the qualifications, experience, and commitment of the SCOR
Director and his/her ability to devote adequate time and effort to
provide effective leadership;
 
o  the competence of the investigators to accomplish the proposed
research goals, their commitment, and the time they will devote to
the program;
 
o  the adequacy of facilities to perform the proposed research
including the laboratory and clinical facilities, access to subjects,
instrumentation, and data management systems when needed;
 
o  the scientific and administrative structure of the program,
including adequate internal and external arrangements and procedures
for monitoring and evaluating the proposed research and for providing
ongoing quality control and scientific review;
 
o  the institutional commitment to the program and the
appropriateness of the institutional resources and policies for the
administration of a research program of the type proposed; and
 
o  the appropriateness of the budget for the proposed program.
 
AWARD CRITERIA
 
Applications must fulfill all the eligibility criteria in order to be
considered for funding.  Since a variety of approaches would
represent valid responses to this RFA, it is anticipated that there
will be a range of costs among individual grants awarded.  The most
important criterion in selecting awardees will be the scientific
merit as reflected in the priority score. However, factors such as
program balance and available funds may enter into selection from
among meritorious applications.
 
Schedule
 
Letter of Intent Receipt Date:  June 30, 1997
Application Receipt Date:       December 11, 1997
Review by NHLBAC:               September 3-4, 1998
Anticipated Award Date:         January 1, 1999
 
INQUIRIES
 
Inquiries concerning this RFA are encouraged.  The opportunity to
clarify any issues or questions from potential applicants is welcome.
 
Direct inquiries regarding programmatic issues to:
 
Dr. Constance Weinstein
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 9144 - MSC 7940
Bethesda, MD  20892-7940
Telephone:  (301) 435-0510
FAX:  (301) 480-1335
Email:  weinstec@gwgate.nhlbi.nih.gov
 
Inquiries regarding fiscal and administrative matters may be directed
to:
 
Mr. William Darby
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7128 - MSC 7926
Bethesda, MD  20892-7926
Telephone:  (301) 435-0177
FAX:  (301) 435-3310
Email:  William_darby@nih.gov
 
AUTHORITY AND REGULATIONS
 
This program is described in the Catalog of Federal Domestic
Assistance No. 93.837, Heart and Vascular Diseases.  Awards will be
made under the 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 requirement 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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