Full Text HL-95-001

GENE-NUTRIENT INTERACTIONS IN THE PATHOGENESIS OF CONGENITAL HEART
DEFECTS

NIH GUIDE, Volume 23, Number 33, September 16, 1994

RFA:  HL-95-001

P.T.


Keywords: 


National Heart, Lung and Blood Institute

Letter of Intent Receipt Date:  December 16, 1994
Application Receipt Date:  April 21, 1995

PURPOSE

The Division of Heart and Vascular Diseases invites applications to
conduct research into the relationship between genes and nutrients in
the etiology and prevention of Congenital Cardiovascular Malformations
(CCVM).  One goal is to foster basic research into the effects of
nutrients on embryologic and fetal development of the cardiovascular
system.  Approaches may include cell and organ culture, the generation
of genetically altered animal models and the use of molecular biology
and molecular genetics to elucidate the mechanisms underlying those
effects.  A second goal is to encourage small epidemiologic
investigations into the role of nutrients in the pathogenesis of human
CCVM.

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), Gene-Nutrient Interactions in the Pathogenesis
of Congenital Heart Defects, is related to the priority areas of
maternal and infant health, infant mortality and nutrition.  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 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.  Applications from
minority individuals and women are encouraged.  Awards in connection
with this RFA will be made to foreign institutions only for research of
very unusual merit, need and promise and in accordance with PHS policy
governing such awards.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) individual
research grant (R01).  Responsibility for the planning, direction, and
execution of the proposed project will be solely that of the applicant.
The total project period for an application submitted in response to
the present RFA may not exceed five years.  This RFA is a one-time
solicitation.  Future unsolicited competing continuation applications
will compete with all investigator-initiated applications and be
reviewed according to the customary peer review procedures.  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.

FUNDS AVAILABLE

The total funds available for the first year of this program (direct
plus indirect costs) are $2.00M.  Funding is expected to begin in
September 1995.  It is anticipated that no more than eight 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 of support may be required at the time of
the award.

In order to more evenly distribute administrative workload and reduce
the number of awards with July 1 or September 30 start dates, the NHLBI
will award ten months of time and money for the first competing budget
period of this project.  This action results in a project period of 58
months. Investigators should plan their research projects and budgets
within these timeframes.

RESEARCH OBJECTIVES

Disciplines and Expertise

Expertise appropriate for investigators includes but is not restricted
to:  developmental biology, human or animal genetics, molecular
biology, epidemiology, experimental nutrition, human nutrition and
dietetics, biochemistry, and biostatistics.

Background

Congenital cardiovascular malformations (CCVM) present our society with
an enormous burden of grief and expense.  About eight percent of all
deaths during the first year of life are due to CCVM.  Each year
approximately 30,000 babies are born with CCVM, of whom 2,900 will die
before their first birthday.

Birth defects comprise the largest component of infant mortality in the
United States and 42 percent of deaths due to birth defects are caused
by CCVM.  All U.S. population groups are afflicted by these relatively
high rates.  For example, although much of the 2.5 fold elevation in
infant mortality of African American infants is due to prematurity and
Respiratory Distress Syndrome, these infants experience excessive
deaths from CCVM as well.

Many of the children with CCVM who survive infancy go on to suffer
sustained disease.  After asthma and mental retardation, CCVM represent
the most frequent cause of serious chronic childhood morbidity, being
more common than cystic fibrosis and hemophilia.  CCVM in older
children and adolescents are accompanied by chronic use of medications,
multiple medical procedures, hospitalizations, and often, repeated open
heart operations requiring cardiopulmonary bypass.  Not surprisingly,
these children are likely to suffer impaired physical and social
development.  Furthermore, deaths due to CCVM occur throughout
childhood, adolescence and young adulthood.  Three thousand six hundred
children under age 15 die annually from CCVM; 700 of these are more
than 1 year old.  In 1992, nearly $500 million was spent to cover the
costs of 44,000 hospitalizations of children under age 15 with CCVM.
The societal costs of serious CCVM are unknown, but are certainly very
high, considering the loss of productive years of life, the burden on
caregivers, and the magnitude of medical expenses.

For many years the etiology of CCVM was thought to be multifactorial,
involving a complex interaction of the feto-placento-maternal unit and
teratogens.  Genes were thought to play only a small role, in part
because few children with CCVM lived long enough to reproduce; this
hampered detection of the genetic nature of many of these defects.
After a decade of focused research, much of which was funded by NHLBI,
there are new insights into the pathogenesis of CCVM.  It now appears
that many if not most CCVM are caused by gene mutations.  A genetic
etiology is now either strongly suspected or confirmed for at least
eight different structural cardiovascular malformations.  One of these,
supravalvular aortic stenosis, is now known to be caused by a mutation
in the elastin gene.  It is possible that the abnormal genotype causing
as many as half of these eight CCVM may be identified relatively soon.

Given the unsatisfactory nature of current treatments for many CCVM, it
seems prudent to consider strategies for prevention.  Other than
genetic counseling and avoidance of pregnancy, there are no
interventions available to reduce the frequency of offspring with
congenital heart disease.  Recent findings in the pathogenesis and
prevention of neural tube defects, however, support the concept that
risk of other birth defects, including CCVM, may in some cases be
related to maternal nutrient intake.  This concept is buttressed by the
results of clinical trials that have focused on  the role of folate in
the prevention of neural tube defects.  Approximately half of all NTD,
whether among the general population or among high risk mothers who
have already borne a child with an NTD, may be prevented by daily
supplementation of the maternal diet with 4 mg of folate interaction
between the genetic background of the mother or fetus and the increased
need for folate or other nutrients but the relative importance of such
interactions in the causation of most cases of NTD is unknown.

Recent genetic research on NTD has associated the location of different
NTDs (ranging from anencephaly to sacral meningocele) with a variety of
specific maternal exposures such as hyperthermia or low folate intake.
NTDs are, by definition, the result of failure of early morphogenetic
processes.  The mechanisms underlying neural tube closure have been
studied in considerable detail.  There appear to be five different
"zippers" that span the length of the neural tube and function to close
it during development.  These zippers are presumably under the control
of one or more genes, mutations in which would cause an NTD in the
region of that zipper.  Proper function of two of these zippers appears
to be sensitive to folate deficiency.  These preliminary findings in
the pathogenesis of NTD support the concept that risk of other types of
birth defects may also be affected by maternal nutrient intake.

Progress being made in elucidating gene-nutrient interactions in organs
other than heart lends credence to the possibility that such
connections could be made for CCVM.  For example, Vitamin C has been
shown to be required growth, malformations mirroring part of the CRBP
I expression pattern during development.  CRABP I transcripts, on the
other hand, are found in tissues which are separate and distinct from
those expressing CRBP I.  Saturation of the cytoplasmic pool of CRABP
I with large doses of exogenous RA could be expected to cause homeobox
or other genes to be turned on inappropriately.  This may be part of
the mechanism by which one metabolite of vitamin A, isotretoin,
consumed in the first trimester of pregnancy, produces conotruncal
malformations in the human embryo.

Not all of the malformations that may be secondary to gene-nutrient
interactions are necessarily the result of inadequate or excessive
maternal nutrient intake.  Rather, mutated genes may interact with
normal nutrient intake to produce an abnormal phenotype.  This concept
is well illustrated by the Pallid (pa) mouse mutant.  When fed a normal
diet, mice homozygous for the pa allele produce offspring which are
ataxic due to failure of otolith formation.  When these same
genotypically mutant mice are fed supraphysiologic supplements of the
trace element manganese, their pups are phenotypically normal, showing
no signs of ataxia.  Moreover, genotypically normal rats fed a diet
deficient in manganese produce offspring with the Pallid phenotype of
ataxia and absent otolith formation.  The manganese deficient phenotype
has also been reported in chick, mouse and guinea pig and appears to
result from depressed mucopolysaccharide synthesis.  According to
Hurley, "Manipulation of a single agent (the nutrient manganese) could,
through deprivation, alter the expression of the wild type gene to
produce a phenocopy of the mutant. On the other hand, administration of
large amounts of the agent (the nutrient manganese) altered the
expression of the mutant allele to produce the normal phenotype."

In this light, it is useful to consider the following paradigm
(modified from Hurley):

LEVEL OF NUTRIENT INTAKE
Mutant Genotype ---------------------> Mutant Phenotype

Normal Genotype ---------------------> Normal Phenotype
Mutant Genotype ---------------------> Normal Phenotype
Normal Genotype ---------------------> Mutant Phenotype

Areas of Research

Two general areas of research are appropriate for this RFA, namely
molecular/genetic studies of cardiovascular morphogenesis in animal
models and small epidemiologic investigations of the role of nutrients
in the pathogenesis of human CCVM.  It is anticipated that both
approaches will yield much needed information on measures that
eventually may prevent some cases of CCVM in humans.  Successful
applications will have hypotheses to direct the course of the research.

The molecular/genetic research will test hypotheses regarding potential
mechanisms by which a nutritional deficiency or toxicity may produce
malformations comparable to human CCVM.  Given the existing body of
literature on Vitamin A/beta-carotene, studies involving retinoid
related genes must address the mechanisms by which decreased RA affects
normal morphogenesis of the cardiovascular system.  Far less
information is available regarding the role of other nutrients in
organogenesis.  Hence, research on the role of vitamins and trace
elements in the pathogenesis of CCVM may be more broadly applied.

The use of well-defined animal models, whether naturally occurring or
transgenic, is encouraged.  Researchers may propose to study
gene-nutrient interactions in 'normal' animals fed a nutrient-deficient
diet.  Investigators also may wish to propose targeted interventions
that may correct the abnormal phenotype of an animal model of inherited
CCVM.  Research resources, such as Keeshond Beagles, which suffer form
conotruncal defects, or Yucatan miniature swine, which have a high
frequency of ventricular septal defects, may be considered.  Similar
investigations in humans would be premature and are not appropriate for
this RFA.

Large new epidemiologic studies are not likely to be feasible with the
budgets allotted for grants awarded under this RFA; 'add-on' projects
may be proposed, however, to take advantage of existing or planned
research programs.  Studies that propose to make use of already
existing epidemiologic data bases or cohorts with well-defined nutrient
intake and pregnancy outcomes are acceptable.  However, diagnosis of
CCVM in children involved in studies must be performed by a pediatric
cardiologist, using appropriate techniques such as echocardiography or
angiography to avoid errors due to mis-diagnosis.

The following examples of potential studies are given for illustrative
purposes only.  Investigators are urged to use their own knowledge of
the field in preparing their grant applications.

o  small epidemiologic studies of cases of specific CCVMs for which
maternal diets are well-defined

o  nutritional investigations in animal strains with known
predispositions toward specific defects

o  studies of the role of nutrients in gene expression during
cardiovascular development

o  studies elucidating the role of nutrients in the proliferation and
differentiation of progenitor cells

o  Tissue culture studies of nutrient requirements for synthesis of the
cardiac extracellular matrix

o  elucidation of the role of nutrients in the migration of cells and
formation of tissues

Exclusions

Clinical intervention trials and treatment studies in humans will not
be considered responsive to this RFA.  Large epidemiologic studies and
multiproject studies similar to program project applications will not
be accepted.

STUDY POPULATIONS

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 new policy results from
the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43)
and supersedes and strengthens the previous policies (Concerning the
Inclusion of Women in Study Populations, and Concerning the Inclusion
of Minorities in Study Populations), which have been in effect since
1990. The new policy contains some provisions that are substantially
different from the 1990 policies.

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 Contracts, Volume 23, Number 11, March
18, 1994.

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

LETTER OF INTENT

Prospective applicants are asked to submit, by December 16, 1994, 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.
It allows NHLBI staff to estimate the potential review workload and to
avoid conflict of interest in the review.

The letter of intent is to be sent to Dr. C. James Scheirer at the
address listed under INQUIRIES.

APPLICATION PROCEDURES

The research grant application for PHS 398 (rev. 9/91) is to be used in
applying for these grants.  These forms are available at most
institutional offices of sponsored research and may be obtained from
the Office of Grants Information, Division of Research Grants, National
Institutes of Health, Westwood Building, Room 240, Bethesda, MD 20892,
telephone 301/435-0714.

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 "Gene-Nutrient Interactions in the Pathogenesis of
Congenital Heart Defects", and the RFA number HL-95-001 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 Dr. Scheirer at the
address listed under INQUIRIES.  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.

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 could be included with the
application.

Applications must be received by April 21, 1995.  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, unless the applicant withdraws the pending
application.  The DRG 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 by NIH staff for
completeness and responsiveness.  Incomplete applications will be
returned to the applicant without further consideration.  If the
application is either late or not responsive to the RFA, NHLBI staff
will contact the applicant to determine whether to return the
application to the applicant or submit it for review in competition
with unsolicited applications at the next review cycle.

Applications that are complete and responsive to the RFA will be
evaluated for scientific and technical merit by an appropriate peer
review group convened by the NHLBI in accordance with the review
criteria stated below.  As part of the initial merit review, a process
(triage) 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 and the official signing for the applicant
organization will be notified.  The second level of review will be
provided by the National Heart, Lung, Blood Advisory Council.

Review criteria for this RFA are generally the same as those for
unsolicited research grant applications.

o  the novelty, originality and feasibility of the approach and the
adequacy of the experimental design

o  the competence of the principal investigator and collaborators to
accomplish the proposed research, and the commitment and time they will
devote to the project

o  the suitability of the facilities to perform the proposed research,
including laboratories, instrumentation and data management systems

o  the appropriateness of the requested budget and duration for the
proposed research

o  adequate plans for interaction and communication of information and
concepts among investigators involved in collaborative studies

AWARD CRITERIA

Awards made 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.

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
stimulate collaboration.  Applicants should 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.

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.

Timetable

Letter of Intent Receipt Date:  December 16, 1994
Application Receipt Date:       April 21, 1995
Review by NHLBAC:               September 1995
Anticipated Award Date:         September 1995

INQUIRIES

Written and telephone inquiries are encouraged.  We welcome the
opportunity to clarify any issues or questions from potential
applicants.  Inquiries regarding programmatic issues may be directed
to:

Dr. Abby G. Ershow
Lipid Metabolism-Atherogenesis Branch
National Heart, Lung, and Blood Institute
Federal Building, Room 401
7550 Wisconsin Avenue MSC 9050
Bethesda, MD  20892-9050
Telephone:  (301) 496-1681
FAX:  (301) 496-9882

Dr. Constance Weinstein
Cardiac Diseases Branch
National Heart, Lung and Blood Institute
Federal Building, Room 3C06
7550 Wisconsin Avenue MSC 9050
Bethesda, MD  20892-9050
Telephone:  (301) 496-1081
FAX:  (301) 480-6282

Direct inquiries regarding review and application procedures, address
the leter of intent to, and mail two copies of the application to:

Dr. C. James Scheirer
Division of Extramural Affairs
National, Heart, Lung, and Blood Institute
Westwood Building, Room 548B
Bethesda, MD  20892
Telephone:  (301) 594-7478
FAX:  (301) 594-7407

Inquiries regarding fiscal and administrative matters may be directed
to:

Mr. William Darby
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Westwood Building, Room 4A11
Bethesda, MD  20892
Telephone:  (301) 594-7458
FAX:  (301) 594-7492

AUTHORITY AND REGULATIONS

The programs of the Division of Heart and Vascular Diseases, National
Heart, Lung, and Blood Institute, are identified in the Catalog of
Federal Domestic Assistance No, 93.837.  Awards will be made under the
authority of the Public Health Service Act, Section 301 (42 USC 241)
and administered under 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.

The Public Health Service (PHS) strongly encourages all grant
recipients to provide a smoke-free workplace and promote the non-use of
all tobacco products.  This is consistent with the PHS mission to
protect and advance the physical and mental health of the American
people.

.

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