COMPARATIVE GENETICS OF STRUCTURAL BIRTH DEFECTS 

RELEASE DATE:  August 7, 2003

RFA Number:  RFA-HD-03-024

National Institute of Child Health and Human Development (NICHD)        
 (http://www.nichd.nih.gov/)
National Institute of Dental and Craniofacial Research (NIDCR)       
 (http://www.nidcr.nih.gov/)

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.865 (NICHD), 93.121 
(NIDCR)

LETTER OF INTENT RECEIPT DATE:  October 20, 2003

APPLICATION RECEIPT DATE:  November 19, 2003

THIS RFA CONTAINS THE FOLLOWING INFORMATION

o Purpose of this RFA
o Research Objectives
o Mechanism of Support
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Where to Send Inquiries
o Letter of Intent
o Submitting an Application
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations

PURPOSE OF THIS RFA

The genomic sequences for a number of invertebrates and vertebrates, 
including man, are completed or nearing completion.  For the developmental 
biology community to maximize its ability to efficiently and effectively use 
this publicly available data, systematic research in the areas of functional 
and comparative genomics needs to be stimulated.  A key component of 
functional and comparative studies must be examinations of a given genetic 
pathway in more than one animal model.  These comparisons, under controlled 
conditions, will allow us to elucidate which genes, gene products, genetic 
networks, and molecular cascades are conserved and which are of critical 
importance in normal and abnormal development.  The purpose of this RFA is to 
solicit applications or competitive supplements for individual research 
projects that will examine a family of genes or gene products, known to be 
important in development, in two or more animal models.  These approaches 
will help us to understand which genes, gene products and modifications are 
of general importance in increasing our understanding of normal and abnormal 
development, as well as allow us to catalog such differences and 
similarities.  These studies will enable us to better understand the 
faithfulness with which developmental processes are conserved across species. 

RESEARCH OBJECTIVES

Background

Animal models have long provided fertile ground for research into the causes 
of structural birth defects.  Studies supported by the NICHD and NIDCR on 
human as well as on mammalian models such as mouse and rat, and nonmammalian 
models, such as chick, zebrafish, frog, fly, and worm, have made major 
inroads into increasing our knowledge of normal and abnormal development.  
While the arena of developmental biology is rapidly advancing, and 
collaborative, translational efforts are increasing, there still is a lack of 
cross-fertilization between scientists who are trained in and continue to use 
a single animal model system.  This is mirrored in the physical disconnect 
that is seen in animal model-specific databases, which may not be user-
friendly to scientists outside that community.  

The field of comparative genomics examines a given family of genes and/or 
gene products in several organisms to identify commonalities and differences. 
In general, comparisons between different animals are drawn from studies that 
were performed by different groups of investigators in different settings and 
experimental conditions.  From these kinds of studies, we have instances 
where 1) a gene is expressed in similar spatial and temporal patterns in two 
animal models, 2) a highly conserved region shows divergent gene expression 
patterns either temporally, spatially or both in two animal models, or 3) a 
gene shown to be important in one model has no ortholog in another model.  
For developmental biology to continue advancing, we need researchers with the 
appreciation for and understanding of a number of animal models.  We need to 
be able to determine which of the genes, gene products, and developmental 
cascades are important to pursue.  By taking advantage of comparative 
genomics approaches, we will have the framework to analyze and prioritize in 
a meaningful way, the vast amount of information generated by the sequencing 
efforts.  With the upcoming completion of the sequencing of a number of 
genomes, the need for scientists with the ability to take advantage of 
comparative genomics has become more urgent.

Research Objectives and Scope

The objective of this RFA is to broaden the range, power, and utility of the 
recently acquired genomic sequences for human, mouse, zebrafish, fly, and 
worm, as well as any other genomes, such as Xenopus tropicalis, that will be 
available by the start date of this initiative.  The goal of this RFA is to 
develop projects comparing genes, gene products, or pathways, that are known 
to be important and well understood in one animal to another, less-
characterized model in order to determine if general developmental principles 
apply across species.  We expect that this solicitation will encourage 
researchers from different animal model communities to collaborate and to 
collectively explore those genes, proteins, networks, and modifications that 
have universal importance.

Objectives to be addressed in applications submitted in response to this RFA 
include, but are not limited to:

o  Proposals to examine, in different animal models, genes or gene products 
that have been shown to be altered in a human structural birth defect.  These 
may include, but are not limited to:  neural tube defects, craniofacial 
anomalies, limb and skeletal defects, and genitourinary abnormalities.

o  Proposals to compare pathways that are well understood in one model to the 
same pathways in another model organism that has not been thoroughly defined 
to determine if the same developmental principles apply.

o  Proposals to determine whether genomic sequence is a good indicator of 
conserved function across animal models.

o  Proposals to determine the extent of consistency of temporal and spatial 
expression patterns across species.

Examples of projects that would be responsive to this RFA include, but are 
not limited to: 

o  An investigator or group of investigators requests support to examine the 
function and/or expression of specific genes in more than one model system 
(R01). 

o  An expert in one model organism examines the function/expression of 
specific genes in that system and includes a subproject in which the same 
genes are examined in a related animal model system by experts in that system 
(R01). 

o  An investigator who is funded to examine the function/expression of 
specific genes in one model system requests support to examine the same genes 
in another system (supplement to existing R01). 

o  An investigator requests support to determine whether a gene known to be 
important in one model is present in another model (supplement to existing 
R01 or R21). 

MECHANISM OF SUPPORT

This RFA will use the NIH Research Project Grant (R01) and 
Exploratory/Developmental Grant (R21) award mechanisms.  In addition to 
applications for new R01s, applications for competitive supplements to 
existing R01s (with at least two years of funding remaining at the time of 
award) supported by the NICHD or the NIDCR will be accepted.  As an applicant 
you will be solely responsible for planning, directing, and executing the 
proposed project.  This RFA is a one-time solicitation.  Future unsolicited, 
competing-continuation applications based on this project will compete with 
all investigator-initiated applications and will be reviewed according to the 
customary peer review procedures.  The anticipated award date is July 01, 
2004.  Applications that are not funded in the competition described in this 
RFA may be resubmitted as NEW investigator-initiated applications using the 
standard receipt dates for NEW applications described in the instructions to 
the PHS 398 application.

Information about the Exploratory/Developmental Grant (R21) mechanism can be 
found at http://grants.nih.gov/grants/guide/pa-files/PA-03-107.html.    

This RFA uses just-in-time concepts.  It also uses the modular budgeting 
format (see http://grants.nih.gov/grants/funding/modular/modular.htm).   
Specifically, if you are submitting an application with direct costs in each 
year of $250,000 or less, use the modular format.  This program does not 
require cost sharing as defined in the current NIH Grants Policy Statement at 
http://grants.nih.gov/grants/policy/nihgps_2001/part_I_1.htm.

FUNDS AVAILABLE

The participating ICs intend to commit approximately $2.5 million in total 
costs [Direct plus Facilities and Administrative (F & A) costs] in FY 2004 to 
support five to eight new and/or competing continuation grants in response to 
this RFA.  An applicant for an R01 may request a project period of up to five 
years and a budget for direct costs of up to $250,000 per year.  An applicant 
for an R21 may request a project period of up to two years with a combined 
budget for direct costs of up to $275,000 for the two-year period.  An 
applicant for a supplement to an existing R01 may request a project period 
equal to the number of years remaining on the parent grant at the time the 
supplement would be awarded, and a budget for direct costs of up to $125,000 
per year.  Because the nature and scope of the proposed research will vary 
from application to application, it is anticipated that the size and duration 
of each award will also vary.  Although the financial plans of the ICs 
provide support for this program, awards pursuant to this RFA are contingent 
upon the availability of funds and the receipt of a sufficient number of 
meritorious applications. 

ELIGIBLE INSTITUTIONS

You may submit an application if your institution has any of the following 
characteristics: 

o For-profit or non-profit organizations 
o Public or private institutions, such as universities, colleges, hospitals, 
and laboratories 
o Units of State and local governments 
o Eligible agencies of the Federal government  
o Domestic or foreign  
o Faith-based or community-based organizations 

INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS

Any individual with the skills, knowledge, and resources necessary to carry 
out the proposed research is invited to work with his/her institution to 
develop an application for support.  Individuals from underrepresented racial 
and ethnic groups as well as individuals with disabilities are always 
encouraged to apply for NIH programs.   

WHERE TO SEND INQUIRIES

We encourage inquiries concerning this RFA and welcome the opportunity to 
answer questions from potential applicants.  Inquiries may fall into three 
areas:  scientific/research, peer review, and financial or grants management 
issues:  

o Direct your questions about scientific/research issues to:  

Deborah B. Henken, Ph.D.
Developmental Biology, Genetics, and Teratology Branch 
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 4B01, MSC 7510
Bethesda, MD  20892-7510
Telephone:  (301) 496-5541
FAX:  (301) 480-0303
Email:  henkend@mail.nih.gov 

Rochelle K. Small, Ph.D.
Developmental Biology and Mammalian Genetics Program
National Institute of Dental and Craniofacial Research
45 Center Drive, Room 4AN-18D, MSC 6402
Bethesda, MD  20892-6402
Telephone:  (301) 594-9898
FAX:  (301) 480-8318
Email:  rochelle.small@nih.gov 

o Direct your questions about peer review issues to:  

Robert Stretch, Ph.D.
Director, Division of Scientific Review
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 5B01, MSC 7510
Bethesda, MD  20892-7510
Telephone:  (301) 496-1485
FAX:  (301) 402-4104
Email:  stretchr@mail.nih.gov 

o Direct your questions about financial or grants management matters to:  

Kathy Hancock
Grants Management Branch
National Institute of Child Health and Human Development
6100 Executive Boulevard, 8A17, MSC 7510
Bethesda, MD  20892-7510
Telephone:  (301) 496-5482
FAX:  (301) 402-0915
Email:  kh246t@nih.gov 

Mary Daley
Chief, Grants Management Officer
National Institute of Dental and Craniofacial Research
45 Center Drive, Room 4AN44B, MSC 6402
Bethesda, MD  20892-6402
Telephone:  (301) 594-4808
FAX:  (301) 480-3562
Email:  md74u@nih.gov 

LETTER OF INTENT

Prospective applicants are asked to submit a letter of intent that includes 
the following information:  

o Descriptive title of the proposed research 
o Name, address, and telephone number of the Principal Investigator 
o Names of other key personnel 
o Participating institutions 
o 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 the ICs staff to estimate the potential review workload and 
plan the review.

The letter of intent is to be sent by the date listed at the beginning of 
this document.  The letter of intent should be sent to:  

Deborah B. Henken, Ph.D.
Developmental Biology, Genetics, and Teratology Branch 
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 4B01, MSC 7510
Bethesda, MD  20892-7510
Telephone:  (301) 496-5541
FAX:  (301) 480-0303
Email:  henkend@mail.nih.gov

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001).  The PHS 398 is available at 
http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive 
format.  For further assistance contact GrantsInfo, Telephone (301) 435-0714, 
Email:  GrantsInfo@nih.gov.   

SUPPLEMENTAL INSTRUCTIONS:  

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS:  Applications 
requesting up to $250,000 per year in direct costs must be submitted in a 
modular grant format.  The modular grant format simplifies the preparation of 
the budget in these applications by limiting the level of budgetary detail.  
Applicants request direct costs in $25,000 modules.  Section C of the 
research grant application instructions for the PHS 398 (rev. 5/2001) at 
http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step 
guidance for preparing modular grants.  Additional information on modular 
grants is available at 
http://grants.nih.gov/grants/funding/modular/modular.htm.

USING THE RFA LABEL:  The RFA label available in the PHS 398 (rev. 5/2001) 
application form must be affixed to the bottom of the face page of the 
application.  Type the RFA number on the label.  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.  The RFA label is also available at: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf.

SENDING AN APPLICATION TO THE NIH:  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 must be 
sent to:  

Robert Stretch, Ph.D.
Director, Division of Scientific Review
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 5B01, MSC 7510
Bethesda, MD  20892-7510
Rockville, MD  20852 (for express/courier service)

APPLICATION PROCESSING:  Applications must be received on or before the 
application receipt date listed in the heading of this RFA.  If an 
application is received after that date, it will be returned to the applicant 
without review.

Although there is no immediate acknowledgement of the receipt of an 
application, applicants are generally notified of the review and funding 
assignment within eight weeks.

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.  
However, when a previously unfunded application, originally submitted as an 
investigator-initiated application, is to be submitted in response to an RFA, 
it is to be prepared as a NEW application.  That is, the application for the 
RFA must not include an Introduction describing the changes and improvements 
made, and the text must not be marked to indicate the changes.  While the 
investigator may still benefit from the previous review, the RFA application 
is not to state explicitly how.

PEER REVIEW PROCESS

Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by the ICs.  Incomplete 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 ICs in accordance with the review criteria stated below.  As 
part of the initial merit review, all applications will: 

o Receive a written critique
o Undergo a process in which only those applications deemed to have the 
highest scientific merit, generally the top half of the applications under 
review, will be discussed and assigned a priority score
o Receive a second level review by the appropriate national advisory council 
or board.

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:

o Significance
o Approach
o Innovation
o Investigator
o Environment 

The scientific review group will address and consider each of these criteria 
in assigning the application's overall score, weighting them as appropriate 
for each application.  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.

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?

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?

INNOVATION:  Does the project employ novel concepts, approaches or methods?  
Are the aims original and innovative?  Does the project challenge existing 
paradigms or develop new methodologies or technologies?

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)?

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?

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following 
items will be considered in the determination of scientific merit and the 
priority score:

CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH:  If vertebrate animals are to 
be used in the project, the five items described under Section f of the PHS 
398 research grant application instructions (rev. 5/2001) will be assessed.

ADDITIONAL CONSIDERATIONS 

DATA SHARING:  The adequacy of the proposed plan to share data. 

BUDGET:  The reasonableness of the proposed budget and the requested period 
of support in relation to the proposed research.

RECEIPT AND REVIEW SCHEDULE

Letter of Intent Receipt Date:  October 20, 2003
Application Receipt Date:  November 19, 2003
Peer Review Date:  February/March 2004
Council Review:  June 2004
Earliest Anticipated Start Date:  July 01, 2004

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

REQUIRED FEDERAL CITATIONS

PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT:  The 
Office of Management and Budget (OMB) Circular A-110 has been revised to 
provide public access to research data through the Freedom of Information Act 
(FOIA) under some circumstances.  Data that are (1) first produced in a 
project that is supported in whole or in part with Federal funds and (2) 
cited publicly and officially by a Federal agency in support of an action 
that has the force and effect of law (i.e., a regulation) may be accessed 
through FOIA.  It is important for applicants to understand the basic scope 
of this amendment.  NIH has provided guidance at 
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.

Applicants may wish to place data collected under this RFA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time.  If so, the application should 
include a description of the archiving plan in the study design and include 
information about this in the budget justification section of the 
application.  In addition, applicants should think about how to structure 
informed consent statements and other human subjects procedures given the 
potential for wider use of data collected under this award.

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.  Furthermore, 
we caution reviewers that their anonymity may be compromised when they 
directly access an Internet site.

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 
RFA is related to one or more of the priority areas.  Potential applicants 
may obtain a copy of "Healthy People 2010" at 
http://www.health.gov/healthypeople.

AUTHORITY AND REGULATIONS:  This program is described in the Catalog of 
Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the 
intergovernmental review requirements of Executive Order 12372 or Health 
Systems Agency review.  Awards are made under the authorization of Sections 
301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) 
and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92.  All 
awards are subject to the terms and conditions, cost principles, and other 
considerations described in the NIH Grants Policy Statement.  The NIH Grants 
Policy Statement can be found at 
http://grants.nih.gov/grants/policy/policy.htm.

The PHS strongly encourages all grant recipients to provide a smoke-free 
workplace and discourage the 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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