Full Text HD-94-009

DEVELOPMENT OF BIOCHEMICAL AND GENETIC MARKERS FOR PREMATURE
ATHEROGENESIS

NIH GUIDE, Volume 22, Number 31, August 27, 1993

RFA:  HD-94-009

P.T. 34

Keywords: 
  Cardiovascular Diseases 
  Biochemical Markers 
  Genetics 


National Institute of Child Health and Human Development
National Heart, Lung, and Blood Institute

Application Receipt Date:  December 9, 1993

PURPOSE

The Endocrinology, Nutrition and Growth (ENG) Branch of the Center
for Research for Mothers and Children, National Institute of Child
Health and Human Development (NICHD) and the Lipid
Metabolism-Atherogenesis (LA) Branch, National Heart, Lung, and Blood
Institute (NHLBI) issue a Request for Applications (RFA) on
Development of Biochemical and Genetic Markers for Premature
Atherogenesis.

Coronary atherosclerosis remains a major killer disease, often
causing deaths during prime productive years.  It has been shown that
the pathological process of coronary atherosclerosis often begins in
adolescence, and it is known that profound changes occur in the
lipoprotein system during infancy and adolescence that may predispose
to atherogenesis.

Preventive measures could be effective in mitigating the ravages of
coronary atherosclerosis if markers of the atherogenic process were
available in susceptible children and adolescents.  The purpose of
this RFA is to ascertain biochemical and genetic markers of the
atherosclerotic process in order to identify those children at high
risk.

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,
Development of Biochemical and Genetic Markers for Premature
Atherogenesis, is related to the priority area of childhood
nutrition.  Potential applicants may obtain a copy of "Healthy People
2000" (Full Report:  Stock No. 017-001-00474-0) or "Healthy People
2000" (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 and local
governments, and eligible agencies of the Federal government.
Applications from minority individuals and women are encouraged.

MECHANISM OF SUPPORT

Applications in response to this RFA will be funded through the
research project grant (R01) program of the NIH.  This announcement
is for a single competition with the application receipt deadline of
December 9, 1993.  Future unsolicited competing continuation
applications will compete with all investigator-initiated
applications and be reviewed by a Division of Research Grants (DRG)
study section.  However, if the NICHD and the NHLBI determine that
there is a sufficient continuing program need, these Institutes may
announce a request for competitive continuation applications.  The
total project period for applications submitted in response to the
present RFA should not exceed five years.  The earliest anticipated
award date is September 1, 1994.

FUNDS AVAILABLE

It is anticipated that six grants will be awarded under this program,
contingent upon receipt of a sufficient number of meritorious
applications and the availability of funds.  To fund these awards the
NICHD has set aside $750,000 and the NHLBI has set aside $250,000 for
direct costs in the first year.

RESEARCH OBJECTIVES

Background

The major emphasis of preventive research in this area is currently
placed on control of hypercholesterolemia.  However, lipoproteins
other than LDL-cholesterol may be important in atherogenesis and
might serve as robust predictors once they are identified.  The
purpose of this RFA is to stimulate investigators to move beyond
cholesterol in exploring biochemical and genetic predictors of
atherogenesis and to encourage investigators to ascertain differences
in lipoprotein profiles and other metabolic, hormonal, or genetic
factors between offspring of families prone to premature coronary
atherosclerosis and offspring of families not so afflicted.  Such
differences may be useful as markers to identify those children at
high risk of developing atherosclerosis later in life.

Objectives and Scope

The NICHD and the NHLBI are devoted to uncovering predictors of
chronic
disease during childhood.  This RFA is aimed at identifying genetic
and
biochemical precursors in childhood and adolescence of
atherosclerosis later
in life.  The prevention of chronic disease in adulthood is best
achieved by
attacking these problems in children.

To maximize the probability of success in developing childhood
markers for atherogenesis, studies should focus on changes in
lipoprotein profiles during childhood and adolescence in offspring of
coronary-prone parents, especially mothers, in comparison to a
matched group of offspring of parents unaffected by coronary
atherosclerosis.  Studies of several generations and studies of
affected twins should also be informative. Investigators are also
encouraged to develop epidemiologic techniques to permit the
correlation of genetic or metabolic markers measurable in childhood
with a familial tendency to premature atherosclerosis.

It is known that high serum levels of LDL-cholesterol predispose to
coronary atherosclerosis.  Children who are homozygous for familial
hypercholesterolemia have very high levels of this serum lipid
fraction and are at risk of clinically significant coronary pathology
in their second and third decades.  The molecular basis for this
hereditary condition is known to be absent or dysfunctional cellular
LDL receptors.  However, the majority of coronary artery occlusions
occur in individuals who have only mild-to-moderate elevations of
LDL-cholesterol.  Therefore, changes in other lipoprotein fractions
need to be explored as possible harbingers of atherosclerosis in
addition to elevations of LDL-cholesterol.

Examples of putative lipoprotein markers include elevated levels of
LDL- apolipoprotein B; low levels of HDL cholesterol (hypo HDL) and
low levels of apolipoprotein AI; isoforms of apolipoprotein E;
elevated levels of Lp(a) lipoproteins; elevated serum triglycerides;
and high levels of oxidized LDL.  Ratios and functional measures,
such as delayed clearing of dietary fat or these or other lipids and
lipoproteins might also serve as markers in childhood for
atherosclerosis later in life.

Factors other than lipoproteins and their receptors that may also
contribute to the process of coronary atherosclerosis in an ancillary
manner include homocysteine, peptide hormones, sex steroids, growth
factors, endothelin-1, thromboxane, fibrinogen, fibrin, fibrin split
products, tissue plasminogen activator, and other components of the
coagulation cascade.

In addition to uncovering markers of atherosclerosis in offspring of
affected parents, evaluating the segregation of such markers in
several generations of coronary-prone families is also encouraged to
ascertain the heritability and penetrance of possible metabolic and
genetic markers.  Studies designed to ascertain how putative markers
track prospectively are also needed.  Genetic studies of individuals
who are heterozygotes or compound heterozygotes for genes that
control the metabolism and transport of lipoproteins are encouraged
as well.

This RFA is designed to study lipoproteins and other putative
biochemical and genetic markers of premature atherosclerosis.  The
scope of the RFA includes infants, children, and adolescents as well
as animal models if they can be shown to be relevant.

STUDY POPULATIONS

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS

NIH policy is that applicants for NIH clinical research grants and
cooperative agreements will be required to include minorities in
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 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 minorities are excluded or
inadequately represented in clinical research, particularly in
proposed population-based studies, a clear and compelling rationale
should be provided.

The racial/ethnic composition of the proposed study population must
be described.  In addition, racial/ethnic issues 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 (rev. 9/91) 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
the broadest possible representation of minority groups.  However,
NIH recognizes that it may not be feasible or appropriate in all
research projects to include representation of the full array of
United States racial/ethnic minority populations (i.e., Native
Americans (including American Indians or Alaskan Natives),
Asian/Pacific Islanders, Blacks, Hispanics).

The rationale for studies on single minority population groups should
be provided.

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

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
racial/ethnic minorities when it is important to apply the results of
the study broadly, and this should be addressed by applicants.

For foreign awards, 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 be returned.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
minorities in a study design 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.

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 offices of sponsored research and from the Office of
Grants Information, Division of Research Grants, National Institutes
of Health, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892,
telephone 301-710-0267.

The RFA label available in the PHS 398 application form must be
affixed to the bottom of the face page.  Failure to use this label
could result in delayed processing of an application such that it may
not reach the review committee in time for review.  In addition, the
RFA title and number must be typed on line 2a of the face page of the
application form and the YES box checked.

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

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

At the time of submission, two additional copies of the application
must also be sent to:

Susan Streufert, Ph.D.
Division of Scientific Review
National Institute of Child Health and Human Development
6100 Building, Room 5E01
Bethesda, MD  20892

Applications must be received by December 9, 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, unless the applicant withdraws the
pending application.  If the application submitted in response to
this RFA is substantially similar to a research grant application
already submitted to the NIH for review, that has not yet been
reviewed, the applicant will be asked to withdraw either the pending
application or the new one.  Simultaneous submission of identical
applications will not be allowed, nor will essentially identical
applications be reviewed by different review committees.  Therefore,
an application cannot be submitted in response to this RFA that is
essentially identical to one that has already been 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

Applications will be reviewed by NICHD and NHLBI staff for
responsiveness to the RFA.  Applications judged to be nonresponsive
will be returned.  The applicant may resubmit the application and
have it assigned for review in the same manner as unsolicited grant
applications.

Responsive applications may be subjected to a triage by a peer-review
group to determine their scientific merit relative to the other
applications received in response to this RFA.  NIH will withdraw
from competition those applications judged to be noncompetitive and
notify the applicant and institutional business official.  Those
applications judged to be competitive will be further evaluated for
scientific/technical merit by a review group convened solely for this
purpose by the Division of Scientific Review, NICHD.  Criteria for
the initial review will include the significance and originality of
research goals and approaches; the feasibility of research and
adequacy of the experimental design; the research experience and
competence of the investigator(s) to conduct the proposed work; the
adequacy of investigator effort devoted to the project; and the
appropriateness of the project duration and cost relative to the work
proposed.  Following review by the Initial Review Group, applications
will be evaluated by the National Advisory Child Health and Human
Development Council and by the National Heart, Lung, and Blood
Advisory Council for program relevance and policy issues before
awards for meritorious proposals are made.

AWARD CRITERIA

The anticipated award date is September 1, 1994.  Scientific merit
and technical proficiency, based on the demonstrated and projected
capabilities described in the application in response to the RFA,
will be the predominant criteria for determining funding priorities.

INQUIRIES

Written and telephone 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:

Gilman D. Grave, M.D.
Center for Research for Mothers and Children
National Institute of Child Health and Human Development
6100 Building, Room 4B11
Bethesda, MD  20892
Telephone:  (301) 496-5593

Direct inquiries regarding fiscal matters to:

Mr. E. Douglas Shawver
Office of Grants and Contracts
National Institute of Child Health and Human Development
6100 Building, Room 8A17
Bethesda, MD  20892
Telephone:  (301) 496-1303

AUTHORITY AND REGULATIONS

This program is described in the catalog of Federal Domestic
Assistance No. 93.865, Research for Mothers and Children.  Awards
will be made under the authority of the Public Health Service Act,
Section 301 (42 USC 241), and administered under PHS grants policies
and Federal Regulations 42 CFR Part 52 and 45 CFR Part 74.  This
program is not subject to review by a Health Systems Agency.

.

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