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 
301-435-0714, 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.

Return to Volume Index

Return to NIH Guide Main Index

	Office of Extramural Research (OER)			National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892			Department of Health and Human Services (HHS)
Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, RealPlayer, Video or Flash files, see Help Downloading Files.