Full Text HL-93-04-H

PEDIATRIC CARDIOVASCULAR DISEASE CENTERS

NIH GUIDE, Volume 21, Number 38, October 23, 1992

RFA:  HL-93-04-H

P.T. 04, AA

Keywords: 
  Cardiovascular Diseases 
  Etiology 
  Pathophysiology 
  Diagnosis, Medical 
  Disease Prevention+ 

0745070

National Heart, Lung, and Blood Institute

Letter of Intent Receipt Date:  January 4, 1993
Application Receipt Date:  March 15, 1993

PURPOSE

The Division of Heart and Vascular Diseases of the National Heart,
Lung, and Blood Institute (NHLBI) invites applications for a single
competition to establish Specialized Centers of Research (SCOR) in
pediatric cardiovascular diseases.

In keeping with the criteria for SCORs, the solicitation requires all
applicants to propose both basic and clinical research.  The emphasis
of this solicitation is on innovative approaches to elucidation of
the etiology and pathophysiology of clinical phenomena and the
translation of research findings into improved diagnosis, treatment
and prevention of cardiovascular diseases in children.  Applicants
are required to select a single theme and to develop interrelated
research projects clearly focussed on that theme.  The goal is to
foster a synergistic environment for basic and clinical
investigations.  All projects must have clearly stated hypotheses and
include original and innovative ideas with respect to the problem to
be studied.

An additional SCOR initiative is available in heart failure, ischemic
heart disease, and sudden cardiac death.  A given institution may
respond to more than one of the current solicitations, but may not
submit more than one application for a given topic.  Additionally,
because a SCOR is a major research commitment, each application must
have a different principal investigator and preferably no overlap in
professional personnel between the SCOR applications.  Applications
must relate clearly to the theme of a specific solicitation.
Potential applicants are therefore urged to consult with staff to
determine which solicitation offers the best fit for their research
ideas.

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 Centers, is related to the priority
area of maternal and infant health. 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 202-783-3238).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic, for-profit and non-profit
organizations, public and private, such as universities, colleges,
hospitals, laboratories, units of State and local governments, and
eligible agencies of the Federal government that have established
clinical programs in pediatric cardiology and the capability to
conduct relevant basic research.  Foreign organizations are
ineligible.  International collaborations in domestic applications
will only be accepted if the resources are clearly shown to be
unavailable in the United States.  Applications from minority
individuals and women are encouraged.

The program director must devote at least twenty-five percent effort
to the SCOR and be the project leader of at least one project or
core.  All other project leaders must commit twenty percent effort to
their respective projects.  Applications not fulfilling these
requirements will be ineligible for participation in the competition.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) specialized
center grant mechanism (P50).  Responsibility for planning the
proposed project will be solely that of the applicant.  The total
project period for applications submitted in response to the present
RFA may not exceed five years.  The anticipated date of award is
September 30, 1993.

Although multidisciplinary approaches are required, it is not the
intent of this announcement to solicit applications for large
clinical trials or large epidemiological studies.  In general, funds
will not be provided for the purchase and installation of expensive,
new equipment.  No awards under this announcement will be made to
foreign institutions.

Upon initiation of the program, the Division of Heart and Vascular
Diseases will sponsor periodic meetings to encourage exchange of
information among investigators who participate in this program, and
to stimulate collaboration.  Applicants must request additional
travel funds for a one-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.  All successful applicants will be eligible for one
competing renewal.  Subsequent renewals will depend on progress and
needs in the field.

FUNDS AVAILABLE

Approximately $3.0 million in total cost will be provided for the
first year of support for the entire program.  No applicant may
request more than $750,000 in direct costs in the first year.
Indirect costs incurred for subcontracts are not included in direct
cost calculations of the upper limit.  Future years may be escalated
at no more than four percent.  It is anticipated that three grants
will be awarded under this program.  This level of support is
dependent on the receipt of a sufficient number of applications of
high scientific merit.  Although this program is provided for in the
financial plan of the NHLBI, awards pursuant to this RFA are
contingent upon the availability of funds for this purpose.
Administrative adjustments in project period and/or amount may be
necessary at the time of the award.

RESEARCH OBJECTIVES

Background (NHLBI Specialized Centers of Research)

A SCOR consists of three or more closely related projects and one or
more core units which provide specialized services to several of the
projects.  At least one of the projects must be clinical and involve
human subjects or human materials or both.  All SCOR applications
must include an administrative core which serves as a focal point for
the SCOR program.

The purpose of the NHLBI SCOR program is the translation of new
scientific information into improved care of patients. Its structure
is designed to create an environment in which basic and clinical
investigators collaborate closely on projects related to a
specifically defined theme.  It is vital that the clinical and basic
science projects be well integrated and have the potential for
contributing to the resolution of clinical issues related to the
theme chosen by the applicant within the general category of
pediatric cardiovascular diseases.

An essential feature of a SCOR is a Director capable of providing
effective scientific and administrative leadership to a cluster of
related individual research projects involving basic, applied and
clinical investigations.  In addition, the Director must devote
twenty-five percent effort to the SCOR and be the project leader of
at least one project or core.  The Director is responsible for the
organization and operation of the Center and for all communications
with the NHLBI on scientific and operational matters.  Each SCOR
Director should encourage and support close collaboration between
individual SCOR investigators by means of frequent meetings and
seminars.

There are two recent NHLBI policies of which potential applicants to
this RFA should take note.  The first is that it is anticipated that
SCOR programs will receive a maximum of ten years support.  To
implement this policy, applicants with already established SCOR
programs are allowed to apply for one final renewal in the topic for
which they are currently funded.  New SCOR programs established as a
result of the current competition will have the opportunity to
compete for one five year renewal.  This policy will be waived only
if deemed advisable after thorough programmatic review.

The second policy relates to a limitation of $750,000 in the amount
of direct costs that may be requested in response to the solicitation
in either new or renewal applications.  Applications requesting
larger amounts will be returned to the applicant.

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.  In such a case, a letter of agreement from
either the GCRC program director or principal investigator could be
included with the application.

Background (Scientific)

The goal of this program is reduction of death and disability from
congenital and acquired cardiovascular diseases in children through
the development of new prevention and treatment strategies.  It is
intended to encourage investigators with a vision of how modern
technologies can be applied to the problem to propose projects that
will provide insight into the etiology and pathophysiology of these
diseases.  For congenital heart disease, this involves new approaches
to postnatal treatment and the development of methods for modifying
the course of evolving cardiac malformations in the fetus.  It also
involves accumulating genetic information that may ultimately lead to
techniques for gene therapy, although at the present time such an
approach appears fraught with complexities.  For acquired heart
disease, this program provides the opportunity to develop knowledge
regarding host factors and pathogenic mechanisms and to utilize that
knowledge in prevention and treatment. The following discussion
illustrates several ways in which clinical investigations might be
integrated with fundamental studies in physiology, cell biology,
genetics, molecular biology and computer technology.  These examples
do not imply Institute priorities.  Applicants should select projects
for their research programs based on their own knowledge of the field
and the available resources at their own institutions.

At present, expansion of therapeutic options for post-natal care will
provide the most immediate opportunities for reduction of mortality
and morbidity.  For example, in complex cardiac malformations choice
of surgical approach is often difficult.  The uncertainties could be,
in part, resolved by systematic evaluation of outcomes, and in part
by the development of sophisticated computer programs for modeling
outcomes of potential reparative approaches.  Pharmacologic
intervention is often required both before and after surgery.  Study
is needed of the effects of cardiovascular drugs used to treat
infants and children since they differ from adults not only in size
but also in fluid volume, body fat, maturation and drug metabolism.
Another important area involves the adverse effects of
cardiopulmonary bypass on outcome of surgery as well as the
developing nervous system of the infant and young child.  Their
immature or dysfunctional immune and coagulation systems may
contribute to poor outcomes in surgical interventions requiring
cardiopulmonary bypass and studies are needed to define immune and
hemostatic factors which influence outcome.  Currently, children who
require valve replacement with mechanical, homograft or xenograft
valves face a shortened life expectancy and increased morbidity due
to mechanical failure, calcification, thromboembolic phenomena,
infection and anticoagulant-induced hemorrhage.  The possibility that
valve leaflets could be generated from a patient's own tissue has not
been explored.  A longterm possibility for overcoming the problems of
valve replacement is to develop a technique to generate the semilunar
and atrioventricular valves from homologous cells.  Clearly, much
basic research is required to lay the foundation for such an
enterprise.

Intensified research on therapeutic fetal intervention could result
in clinical application in the near future.  If this 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 approximately four and one half months' gestation.
Early and accurate visualization of cardiac defects would allow the
option of in utero intervention, either by surgery or by
percutaneously delivered catheters, or perhaps ultimately by local
delivery of DNA constructs or genetically altered cells.  Refinement
of current imaging techniques and miniaturization of interventional
catheters for use in fetal therapy would be valuable.  Second
trimester repair of congenital diaphragmatic hernia has shown that
tissue hypoplasia can be reversed if correction is made early in
gestation.  The possibility that stenotic atrioventricular heart
valves cause hypoplasia of structures downstream from the stenosis is
an issue central to our understanding of CCVM fetal pathophysiology.
Hence, second trimester catheter dilation of the stenotic or atretic
pulmonary valve and outflow tract of Tetralogy of Fallot could
increase pulmonary blood flow sufficiently to allow adequate growth
in cases otherwise destined to develop hypoplasia of the pulmonary
vasculature.  Large animal models exist for some CCVM (Tetralogy of
Fallot, VSD) which will permit experimentalists to begin work
immediately on at least some of these lesions.

Another approach to treatment of the fetus is the development of
techniques for the delivery of genetically altered cells or DNA
constructs to modify malformed structures.  It is possible that
stenoses of the aorta and pulmonary arteries could be prevented by
therapy designed to modify the proliferation of vascular smooth
muscle cells.  Study of the cells of the developing vasculature could
define the mechanisms of altered growth and lead to techniques for
the generation of larger vessels and vascular remodelling.

Another long-term prospect of cellular manipulation involves the
ventricular septum.  In hypertrophic cardiomyopathy, which in some
cases leads to sudden death and in other cases to symptomatic
limitation due to fatigue, dyspnea and chest pain, obstruction of the
left ventricular outflow tract is caused by abnormal growth or
proliferation of myocytes.  On the other hand, in ventricular septal
defects, which often require surgical closure and incur the sequelae
of complications from scars in the myocardium, there is inadequate
growth and/or failure of cell migration.  Fundamental studies of the
defects of the cells in this region and of the factors that promote
and retard myocyte growth could lead to cellular manipulation in
vivo.

At the present time there is a relative paucity of knowledge about
the molecular genetics of congenital heart disease.  The feasibility
of rapid progress in the study of human cardiac malformations is
demonstrated by recent advances.  The epidemiologic
Baltimore-Washington Infant Study has shown that at least one complex
CCVM appears to be a single-gene defect.  Researchers have found that
the risk of  Hypoplastic Left Heart Syndrome (HLHS) may be controlled
by a single major gene.  Other left-sided obstructive lesions such as
bicuspid aortic valve and aortic coarctation are strongly associated
with the HLHS lesion.  Pedigree and chromosome fingerprinting of
these families could very likely lead to rapid progress in
identifying a candidate gene.  Chromosome fingerprinting refers to
the unique hybridization pattern (i.e., 'fingerprint') seen when an
individual's Southern Blot DNA is probed with a sequence known to be
associated with a mutational 'hot spot.'  The pattern for each sample
probed is unique to that individual and is a sensitive means of
identifying regions of DNA mutation.  These data combined with
echocardiograms of affected family members in a pedigree could
provide much needed information about the gene implicated in a
specific malformation.

At least eight other forms of congenital heart disease are now
recognized as being caused by single gene defects and in all but two
of them the responsible genes cause multisystem syndromes.  In Noonan
syndrome the most common cardiac defect is valvular pulmonary
stenosis, although about twenty percent may have atrial septal defect
or hypertrophic cardiomyopathy.  Electrocardiographic abnormalities
are also seen.  In the Leopard syndrome pulmonic valve stenosis and
conduction defects are observed.  The Holt-Oram syndrome also
includes congenital heart defects, most often atrial septal defect of
the secundum type accompanied by electrophysiological abnormalities.
Molecular studies of these and other inherited defects such as the
Jervell and Lange-Nielsen and Romano-Ward long QT syndromes, and the
familial form of Wolff-Parkinson-White syndrome, could lead to
elucidation of the fundamental mechanisms which are perturbed in
patients with CCVM and congenital arrhythmias.

Although single gene defects and chromosomal abnormalities account
for a large proportion of congenital heart disease, it is also
becoming clear that the gene defect is not necessarily the same in
all affected individuals.  Further, many others may be oligogenic and
a few may be polygenic. Teratogenicity and familial susceptibility to
environmental toxins could account for still other lesions.
Dissecting the origins of genetic diseases could be accomplished
using animal models, genetic linkage mapping and quantitative trait
locus determination.  Study of the molecular mechanism(s) by which
teratogens produce structural or functional abnormalities is another
area where research would be very informative.

Although it is clear that aberrations in embryonic and fetal
development have their origins in factors that control gene
expression, only a few of the genes involved have been described.  Of
particular interest are those involved in pattern formation.  The
role of pattern formation genes in mammalian heart development was
apparent when the murine hox-7 gene was found to be expressed in the
endocardial cushions of fetal mice.  Homologous recombination of
another mouse homeobox gene, hox-1.5, has produced cardiovascular
abnormalities in homozygous mouse pups.  Homeobox, other pattern
formation genes as well as cell proliferation and differentiation
genes are a rich field for collaboration among molecular biologists
and cardiac embryologists.

An alternative technique by which developmental cardiac genes could
be identified is that of Gene Trapping.  This technique incorporates
a non-lethal reporter gene into embryonic stem cells used to make
transgenic mice.  Occasionally this integration will occur in the
regulatory region of a developmental cardiac gene.  That gene can be
located and has already proven capable of identifying genes expressed
in cardiac morphogenesis.

An approach that has proven successful in isolating thousands of new
brain genes is the sequencing of cDNA libraries of human fetal and
child brain.  Scientists have identified portions or Expressed
Sequence Tags (ESTs) of more than 2500 new genes expressed only in
the brain.  Although such a technique would be more complex in
studies of the heart, it is possible that similar libraries could be
constructed from embryonic mouse or chick heart leading to a rapid
selection of genes important in cardiac development.

Some genetically determined forms of pediatric cardiovascular disease
are not expressed at birth but develop during childhood.  At least
ten single-gene-determined forms of cardiomyopathy are currently
recognized.  Studies of these together with the cardiac abnormalities
seen in Duchenne's and myotonic dystrophies could lead to
understanding of the genetic factors which are associated with
formation and maintenance of normal heart structure and function.
Identification of the myotonic dystrophy gene product could yield
information about a molecular mechanism of defective cardiac
conduction and abnormal muscle relaxation.  Studies of heritable
connective tissue disorders such as Marfan Syndrome could throw light
on aspects of the remodelling process which occurs in aortic
aneurysms, hypertrophy, and cardiomyopathy.

Although structural defects of the cardiovascular system are the most
dramatic in terms of infant mortality, there are functional defects
that lead to morbidity and mortality, often not manifest until
childhood or adolescence.  These include heritable,
chemotherapy-related, and idiopathic cardiomyopathies and arrhyth-
mias.  These represent areas of investigation that could lead to
improved health for affected individuals, once fundamental mechanisms
underlying the expression of these diseases have been elucidated.
Aberrations in mitochondrial DNA are thought to be at fault in at
least a few cardiomyopathies and that is consistent with recent
findings of heritability.  Another emerging problem is the occurrence
of cardiomyopathies in children successfully treated for cancer with
anthracyclines.  Much needs to be known before effective treatment
and prevention can be developed.

Acquired heart diseases such as Rheumatic Fever (RF), Kawasaki
Disease (KD), HIV-related heart disease (HIVHD), and other
cardiomyopathies represent another area of research.  Prevention of
RF or treatment of the acute sequelae of KD are quite effective
though little is understood of the host factors which render some
individuals susceptible to these diseases.  A role for bacterial or
viral "Super Antigens," particularly in RF, has been postulated, but
little is known other than the majority of patients with RF have the
major histocompatibility genotype of DR2 or DR4.  Whether the heart
disorders of vertically transmitted HIV are due to HIV itself, the
immune environment in utero, concurrent infections in the mother, or
high risk behavior is unknown. Research in this field could lead to
much important knowledge on how infections or other environmental
factors affect the developing fetus.

Objectives and Scope

All applications must include basic and clinical research projects
that are interrelated.  Research focussed mainly on areas which are
traditionally under the purview of the atherosclerosis and
hypertension programs will be considered unresponsive to this
solicitation.

Proposed Research

The suggestions provided below are for illustrative purposes only.
They do not represent the full range of possible research projects
that would be responsive to this solicitation nor do they indicate
Institute priorities.  Applicants are urged to develop their own
programs of research that would advance knowledge, treatment and
prevention of cardiovascular disease in children.

o  Identification of new cardiac genes expressed in normal
development

o  Detailed studies of the timing of gene expression in developing
heart and correlation with developmental events in the embryo

o  Investigations of the contributions of genetic information in the
sperm and oocyte to congenital heart defects coupled with further
knowledge of the patterns of inheritance of congenital heart defects
from male and female progenitors

o  Studies designed to identify defective genes in CCVM and to
elucidate their roles

o  Investigations of the possibilities of gene therapy or the
insertion of DNA constructs to modify cardiac malformations

o  Elucidation of factors controlling vascular growth in the embryo
and fetus, particularly with reference to pulmonary hypoplasia and
pulmonary vascular obstructive disease

o  Development of imaging techniques applicable to human embryonic
hearts for early detection of structural defects

o  Study of corrective cardiac surgery in the fetus

o  Adaptation of interventional catheterization procedures and bypass
technology to fetuses and studies of outcome

o  Fundamental studies designed to elucidate the role of immature or
dysfunctional immune and coagulation systems in poor outcome of
infant heart surgery

o  Evaluation of outcomes of interventional, device implantation,
pharmacologic and surgical therapies, including cardiac
transplantation

o  Studies designed to elucidate the etiology of childhood
cardiomyopathies

o  Exploration of new therapeutic modalities to prevent the
deleterious effects of anthracyclines on the heart

o  Elucidation of the factors predisposing patients to cardiovascular
sequelae of infections

o  Exploration of techniques to develop valve leaflets from a
patient's own tissue

o  Experiments focussed on the defects of mitochondrial DNA which
lead to idiopathic cardiomyopathy and the possibilities of gene
therapy

SPECIAL INSTRUCTIONS FOR INCLUSION OF WOMEN AND MINORITIES IN
CLINICAL RESEARCH STUDIES

The following statement is required for all RFAs.  In this case
"women" applies to female children.

NIH policy is that applicants for NIH clinical research grants and
cooperative agreements will be required to include minorities and
women on study populations so that research findings can be of
benefit to all persons at risk of the disease, disorder or condition
under study; special emphasis should be placed on the need for
inclusion of minorities and women in studies of diseases, disorders
and conditions which disproportionately affect them.  This policy is
intended to apply to males and females of all ages.  If women or
minorities are excluded or inadequately represented in clinical
research, particularly in proposed-population based studies, a clear
compelling rationale must be provided.

The composition of the proposed study population must be described in
terms of gender.  In addition issues of gender should be addressed in
developing a research design and sample size appropriate for the
scientific objectives of the study.  This information should be
included in the form PHS 398 in Sections 1-4 of the research plan AND
summarized in Section 5, Human Subjects.  Applicants are urged to
assess carefully the feasibility of including adequate numbers of
women.

For the purpose of this policy, clinical research includes human
biomedical and behavioral studies of etiology, epidemiology,
prevention (and prevention strategies), diagnosis, or treatment of
diseases, disorders or conditions, including but not limited to
clinical trails.

The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded.  However,
every effort should be made to include human tissues from women when
it is important to apply the results of the study broadly, and this
should be addressed by applicants.

For foreign awards, the policy on inclusion of women applies fully;
since the definition of minority differs in other countries, the
applicant must discuss the relevance of research involving foreign
population groups to the United States' populations, including
minorities.

If the required information is not contained within the application,
the application will not be accepted for review.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
women is inadequate to answer the scientific question(s) addressed
AND the justification for the selected study population is
inadequate, it will be considered a scientific weakness or deficiency
in the study design and will be reflected in assigning the priority
score to the application.

All applications for clinical research submitted to NIH are required
to address these policies.  NIH funding components will not award
grants or cooperative agreements that do not comply with these
policies.

LETTER OF INTENT

Prospective applicants are asked to submit, by January 4, 1993 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:

Chief, Centers and Special Projects Section
Review Branch/Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Westwood Building, Room 553A
Bethesda, MD  20892

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 9/91) is to be used
in applying for these grants.  These forms are available at most
institutional business offices and may be obtained from the Office of
Grants Inquiries, Division of Research Grants, National Institutes of
Health, Westwood Building, Room 449 Bethesda, MD 20892, telephone
301-496-7441.

Applicants must follow the instructions provided in the supplement to
the RFA.

The RFA label available in the PHS 398 application form must be
affixed to the bottom of the fact 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 "Pediatric Cardiovascular
Disease Centers," HL-93-04-H on line 2a 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
Westwood Building, Room 240
Bethesda, MD  20892**

Send two additional copies of the application to Chief, Centers and
Special Projects Section 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, or the NHLBI cannot guarantee that the application will be
reviewed in competition for this RFA.

Applications must be received by March 15, 1993.  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 announcement 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 by NIH staff for
completeness and responsiveness.  Incomplete applications will be
returned to the applicant without further consideration.  If the
application is not responsive to the RFA, it will be returned.

Applications will be triaged by a peer review group convened by the
NHLBI on the basis of relative competitiveness.  The NHLBI will
withdraw from further competition those applications judged to be
non-competitive for award and notify the applicant Principal
Investigator and institutional official.  Those applications judged
to be competitive will undergo further scientific merit review.  They
will be evaluated in accordance with the criteria stated below for
scientific/technical merit by an appropriate peer review group
convened by the NHLBI.  The initial review may include a site visit
or applicant interview.  The second level of review will be provided
by the National Heart, Lung, and Blood Advisory Council in September
1993.

Review criteria for RFAs are generally the same as those for
unsolicited interdisciplinary research grant applications.

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 project 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 to be
considered for funding.

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.

Since a variety of approaches would represent valid responses to this
announcement, it is anticipated that there will be a range of costs
among individual grants awarded.

The anticipated date of award is September 30, 1993.

INQUIRIES

Inquiries regarding this announcement may be directed to the program
administrator:

Dr. Constance Weinstein
Chief, Cardiac Diseases Branch
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
Federal Building, Room 3C06
Bethesda, MD  20892
Telephone:  (301) 496-1081
FAX:  (301) 480-6282

Inquiries regarding fiscal and administrative matters may be directed
to:

Mr. William Darby
Grants Operations Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Westwood Building, Room 4A11
Bethesda, MD  20892
Telephone:  (301) 496-7536
FAX: (301) 402-1200

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance No. 93.837, Heart and Vascular Diseases.  Awards are made
under the authority of the Public Health Service Act, Section 301 (42
USC 241) and administered under PHS grants policies and Federal
regulations, most specifically 42 CFR Part 52 and 45 CFR Part 74.
This program is not subject to the intergovernmental review
requirements of Executive Order 12372, or to Health Systems Agency
Review.

.

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