DEVELOPMENTAL MECHANISMS OF HUMAN MALFORMATIONS

Release Date:  October 15, 1999

RFA:  HD-99-008 

National Institute of Child Health and Human Development
National Institute of Environmental Health Sciences

Letter of Intent Receipt Date:  February 1, 2000
Application Receipt Date:  March 22, 2000 

PURPOSE

The National Institute of Child Health and Human Development (NICHD) and the 
National Institute of Environmental Health Sciences (NIEHS) invite new, 
innovative, multidisciplinary, and synergistic program project (P01) grant 
applications that integrate basic and clinical approaches to study the 
developmental biology and molecular genetics of human malformations.  
This RFA is designed to exploit the use of animal models to elucidate the 
molecular and genetic bases of human malformations.  The purpose is to encourage 
applications that will capitalize on the latest knowledge of structural, 
functional, and comparative genomics, proteomics, and biotechnology to dissect 
and unravel the complex developmental biological processes, pathways, genetics, 
and molecular mechanisms responsible for human structural birth defects.  The 
objective is to enhance our knowledge and understanding of normal and abnormal 
embryonic and fetal development, and of the etiology and pathogenesis of human 
malformations.  Each program project application must include interrelated 
basic, translational, or clinical component projects addressing a common central 
theme, research focus, or objective.  This strategy is intended to maximize the 
opportunities for translating the basic findings from animal studies into 
clinical applications in humans.  

This initiative was developed primarily in response to a 1998 NICHD-sponsored 
workshop focusing on the developmental biology and genetics of structural birth 
defects in animal models and humans.  The RFA will serve as a major component of 
a high-priority NICHD strategic plan to address the important public health 
problem of human birth defects.  It will also enhance the strategy of the 
President’s Task Force on Children’s Environmental Health and Safety Risks to 
prevent developmental disorders associated with environmental factors.  The most 
important long-term goal of this RFA is to translate the advances in basic 
biomedical science into molecular and genetic diagnostic tests, safe and 
efficacious therapeutic interventions, and effective and economic strategies for 
preventing birth defects.

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 is related to one or more of the 
priority areas.  Potential applicants may obtain "Healthy People 2000" at 
http://odphp.osophs.dhhs.gov/pubs/hp2000.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic for-profit and non-profit 
organizations, public and private, such as universities, colleges, hospitals, 
laboratories, units of State and local governments, and eligible agencies of the 
Federal government.  Foreign institutions are not eligible to apply.  
Racial/ethnic minority individuals, women, and persons with disabilities are 
encouraged to apply as Principal Investigators/Program Directors.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) program project grant 
(P01) award mechanism.  Responsibility for the planning, direction, and 
execution of the proposed projects 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 P01 supports broadly based multidisciplinary research programs that have a 
well-defined central research focus or objective.  An important feature is that 
the interrelationships among the individual projects will result in a greater 
contribution to the overall program goals than if each project were pursued 
independently.  The program project grant requires a minimum of three 
interrelated individual research projects that contribute to the overall program 
objective.  At least one component project must be translational or clinical in 
nature.  The application may request support for certain common core resources.  
Complete guidelines for the NICHD Program Project Grant may be found at:
http://www.nichd.nih.gov/funding/mechanism/p01_guide.cfm.  See also, APPLICATION 
PROCEDURES, below.

FUNDS AVAILABLE

The NICHD intends to commit approximately $5 million and the NIEHS intends to 
commit approximately $1 million in total costs (direct plus Facilities and 
Administrative) in FY 2001 to fund new grants in response to this RFA.  It is 
anticipated that approximately six new awards will be made (five by the NICHD 
and one by the NIEHS).  An applicant may request a project period of three to 
five years, and a budget for direct costs of up to $750,000 in the first year, 
excluding facilities and administrative costs (F&A) on consortium/contractual 
arrangements.  Applicants may request no more than $4 million in direct costs 
over the five-year award period.  Because the nature and scope of the research 
proposed may vary, it is anticipated that the size of awards also will vary.  
Although this program is provided for in the financial plans of the NICHD and 
NIEHS, awards pursuant to this RFA are contingent upon the availability of funds 
and the receipt of a sufficient number of applications of outstanding scientific 
and technical merit. 

RESEARCH OBJECTIVES

Background

In the United States, birth defects are the leading cause of infant mortality, 
accounting for one in five infant deaths.  It is estimated that more than 
120,000 babies in the United States (about three to four percent of all live 
births) are born with major birth defects each year.  Birth defects account for 
half of all pediatric hospital admissions and, next to accidents, are the 
leading cause of death in children.  Moreover, the estimated lifetime cost of 
children born each year with any of 17 major birth defects costs the U.S. 
economy billions of dollars. 

Considering the great impact of structural birth defects on public health, 
socioeconomics, and family life, the Center for Research for Mothers and 
Children (CRMC), NICHD, convened two workshops to address this significant 
problem.  The purpose was to develop a comprehensive program and strategy to 
support epidemiological, basic, translational, and clinical research on human 
congenital malformations.  The ultimate goal of this strategy is to translate 
the research findings into improved diagnostic techniques, safe therapeutic 
interventions, and effective prevention strategies for human malformations.  The 
workshops reviewed the current knowledge of structural birth defects, identified 
gaps in our understanding, and recommended and prioritized areas of future 
research.  The first workshop, in October 1997, addressed the clinical and 
epidemiological aspects of human malformations.  At the workshop, participants 
identified a timely opportunity and need to use molecular genetic approaches to 
study the genetic susceptibility and epidemiology of human malformations.  In 
response, on May 25, 1999, the NICHD, NIEHS, and co-sponsoring Institutes and 
agencies, issued RFA HD-99-002, "Genetic Susceptibility and Variability of Human 
Malformations." 

Recommendations from the second NICHD workshop, held in July 1998, served as the 
basis of the present solicitation.  This workshop focused on basic studies of 
genes, molecular mechanisms, and biological processes responsible for normal and 
abnormal early development in animal models and humans.  Moreover, the workshop 
affirmed that conservation of genes during evolution and recapitulation during 
embryonic and fetal development make animal models indispensable for 
understanding normal and abnormal development in humans.  After receiving an 
update on the progress of the Human Genome Project, the workshop participants 
reviewed specific genes, gene/environmental interactions, environmental factors, 
teratogens, and developmental processes that cause structural birth defects in 
animal models and humans.  They explored how the genomic information emerging 
from the Human Genome Project can be exploited to study normal and abnormal 
early development.  For example, they emphasized how structural, comparative, 
and functional genomic databases and genetic, physical, and functional maps are 
critical for identifying genes, polymorphisms, and genotype/phenotype 
relationships and for elucidating the pathogenesis of structural birth defects.  
Furthermore, the participants expressed how the revolutionary advances in 
biotechnology will provide the tools for discovering new genes, dissecting 
underlying molecular mechanisms, and unraveling the etiopathogenesis of many 
human malformations.  While a number of diverse recommendations emerged from 
this workshop, one recommendation was to establish and support interdisciplinary 
and integrated bench-to-bedside basic and clinical research projects on human 
malformations.  In addition to the second NICHD workshop, the current RFA was 
encouraged in 1998 by an NICHD-sponsored symposium on "Genomics in Birth Defects 
Research" and the report by the President’s Task Force on Children’s 
Environmental Health and Safety Risks entitled "An Initiative to Prevent 
Developmental Disorders Associated with Environment Factors." 

The program project mechanism was selected because it is ideal for combining 
multiple clinical and basic component projects with a central theme, focus, or 
objective, and for fostering interactions and collaborations between basic and 
clinical scientists.  Furthermore, the nucleus of multidisciplinary scientists 
in each program project will provide a fertile environment for cross-training 
basic and clinical scientists.

Research Scope

The purpose of this RFA is to support new, innovative, multidisciplinary, 
interactive and synergistic program projects that integrate basic, 
translational, and clinical approaches to understand the developmental biology 
and genetic basis of congenital human malformations.  

Each program project must consist of at least three component projects and 
include both basic science and clinical component projects.  At least one 
component project must be clinical or translational in nature.  The component 
projects must share a common central theme, focus, or objective on a specific 
developmental defect or malformation that is genotypically, mechanistically, 
biologically, or phenotypically analogous or homologous in both animal models 
and humans.  Any non-mammalian or mammalian animal model may be used, as long as 
it contributes to the common overall theme or objective of the program project.  
If the component projects do not share a common developmental gene, process, 
mechanism, pathway, or phenotype, the application will be considered non-
responsive to this RFA. 

Of particular interest to the NICHD are applications to study embryonic 
developmental defects of generalized body patterning and localized dysmorphic 
anomalies of the skeletal, nervous, and visceral systems that lead to clinically 
significant and major congenital structural malformations.   

While applications focusing on developmental disorders that result in mental 
retardation and related neurobehavioral disabilities are of interest to the 
NICHD, they are outside the scope of this RFA.  The NIEHS is especially 
interested in research projects that study the mechanisms and pathogenesis of 
how environmental exposure to physical and chemical agents alter embryonic and 
fetal development and result in human malformations.  Prior to preparing an 
application, it is important to ascertain that the proposed research is within 
the mission and areas of interest of the NICHD or NIEHS.  For clarification, the 
potential applicant is strongly encouraged to consult NICHD and NIEHS program 
staff listed under INQUIRIES, below, before submitting a Letter of Intent.

The basic science component projects may include studies to:  1) identify and 
characterize the genes, gene products, mutations, polymorphisms, multigene and 
gene/environment interactions that play a role in normal and abnormal embryonic 
patterning and organogenesis, 2) elucidate the developmental biological 
processes and pathways, the biochemical, cellular, molecular, genetic 
mechanisms, and spatial and temporal gene expression patterns which are involved 
in dysontogenesis, and 3) examine how teratogens, nutritional deficiencies, and 
environmental factors disrupt or modify gene expression and basic developmental 
processes.  

The translational/clinical component projects may include studies to:  1) 
characterize and classify genotypes and phenotypes of human malformations that 
are comparable in the animal models being examined, 2) develop physical, 
genetic, and comparative maps for genes involved in human malformations, 3) 
identify the developmental genetic processes and molecular pathogenesis of human 
malformations utilizing animal models, and 4) develop innovative molecular 
genetic methods, technologies, and strategies to enhance the diagnosis and 
methods for intervention of the human malformations.    

Applicants are encouraged to incorporate the recent scientific advances in 
developmental biology and genetics in their projects and to utilize the many 
research resources, bioinformatic databases, and biotechnological tools in their 
research cores.  The research cores should be structured to share work effort 
and research resources (e.g., biotechnology, high-throughput instrumentation, 
microarrays, oligonucleotide chips, animal model development, and technical 
assistance) among the research projects.  The aim of the core is to enhance the 
progress, productivity, cost-effectiveness, and outcome of the research 
projects. 

Applications may include new and innovative approaches to investigate: 1) 
genetic defects, nutritional deficiencies, teratogens, or environmental 
chemicals or factors that perturb, modify, or alter gene expression during early 
development, 2) the identity and function of transcription and growth factors in 
normal and abnormal gastrulation, embryogenesis, organogenesis, and patterning, 
and 3) defective embryonic developmental processes and pathways that ultimately 
lead to malformations.  Research projects responsive to this RFA include, but 
are not limited to, the following: 

o  Investigations on the identity, characteristics, and mechanisms of growth 
factors and growth factor receptors that function in embryonic development and 
dysmorphogenesis of the skeletal, nervous, and visceral systems,

o  Studies of transcription factors regulating gene expression and temporal and 
spatial expression patterns during normal and abnormal embryonic development, 

o  Studies of developmental genes, gene products, transcription factors, and 
growth factors that function and interact to regulate cell proliferation, cell 
differentiation, apoptosis, cell migration, and cell fate in embryonic 
development, 

o  Examination of genes and molecular mechanisms and interactions that control 
normal and abnormal body axes and symmetry during development,

o  Studies to identify, map, and characterize genes that play a role in: signal 
transduction and biochemical pathways, cell fate determination, gastrulation, 
embryogenesis, organogenesis, body patterning and how developmental defects, 
mutations, or susceptible polymorphisms lead to malformations,

o   Investigations of pharmaceutical, nutritional, environmental, and 
teratogenic agents and factors that alter genes and developmental processes and 
pathways that result in dysmorphologies,

o  Investigations to characterize and classify genotype/phenotypes of hereditary 
human malformations and correlate them to homologs in animal models,   

o  Efforts to define pleiotropic effects that genes and their modifiers have in 
the spatial and temporal development of embryonic and/or fetal anomalies,

o  Studies on the interaction between toxic and environmental factors and 
modifiers of gene expression,

o  Development and validation of new and/or improved animal models to study the 
genes, mutations, mechanisms, environmental factors, and developmental processes 
and pathways that cause human malformations, 

o  Imaging and gene expression studies to investigate and monitor the 
developmental pathogenesis of dysmorphologies,

o  Investigations of the role of imprinting and epigenetic factors in the 
development of major congenital malformations, 

o  Studies on nutritional factors (e.g., folic acid deficiency) and teratogens
(e.g., retinoids and valproic acid) affecting gene/gene, gene/receptor, 
gene/modifier, and gene/teratogen interactions that lead to neural tube defects,

o  Examination of the role and developmental biology of neural crest cells in 
normal embryonic development and how defects in cell proliferation, 
differentiation, migration, and patterning may result in major structural birth 
defects, 

o  Elucidation of the underlying genetic and molecular mechanisms that alter 
normal developmental processes in drug-induced (e.g., Accutane, Thalidomide) 
malformations,

o  Identification and characterization of polymorphisms/mutations of metabolic 
genes that function in the development of structural birth defects.

The topics listed above are only examples, are not in priority order, and are 
not intended to be all-inclusive.  Investigators are encouraged to explore and 
develop new, innovative projects and research cores that are consistent with the 
overall objectives of this RFA.  

SPECIAL REQUIREMENTS

The Program Director for the overall grant and the principal investigator for 
each component project should plan to attend an annual NIH-sponsored two-day 
meeting in Bethesda, MD.  This meeting will be attended by investigators 
supported through this RFA and through the earlier RFA on genetic susceptibility 
and variability of human defects.  The meetings will provide an opportunity for 
these investigators to communicate, discuss the progress of their research, 
exchange ideas and information, share resources, and foster collaborations that 
are relevant to the research goals of the NICHD birth defects initiative.  This 
requirement is designed to establish an interactive network of investigators who 
are interested in multidisciplinary approaches to enhancing our understanding of 
the epidemiology, etiology, pathogenesis, and developmental biology and genetics 
of structural birth defects.  

All applications should include a request for funds to support attendance of the 
Program Director and project principal investigators at the annual meetings, as 
well as a statement of agreement to participate in these meetings and to 
cooperate with investigators at other program project sites.

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, Volume 23, Number 11, 
March 18, 1994, and available at: 
http://grants.nih.gov/grants/guide/notice-files/not94-100.html.

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, e-mail, telephone 
and fax number of the Program Director, and the identities of other key 
personnel and participating institutions. 

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 and NIEHS staff to estimate the potential review workload and avoid 
conflict of interest in the review. 

The letter of intent is to be sent by February 1, 2000 to Dr. Allan Lock at the 
address listed under INQUIRIES. 

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev.4/98) is to be used in applying 
for these grants.  

Applications kits are available at most institutional offices of sponsored 
research and may be obtained 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, and on the Internet at:  
http://grants.nih.gov/grants/funding/phs398/phs398.html .

Application Instructions

Applicants for P01 grants must follow special application guidelines in the 
NICHD PROGRAM PROJECT (P01) GUIDELINES (June 1998) that is available from NICHD 
program staff listed under INQUIRIES.  The guidelines are also available on the 
Internet at: http://www.nichd.nih.gov/funding/mechanism/p01_guide.cfm.  These 
guidelines contain important information on the suggested format of applications 
and on review criteria.  

For the purposes of this RFA, each core must be utilized by two or more 
component projects at all times during the period of award.  This is an 
exception to the NICHD P01 Guidelines stating that each core should be utilized 
by three or more component projects.

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.

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 
number of this RFA, HD-99-008. 

A sample modified RFA label is available at 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf.  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 the signed, typewritten original of the application, including the 
Checklist, plus 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 time of submission, two additional copies of the application and all five 
sets of any appendices should be sent to:

Director
Division of Scientific Review
National Institute of Child Health and Human Development
Executive Building, Room 5E03, MSC 7510
6100 Executive Boulevard
Bethesda, MD  20892-7510
Rockville, MD 20852 (for express/courier service)
Telephone:  (301) 496-1485
FAX:  (301) 402-4104

Applications must be received by March 22, 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 previously reviewed, but such applications must include an 
introduction addressing the previous critique.

NIH policy permits a component research project of a multi-project grant 
application to be concurrently submitted as a traditional individual research 
project (R01) application.  If, following review, both the multi-project 
application and the R01 application are found to be in the fundable range, the 
investigator must relinquish the R01 and will not have the option to withdraw 
from the multi-project grant.  This policy is intended to preserve the 
scientific integrity of a multi-project grant, which may be seriously 
compromised if a strong component project(s) is removed from the program.  
Investigators wishing to participate in a multi-project grant must be aware of 
this policy before making a commitment to the Program Director and applicant 
institution.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by CSR and for 
responsiveness to the RFA by the NICHD 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, a process may be used by the initial review 
group in which all applications receive a written critique and undergo a process 
in which only those applications with the highest scientific and technical merit 
will be discussed, assigned a priority score, and receive a second level review 
by the National Advisory Child Health and Human Development (NACHHD) Council or 
the National Advisory Environmental Health Sciences (NAEHS) 
Council.  

Applications will not be reviewed by a site visit team.  

Review Criteria

For program projects, peer review of scientific and technical merit focuses on 
three areas: 1) review of the individual component projects, 2) review of the 
individual cores, and 3) review of the program as an integrated effort and the 
overall merit of the program.

The review criteria to be used to evaluate applications submitted in response to 
this RFA are presented in APPENDIX II, GUIDELINES FOR REVIEWERS COMMENTS, of the 
NICHD PROGRAM PROJECT (P01) GUIDELINES (June 1998), available at: 
http://www.nichd.nih.gov/funding/mechanism/p01_guide.cfm.

SCHEDULE

Letter of Intent Receipt Date:    February 1, 2000
Application Receipt Date:         March 22, 2000
Peer Review Date:                 May 2000
Council Review:                   September/October 2000
Earliest Anticipated Start Date:  December 1, 2000

AWARD CRITERIA

Funding decisions will be based on the following: 

o Scientific and technical merit of the proposed program as determined by peer 
review,

o  Cost effectiveness of the proposed strategy,

o  Program priorities and program balance,

o  Promise that the proposed program will accomplish the goals of this RFA,

o  Availability of funds.

INQUIRIES

Written and telephone inquiries concerning this RFA are strongly encouraged.  
The opportunity to clarify any issues or questions from potential applicants is 
welcome.  Contact information for inquiries regarding both programmatic and 
fiscal issues may be found at: 
http://www.nichd.nih.gov/rfa/HD-99-008/HD-99-008.htm.

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.  
93.865 (Research for Mothers and Children, NICHD) and No. 93.113 (Biological 
Responses to Environmental Health Hazards, NIEHS).  Awards are made under 
authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-
410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under 
PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74.  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 and contract 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.

Weekly TOC for this Announcement
NIH Funding Opportunities and Notices

	Office of Extramural Research (OER)			National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892			Department of Health and Human Services (HHS)
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