FETAL ORIGINS OF ADULT DISEASE
Release Date: August 10, 2000
RFA: HD-00-021
National Institute of Child Health and Human Development
(http://www.nichd.nih.gov/)
National Institute on Aging
(http://www.nih.gov/nia/)
National Institute of Diabetes and Digestive and Kidney Diseases
(http://www.niddk.nih.gov/)
National Institute of Environmental Health Sciences
(http://www.niehs.nih.gov/)
Letter of Intent Receipt Date: September 15, 2000
Application Receipt Date: October 24, 2000
THIS RFA USES THE MODULAR GRANT AND JUST-IN-TIME CONCEPTS. IT INCLUDES
DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED
WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA.
PURPOSE
The purpose of this solicitation is to determine the mechanisms by which the
intrauterine environment programs fetal metabolism to predispose individuals
to chronic disease later in life and to determine whether these mechanisms may
contribute to disparities in the prevalence of obesity, diabetes,
hypertension, atherosclerosis, and neurodegeneration among various races and
ethnic groups. The National Institute of Child Health and Human Development
(NICHD), the National Institute on Aging (NIA), the National Institute of
Diabetes and Digestive and Kidney Diseases (NIDDK), and the National Institute
of Environmental Health Sciences (NIEHS) seek to encourage research on the
basic mechanisms that may explain the lifelong consequences of intrauterine
growth retardation and/or exposure to deficient and/or stressful intrauterine
environments.
HEALTHY PEOPLE 2010
The Public Health Service (PHS) is committed to achieving the health promotion
and disease prevention objectives of "Healthy People 2010," a PHS-led national
activity for setting priority areas. This Request for Applications (RFA),
Fetal Origins of Adult Disease, is related to one or more of the priority
areas. Potential applicants may obtain "Healthy People 2010" at
http://www.health.gov/healthypeople/.
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. Racial/ethnic minority individuals,
women, and persons with disabilities are encouraged to apply as Principal
Investigators.
MECHANISM OF SUPPORT
This RFA will use the National Institutes of Health (NIH) Research Project
Grant (R01) award mechanism. 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 this 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. The anticipated award date is August 1, 2001.
Specific application instructions have been modified to reflect MODULAR
GRANT and JUST-IN-TIME streamlining efforts being examined by the NIH.
Complete and detailed instructions and information on Modular Grant
applications can be found at
http://grants.nih.gov/grants/funding/modular/modular.htm.
FUNDS AVAILABLE
The NICHD, NIA, NIDDK, and NIEHS intend to commit approximately $3.8 million
in total costs [direct plus Facilities and Administrative (F&A) costs] in FY
2001 to fund seven to 10 new and/or competing continuation grants in response
to this RFA. An applicant may request a project period of up to five years.
Because the nature and scope of the research proposed may vary, it is
anticipated that the size of awards also will vary. Although the financial
plans of the NICHD, NIA, NIDDK, and NIEHS provide support for this program,
awards pursuant to this RFA are contingent upon the availability of funds, the
receipt of a sufficient number of meritorious applications, and relevance to
programmatic interests of the participating institutes.
RESEARCH OBJECTIVES
Background
The problem of health disparities in the United States, particularly the high
prevalence of obesity, hypertension, stroke, Type 2 diabetes, and coronary
artery disease in minority populations, may result in part from interactions
of the fetus with its intrauterine environment. Epidemiologic studies have
demonstrated that low birth weight and, more specifically, intrauterine growth
retardation are associated with insulin resistance, Type 2 diabetes mellitus,
hypertension, coronary artery disease, and lowered cognitive performance
later in life. A prospective case-control study has shown that levels of
amniotic fluid insulin predict obesity and insulin resistance later in life.
Based on these observational studies, it has been suggested that metabolic
programming occurs during fetal life in response to intrauterine growth
constraints and/or exposure in utero to deficiencies or surfeits of nutrient
substrates, oxygen, hormones, growth factors, and cytokines. While
epidemiological studies have identified the phenomenon of metabolic
programming, little is known about the mechanisms by which fetal insults lead
to disease later in life.
At the most general level, metabolic programming represents a fetal response
to accommodate an inimical intrauterine environment in order to optimize
chances for fetal survival. In its drive for survival, the fetus appears to
favor the metabolic demands of the growing brain over the metabolic demands of
the kidneys, liver, muscle, pancreas, and other organs. The molecular
mechanisms that govern this phenomenon are unknown and need to be elucidated,
especially because the intrauterine survival advantage gained by this maneuver
may entail a cost of metabolic impairment and chronic disease later in life.
For example, deprivation of intrauterine nutrient supply to the kidney may
result in fewer nephrons than normal with a reduced filtration capacity,
paving the way for hypertension later in life. Similarly, impaired substrate
supply to the pancreas during fetal development may result in a smaller than
normal beta cell mass leading to glucose intolerance later in life. Whether,
in fact, these intrauterine accommodations lead to chronic disease later in
life remains to be established. Other mechanisms beside blood flow
redistribution may account for the observed associations between low birth
weight and chronic disease later in life. In fact, the more general question
of fetal metabolic response to the intrauterine environment, whether stressed
or nutrient restricted or not, may have implications for health and disease
later in life. This is a key issue that needs to be studied in depth. In
order to do so, more precise predictors of chronic disease are needed in
addition to the anthropometric markers currently in use such as birth weight,
birth length, and ponderal index. Biochemical or genetic markers may more
accurately reflect fetal metabolic programming and predict chronic disease and
health disparities later in life. Such biochemical and genetic markers need
to be determined, and research directed towards this aim is of the highest
priority.
Research Scope
To address these research needs, this RFA seeks research projects focused on
one or more of the following goals:
(a) To identify biochemical and genetic markers during fetal and early
postnatal life for prediction of risk for chronic disease and disabilities
later in life.
(b) To elucidate the effect of psychosocial stress during pregnancy on fetal
growth, metabolism, neuroendocrine development, and behavior later in life.
(c) To ascertain the mechanisms by which the fetus senses an intrauterine
environment that is deleterious for brain development and responds by shunting
blood away from other organs to the brain.
(d) To develop interventions designed to mitigate the metabolic derangements
associated with intrauterine growth retardation and its consequences for adult
disease later in life.
Research Topics
Relevant research topics include, but are not limited to, the following:
o Potential mechanisms by which the normal fetal growth trajectory goes awry,
including impaired placental function and the pathogenesis of placental
malfunction.
o Placentation and fetal growth, including placental-fetal interaction, with
emphasis on the molecular mechanisms by which the fetus provokes compensatory
placental functions.
o Elucidation of the molecular and genetic mechanisms by which the fetus
adapts to its intrauterine environment, including especially the phenomenon of
metabolic programming.
o Interactions among nutrients, trophic hormones, cytokines, and genes and
their effect on fetal growth and long-term development.
o Late-life neural, cognitive, and behavioral sequelae of fetal
perturbations.
o Effect of perturbations of the intrauterine environment on fetal
cardiovascular development and blood pressure regulation later in life.
o Effects of maternal psychosocial stress on the development of the
hypothalamic-pituitary-adrenal axis in the offspring, including long-term
consequences and intergenerational effects on behavior and organ and system
function.
o Effects of intrauterine environments on beta cell development, beta cell
mass, glucose sensing, insulin signaling, and insulin action.
o Metabolic programming and insulin resistance in multiple generations in
both humans and animal models.
o Identification of subsets of growth-retarded fetuses at high risk for
metabolic derangements later in life.
o Elucidation of the mechanisms that account for the metabolic derangements
that ensue when growth-retarded newborns are exposed to a surfeit of food
during infancy and childhood, and how these derangements lead to chronic
metabolic disease later in life.
o Development of interventions designed to mitigate the metabolic
derangements of intrauterine growth retardation and its consequences later in
life. Studies are needed to determine if limiting caloric intake during
infancy and childhood can ameliorate the impact of intrauterine growth
retardation.
o Elucidation of the interrelationship between the socioeconomic and health
environment early in life and its consequences later in life on health,
disability, and survival.
o Interactions of genes and the intrauterine environment as determinants of
disease later in life.
Research Resources
Applicants are encouraged to exploit existing longitudinal multi-generational
cohorts with stored maternal and fetal serum to assess the contributions of
the intrauterine environment to adult conditions later in life. Applicants
also are encouraged to utilize existing animal models or to develop new animal
models to address the issues of maternal stress during pregnancy and
consequences of metabolic programming during fetal life.
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 are 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," published in the Federal Register of March 28, 1994 (FR 59 14508-
14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March
18, 1994, and available on the Internet at:
http://grants.nih.gov/grants/guide/notice-files/not94-100.html.
INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS
It is the policy of NIH that children (i.e., individuals under the age of 21)
must be included in all human subjects research, conducted or supported by the
NIH, unless there are scientific and ethical reasons not to include them.
This policy applies to all initial (Type 1) applications submitted for receipt
dates after October 1, 1998.
All investigators proposing research involving human subjects should read the
"NIH Policy and Guidelines on the Inclusion of Children as Participants in
Research Involving Human Subjects, published in the NIH Guide for Grants and
Contracts, March 6, 1998, and available on the Internet at:
http://grants.nih.gov/grants/guide/notice-files/not98-024.html.
Investigators also may obtain copies of these policies from the program staff
listed under INQUIRIES. Program staff may also provide additional relevant
information concerning the policy.
URLS IN NIH GRANT APPLICATIONS OR APPENDICES
All applications and proposals for NIH funding must be self-contained within
specified page limitations. Unless otherwise specified in an NIH
solicitation, Internet addresses (URLs) should not be used to provide
information necessary to the review because reviewers are under no obligation
to view the Internet sites. Reviewers are cautioned that their anonymity may
be compromised when they directly access an Internet site.
LETTER OF INTENT
Prospective applicants are asked to submit 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 this RFA.
Although a letter of intent is not required, is not binding, and does not
enter into the review of a subsequent application, the information that it
contains allows NICHD staff to estimate the potential review workload and plan
the review.
The letter of intent is to be sent to Dr. Gilman D. Grave, at the address
listed under INQUIRIES, below, by September 15, 2000.
APPLICATION PROCEDURES
The research grant application form PHS 398 (rev. 4/98) is to be used in
applying for these grants. These forms are available at most institutional
offices of sponsored research, on the Internet at
http://grants.nih.gov/grants/funding/phs398/phs398.html, and from the Division
of Extramural Outreach and Information Resources, National Institutes of
Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone
301-710-0267, E-mail: grantsinfo@nih.gov.
Application Instructions
The modular grant concept establishes specific modules in which direct costs
may be requested as well as a maximum level for requested budgets. Only
limited budgetary information is required under this approach. The just-in-
time concept allows applicants to submit certain information only when there
is a possibility for an award. It is anticipated that these changes will
reduce the administrative burden for the applicants, reviewers, and NIH staff.
The research grant application form PHS 398 (rev. 4/98) is to be used in
applying for these grants, with the modifications noted below.
For responses to this RFA, Modular Grant applications will request direct
costs in $25,000 modules, up to a total direct cost request of $250,000 per
year. (Applications that request
more than $250,000 direct costs in any year must follow the traditional PHS
398 application instructions.) The total direct costs must be requested in
accordance with the program guidelines and the modifications made to the
standard PHS 398 application instructions described below:
o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs
(in $25,000 increments up to a maximum of $250,000) and Total Costs [Modular
Total Direct plus Facilities and Administrative (F&A) costs] for the initial
budget period. Items 8a and 8b should be completed indicating the Direct and
Total Costs for the entire proposed period of support.
o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD: Do not complete Form Page
4 of the PHS 398. It is not required and will not be accepted with the
application.
o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT: Do not complete the
categorical budget table on Form Page 5 of the PHS 398. It is not required
and will not be accepted with the application.
o NARRATIVE BUDGET JUSTIFICATION: Prepare a Modular Grant Budget Narrative
page. (See http://grants.nih.gov/grants/funding/modular/modular.htm for
sample pages.) At the top of the page, enter the Total Direct Costs requested
for each year. This is not a Form Page.
Under Personnel, list ALL project personnel, including their names, percent of
effort, and roles on the project. No individual salary information should be
provided. However, the applicant should use the NIH appropriation language
salary cap and the NIH policy for graduate student compensation in developing
the budget request.
For Consortium/Contractual costs, provide an estimate of Total Costs (Direct
plus F & A) for each year, each rounded to the nearest $1,000. List the
individuals/organizations with whom consortium or contractual arrangements
have been made, the percent effort of key personnel, and the role on the
project. Indicate whether the collaborating institution is foreign or
domestic. The total cost for a consortium/contractual arrangement is included
in the overall requested modular direct cost amount. Include the Letter of
Intent to establish a consortium.
Provide an additional narrative budget justification for any variation in the
number of modules requested.
o BIOGRAPHICAL SKETCH: The Biographical Sketch provides information used by
reviewers in the assessment of each individual's qualifications for a specific
role in the proposed project, as well as to evaluate the overall
qualifications of the research team. A biographical sketch is required for
all key personnel, following the instructions below. No more than three
pages may be used for each person. A sample biographical sketch may be viewed
at:
http://grants.nih.gov/grants/funding/modular/modular.htm.
- Complete the educational block at the top of the Form Page;
- List position(s) and any honors;
- Provide information, including overall goals and responsibilities, on
research projects ongoing or completed during the last three years;
- List selected peer-reviewed publications, with full citations.
o CHECKLIST: This page should be completed and submitted with the
application. If the F&A rate agreement has been established, indicate the
type of agreement and the date. All appropriate exclusions must be applied in
the calculation of the F&A costs for the initial budget period and all future
budget years.
o The applicant should provide the name and telephone number of the
individual to contact concerning fiscal and administrative issues if
additional information is necessary following the initial review.
Submission Instructions
The RFA label available in the PHS 398 (rev. 4/98) application form must be
stapled to the bottom of the face page of the application and must display the
RFA number HD-00-021. A sample RFA label is available at
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. Please note this is
in the pdf format. Failure to use this label could result in delayed
processing of the application such that it may not reach the review committee
in time for review. In addition, the RFA title and number must be typed on
line 2 of the face page of the application form and the YES box must be
marked.
Submit a signed, typewritten original of the application, including the
Checklist, and three signed photocopies, in one package to:
CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710
BETHESDA, MD 20892-7710
BETHESDA, MD 20817 (for express/courier service)
At the time of submission, two additional copies of the application should be
sent to:
L. R. Stanford, Ph.D.
Director, Division of Scientific Review
National Institute of Child Health and Human Development
6100 Executive Blvd., Room 5E01, MSC 7510
Bethesda, MD 20892-7510
Rockville, MD 20852 (for express/courier service)
Telephone: (301) 496-9254
Applications must be received by October 24, 2000. If an application is
received after that date, it will be returned to the applicant without review.
The Center for Scientific Review (CSR) will not accept any application in
response to this RFA that is essentially the same as one currently pending
initial review, unless the applicant withdraws the pending application. The
CSR will not accept any application that is essentially the same as one
already reviewed. This does not preclude the submission of substantial
revisions of applications already reviewed, but such applications must include
an introduction addressing the previous critique.
REVIEW CONSIDERATIONS
Upon receipt, applications will be reviewed for completeness by the CSR and
for responsiveness to the RFA by NICHD, NIA, NIDDK, and NIEHS staff.
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 an appropriate peer review group convened by
the NICHD in accordance with the review criteria stated below. As part of the
initial merit review, all applications will receive a written critique and may
undergo a process in which only those applications deemed to have the highest
scientific merit will be discussed, assigned a priority score, and receive a
second level review by the National Advisory Council of NICHD, NIA, NIDDK,
and/or NIEHS.
Review Criteria
The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health. In
the written comments reviewers will be asked to discuss the following aspects
of the application in order to judge the likelihood that the proposed research
will have a substantial impact on the pursuit of these goals. Each of these
criteria will be addressed and considered in assigning the overall score,
weighting them as appropriate for each application. Note that the application
does not need to be strong in all categories to be judged likely to have major
scientific impact and thus deserve a high priority score. For example, an
investigator may propose to carry out important work that by its nature is not
innovative but is essential to move a field forward.
(1) Significance: Does this study address an important problem? If the aims
of the application are achieved, how will scientific knowledge be advanced?
What will be the effect of these studies on the concepts or methods that drive
this field?
(2) Approach: Are the conceptual framework, design, methods, and analyses
adequately developed, well-integrated, and appropriate to the aims of the
project? Does the applicant acknowledge potential problem areas and consider
alternative tactics?
(3) Innovation: Does the project employ novel concepts, approaches or method?
Are the aims original and innovative? Does the project challenge existing
paradigms or develop new methodologies or technologies?
(4) Investigator: Is the investigator appropriately trained and well suited
to carry out this work? Is the work proposed appropriate to the experience
level of the Principal Investigator and other researchers (if any)?
(5) Environment: Does the scientific environment in which the work will be
done contribute to the probability of success? Do the proposed experiments
take advantage of unique features of the scientific environment or employ
useful collaborative arrangements? Is there evidence of institutional
support?
In addition to the above criteria, in accordance with NIH policy, all
applications also will be reviewed with respect to the following:
o The adequacy of plans to include both genders, minorities and their
subgroups, and children as appropriate for the scientific goals of the
research. Plans for the recruitment and retention of subjects will also be
evaluated.
o The reasonableness of the proposed budget and duration in relation to the
proposed research.
o The adequacy of the proposed protection for humans, animals or the
environment, to the extent they may be adversely affected by the project
proposed in the application.
Schedule
Letter of Intent Receipt Date: September 15, 2000
Application Receipt Date: October 24, 2000
Peer Review Date: February/March 2001
Council Review: June 2001
Earliest Anticipated Start Date: August 1, 2001
AWARD CRITERIA
Criteria that will be used to make award decisions include:
o scientific merit (as determined by peer review)
o availability of funds
o programmatic priorities.
INQUIRIES
Potential applicants are strongly encouraged to contact program staff with any
questions regarding the responsiveness of their proposed project to the goals
of this RFA.
Written and telephone inquiries concerning this RFA are encouraged. The
opportunity to clarify any issues or questions from potential applicants is
welcome.
A complete listing of contacts for both programmatic and fiscal/administrative
inquiries may be found at: http://www.nichd.nih.gov/RFA/HD-00-021/HD-00-021.htm
AUTHORITY AND REGULATIONS
This program is described in the Catalog of Federal Domestic Assistance Nos.
93.113, 93.865, 93.866, and 93.849. Awards are made under authorization of
Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241
and 284) and administered under NIH grants policies and Federal Regulations 42
CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the
intergovernmental review requirements of Executive Order 12372 or Health
Systems Agency review.
The PHS strongly encourages all grant 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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