This Program Announcement expires on November 1, 2003, unless re-issued.


Release Date:  October 25, 2000

PA NUMBER:  PA-01-005 (see replacement PA-04-049)

National Institute of Child Health and Human Development



The National Institute of Child Health and Human Development (NICHD) invites 
qualified researchers to submit new applications for research projects that 
address issues in reproductive genetics. The purpose of this initiative is to 
support new studies on the genes and genetic mechanisms influencing sex 
determination, human fertility, the role of differential expression of 
parental alleles (i.e., genomic imprinting and X-inactivation) in 
reproduction, and other topics in reproductive genetics.  The studies 
targeted by this program announcement are expected to identify and 
characterize the relevant genes, determine their function in normal human 
reproduction and reproductive development, identify functional partners and 
the nature of their interactions, and further our understanding of the 
multiple adverse health consequences of mutations or dysregulation of these 

As the human genome project nears its goal, the coding sequence of all the 
human genes is becoming available and the focus of research must shift from 
gene identification to functional genomics.  Studies using innovative 
statistical or technical methods, such as quantitative trait locus (QTL) 
analysis or gene chip technology, are highly encouraged.  NICHD encourages 
researchers interested in reproduction to lead the way in determining the 
functional role of genes involved in the development of the gonads and 
external genitalia, gametogenesis, infertility, endometriosis, polycystic 
ovarian syndrome (PCOS) and premature ovarian failure (POF), and reproductive 
aging.  Studies on the genetic epidemiology of reproductive disorders, such 
as those listed above, must begin with the collection of large affected 
families for classic linkage studies, and/or QTL analysis. We also encourage 
research into epigenetic mechanisms crucial in embryonic development, such as 
the establishment and maintenance of imprinting patterns, the role of 
methylation in gametogenesis, the implications of imprinting for assisted 
reproductive technologies (ART), and the reproductive determinants and 
consequences of X-inactivation (or the escape from X-inactivation). 


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 Program Announcement 
(PA) is related to one or more of the priority areas.  Potential applicants 
may obtain “Healthy People 2010” at 


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 


This Program Announcement will use the National Institutes of Health (NIH) 
Research Project Grant (R01) and Small Grant (R03) award mechanisms.  
Supplements to existing NIH grants also will be considered.  Information and 
application instructions for the NICHD Small Grant Program are available in 
the NIH Guide for Grants and Contracts at:  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 PA may not exceed five years.

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   

Reproductive genetics is a broad research area, and the topics listed below 
are not meant to be exclusive areas of interest, but rather a sampling of the 
types of problems this program announcement is intended to address. 

The Genetics of Sex Determination

Sex determination is the translation of the chromosomal sex (XX or XY) into 
the development of the gender-appropriate internal and external reproductive 
structures.  The initial events of sex determination are, therefore, 
genetically determined.  Errors in the process are fairly common and can 
range in severity from complete sex reversal to minor genital abnormalities.  
Sex determination, as an early embryological event, is a dynamic 
morphological process that can help us address basic questions of gene 
expression, cell-fate determination, and hormone signaling.

Approximately one in 1,000 newborns has some abnormality of genital and/or 
gonadal development. In many cases, gonadal dysgenesis is one part of a 
larger pathologic syndrome. Examples include Frasier syndrome, Denys-Drash 
syndrome, campomelic dysplasia, Perrault syndrome, and Rutledge lethal 
multiple congenital anomaly syndrome. The genes involved in sex determination 
often act as growth and/or differentiation factors, and there is mounting 
evidence that they may be important in gonadal (or other tissue) 

The mechanisms involved in normal sex differentiation are not yet well 
defined and, while many genes are known to contribute to the process, the 
nature and timing of their interactions remain unclear. 			  
Studies of sex-reversed XX males revealed that the vast majority has a small 
piece of the Y chromosome fused to one X chromosome.  Investigation of that Y 
translocation led to the identification of the testis-determining SRY gene. 
In the absence of SRY, the embryo will develop along the “default” or female 
pathway.  However, the view of SRY as a “switch” that confers maleness is 
overly simplistic, as illustrated by the enormous potential for ambiguity in 
the sex determination process. Other autosomal genes, such as SOX-9 and WT-1, 
play critical roles in normal sex determination. Another sex-determining 
gene, Dax-1, has different effects based on the level of its expression. A 
functional loss of Dax-1 causes X-linked congenital adrenal hypoplasia and 
hypogonadotropic hypogonadism in affected males surviving to adolescence.  
However, duplication of Dax-1 causes dosage sensitive sex reversal despite 
the presence of functional SRY.  Therefore, a functional copy of Dax-1 is not 
necessary for normal testis formation, but a double dose of Dax-1 disrupts 
testis formation.

There is mounting evidence that the genes involved in sex determination do 
not cease to be important once the sexual phenotype is established. These 
genes may be expressed in common embryonal precursors to different organ 
systems, or have a broad expression pattern in many cell lineages. Many have 
pleiotropic effects and somatic mutations may predispose to tumor formation. 
For example, malignant gonadoblastomas develop in approximately 30 percent of 
XY females. Speculation that defects in the genes crucial to sex 
determination may also cause tumorigenesis is consistent with the fact that 
many encode growth and differentiation factors that affect cell 
proliferation. Such examples clearly demonstrate that the continued study of 
sex determination will benefit not only those born with gonadal dysgenesis, 
but also will advance our knowledge of the development and regulation of 
other organ systems.
Specific topics of interest include, but are not limited to: 

o Identification of the target genes regulated by SRY and other related 

o Clarification of the functional interactions between the known sex 
determination genes; 

o Cloning of genes at other chromosomal regions associated with sex reversal 
(human regions 2q31, 9p, 10q25, and 22q13) and discovering their function; 
this may entail collection of affected families and careful phenotypic 

o Human epidemiological studies, including the collection of families 
affected with gonadal dysgenesis; 

o Creation of new animal models, especially transgenic and knock-out mice, to 
precisely characterize the functions of sex-determination genes.
Genes Regulating Fertility and Reproductive Aging

Infertility is a major public health problem in our country, affecting 10-15 
percent of couples, or about 2.5 million couples in the U.S. The annual cost 
of services to diagnose and combat infertility is now estimated at over one 
billion dollars. In recent years, great advances have been made in medical or 
surgical treatments for infertility due to hormonal and structural defects. 
However, these treatments do not benefit the 30 percent of couples who are 
infertile due to idiopathic or genetic causes. These couples may suffer 
through failed conventional treatments before resorting to assisted 
reproductive technologies (ART) to conceive their biological children. Given 
the problems inherent in the use of ART, it is imperative that we focus our 
efforts on identifying and treating the underlying causes of infertility. 

The most common identifiable genetic cause of human male infertility is 
Klinefelter’s syndrome, occurring in one in 400 live births. The causative 
XXY genotype results in failure of normal testicular development and 
infertility due to low sperm count.  Another frequent cause of male 
infertility is mutation in the gene encoding the beta subunit of luteinizing 
hormone, an important factor in the spermatogenesis pathway.  Recently, 
scientists found that a point mutation in a specific Y chromosome gene, 
USP9Y, can abolish spermatogenesis, leading to male infertility.  USP9Y lies 
in the AZFc region of the Y chromosome; deletions of this region are 
responsible for 20 percent of all cases of infertility caused by a low sperm 
count.  Another Y chromosome gene, Ube1y, may represent the spermatogenesis 
factor Spy that is deleted in some infertile men.

The situation in females is more complex. Finely tuned cyclic fluctuations in 
hormones coordinate the follicular development, ovulation, and uterine 
preparation for implantation that comprise a normal menstrual cycle. This 
complexity suggests that there are hundreds of genes, each contributing a 
small effect on female fertility. Perhaps because of this complexity, little 
is known about the genetics of female infertility.  Recently, however, one 
gene controlling ovulation rate and fertility in sheep was identified. This 
naturally occurring mutation in BMP15 (a member of the TGFbeta superfamily, 
also known as GDF9B) increases ovulation rate and twinning in heterozygotes, 
but causes sterility in homozygotes because follicles fail to mature beyond 
the primary stage. The human ortholog of ovine BMP15 maps to human Xp11.2-
11.4, making it a candidate for premature ovarian failure, primary and 
secondary amenorrhea, and twinning in humans.
Polycystic ovarian syndrome (PCOS) is the most common female reproductive 
endocrine pathology, affecting approximately five percent of all 
premenopausal women.  PCOS ovaries contain multiple immature follicles that 
are rarely ovulated.  Genetic studies of PCOS are strongly suggestive of a 
role of the follistatin gene, with weaker evidence for disruptions of the 
CYP11A gene. Other, as yet unknown, genes probably contribute to PCOS as 

Endometriosis causes pelvic pain and infertility in 10-15 percent of women. 
There is increasing evidence that endometriosis is inherited as a complex 
trait, with multiple genes contributing to the eventual phenotype.  Specific 
polymorphisms in the estrogen receptor gene, and in the detoxification system 
genes NAT2 and GSTM1, have been linked to endometriosis.  A recent study 
found altered expression of HOX genes in the endometrium of affected women.  
Finally, a mutation in the gene encoding the beta subunit of LH was found in 
two women with endometriosis. Genome-wide studies have detected loss of 
material from chromosomes 1p and 22q in endometriotic lesions, but candidate 
genes have not been identified.

The incidence of infertility is growing due to the increasing number of women 
who opt to have children later in life, and the sharp decline in female 
fertility with age. The genes and mechanisms contributing to reproductive 
aging have not been well characterized. The accumulation of chromosomal 
errors in oocytes contributes to age-related declines in female fertility:  
the majority of oocytes in women over 35 years old have defects in the second 
phase of meiosis.  Such chromosomally aberrant oocytes fail to produce viable 
embryos.  Further studies are necessary to follow up on recent findings in 
reproductive aging, such as the association of the fragile X pre-mutation 
with the incidence of familial premature ovarian failure.  The cessation of 
ovarian function before the age of 40 occurs in about one percent of the 
general population of women.  However, 16 percent of women carrying the 
fragile X pre-mutation experienced premature ovarian failure. 
Specific topics of interest include, but are not limited to:

o Identifying the genes responsible for azoospermia/oligospermia in the AZF 
regions of chromosome Y, and elucidating their functions;

o Investigations of the possible association between the use of ART, 
especially for cases of azoospermia/oligospermia, and resulting chromosomal 
aberrations or birth defects (especially of the gonads or genitourinary 
tract); and studies of the fertility of ART offspring;

o Genetics of reproductive disorders, such as PCOS and endometriosis, 
including genetic epidemiology and family studies;

o The role of the second X chromosome in the Klinefelter’s phenotype, 
especially infertility; 

o The mechanisms responsible for the accumulation of meiotic errors in aging 
oocytes, and identification of factors that impede or advance the process.

Role of Differential Inheritance and Expression of Parental Alleles in 

The wealth of gene sequence data generated by the Human Genome Project will 
significantly improve our ability to treat human genetic diseases.  However, 
diseases caused by epigenetic defects, such as imprinting and X-inactivation, 
clearly demonstrate that the timing, specificity, and degree of gene 
expression, and even the parental origin of the gene, are critical to normal 
human development and continued health. These processes are intimately tied 
to reproduction, because the patterns are established during gametogenesis 
and implantation. In addition, defects in these processes may affect 
gametogenesis, embryogenesis, gonadal/genital development, and fertility.

Imprinting refers to the phenomenon whereby only one of the two autosomal 
alleles is expressed and the other remains inactive, depending on its 
parental origin. The mechanisms responsible for establishing and maintaining 
imprinting are under intensive investigation. Imprints are believed to be 
encoded by gene methylation patterns that differ between the maternal and 
paternal alleles. Parental imprints from the previous generation are erased 
in the germ cells at an early stage of development, and then new sex-specific 
imprints are established, through mechanisms that remain to be elucidated. In 
embryogenesis, a genome-wide wave of demethylation occurs during pre-
implantation, and de novo methylation of CpG islands re-establishes the 
pattern shortly after implantation. However, the methylation of core 
differential methylation regions of imprinted genes is somehow protected from 
both of these changes. “Imprinting centers,” DNA sequences in close proximity 
to imprinted genes, may establish the parental imprint in the germ line and 
maintain it post-zygotically, although the mechanism and timing of such 
events remain unclear.  

Recently, many key molecules regulating genomic methylation and 
transcriptional silencing have been identified. The DNA methyltransferase 
DNMT1 maintains methylation after each round of DNA replication. Deficiency 
of DNMT1 is embryonic lethal due to genome-wide demethylation, dysregulating 
gene expression. Methyl-CpG-binding proteins, such as MeCP2, bind to 
methylated DNA and recruit histone deacetylases. Hypoacetylated DNA is 
presumably inactive because its tightly compacted configuration renders it 
inaccessible to the transcriptional machinery. In addition to maintaining 
methylation, DNMT1 also functions in transcriptional repression through 
direct association with histone deacetylases. Other DNA methyltransferases, 
DNMT3A and DNMT3B, are the de novo methyltransferases that restore 
methylation following the wave of demethlyation in early embryonic 
development. It is not known if these molecules participate in establishing 
imprints in germ cells. Two human syndromes, Rett Syndrome and ICF 
(immunodeficiency, centromere instability, and facial anomalies) are known to 
result from defects in the DNA methylation process.  Rett syndrome is a 
relatively rare X-linked dominant disorder of inappropriate gene activation 
due to a mutation in MeCP2. ICF is the first human genetic disorder known to 
involve constitutive abnormalities of genomic methylation patterns. In ICF, 
inactivation of DNMT3B specifically in lymphocytes results in 
immunodeficiency that is lethal before adulthood.  It seems likely that other 
phenotypes will be linked to dysfunction in the methylation/deacetylation 
pathway; exploration of these pathways specifically in reproductive tissues 
is encouraged. 

Recent findings show that culture conditions can significantly and 
selectively alter the expression of imprinted genes in embryonic mice, a 
finding that may be critical to human in vitro fertilization protocols. There 
is an increasing trend among ART clinics to culture embryos for longer 
periods of time to ensure implantation of “higher quality” embryos. It is not 
known if loss-of-imprinting occurs under such conditions and, if so, if it is 
harmful to the resulting embryos.  Likewise, the imprinting effects of ICSI 
and the use of male gametes that are not fully mature, remain to be studied. 

Another type of gene silencing is dosage compensation, or the inactivation of 
one X chromosome in females. This inactivation is usually random so that in 
each cell, the paternal and maternal X have an equal probability of 
inactivation. Some critical X-linked genes “escape” inactivation and are 
expressed from both copies of the X chromosome.  Turner Syndrome, resulting 
from a 45, X karyotype, clearly demonstrates the importance of genes on the 
second X chromosome in normal ovarian development and fertility. In addition, 
some studies suggest phenotypic differences associated with the parental 
origin, or imprinting, of the one X chromosome.

Genes on Xp22.3, the pseudo-autosomal region, normally escape inactivation. 
Gene deletions at this locus result in short stature, mental retardation, X-
linked ichthyosis, and Kallmann’s syndrome.  In this syndrome, loss of 
function of the X-linked KAL1 gene disrupts migration of the LHRH-secreting 
cells to the hypothalamus during embryonic development, resulting in 
hypogonadotropic hypogonadism, anosmia, ataxia, unilateral renal agenesis, 
and in males, genital abnormalities including micropenis, cryptorchidism, and 
testicular atrophy.  The specific genes involved, and their particular roles, 
are unknown.

Recent studies show that extreme skewing of X-inactivation can have either 
protective or negative effects on a variety of conditions. For example, 
normal mothers of girls with Rett syndrome may have the MECP mutation, but 
are protected from its consequences by almost 100 percent inactivation of the 
X chromosome carrying the mutation. On the other hand, extreme skewing of X-
inactivation may also be associated with recurrent spontaneous abortion in 
otherwise healthy women.  “Intermediate” phenotypes may in some cases be a 
result of skewed but incomplete inactivation of a mutation-bearing X 
chromosome.  This suggests that X-inactivation and skewing may have 
significant effects on X-linked reproductive phenotypes.
Elucidation of the basic mechanisms of imprinting, gene silencing, and X-
inactivation will be crucial to clarifying the differential temporal, 
spatial, and developmental expression of genes involved in reproduction; this 
knowledge is indispensable in translating the raw human genetic code into a 
blueprint for human reproductive health. 

Specific topics of interest include, but are not limited to:

o Genes and mechanisms important in erasing and re-establishing genomic 
imprinting and genome-wide methylation during gametogenesis and 

o The effects of various manipulations of gametes or fertilized eggs, 
especially those commonly used in assisted reproductive therapies, on gene 
methylation patterns or the differential expression of parental alleles;

o Evidence for defects in imprinting or methylation patterns in abnormal 
reproductive phenotypes including effects on gametogenesis, fertility, 
implantation, or gonadal/genital development;

o The effects of targeted deletion of DNA methyltransferases, deacetylases, 
or associated molecules, in gametes and reproductive tissues;

o Elucidation of the genetic influences on the differential survival and 
phenotypes of girls with Turner Syndrome;

o Clarification of the genes and genetic mechanism(s) responsible for normal 
and skewed X chromosome inactivation;

o Studies of the association between skewed X-inactivation and various 
reproductive manifestations, whether having protective or deleterious 


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 
UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in 
Clinical Research," published in the NIH Guide for Grants and Contracts on 
August 2, 2000 
(; a 
complete copy of the updated Guidelines are available at  The 
revisions relate to NIH defined Phase III clinical trials and require: a) all 
applications or proposals and/or protocols to provide a description of plans 
to conduct analyses, as appropriate, to address differences by sex/gender 
and/or racial/ethnic groups, including subgroups if applicable; and b) all 
investigators to report accrual, and to conduct and report analyses, as 
appropriate, by sex/gender and/or racial/ethnic group differences.  


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 or 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 at:  

Investigators also may obtain copies of these policies from the program staff 
listed under INQUIRIES.  Program staff also may provide additional relevant 
information concerning the policy.


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. 


Applications are to be submitted on the grant application form PHS 398 
(revised 4/98) and will be accepted at the standard application deadlines as 
indicated in the application kit.  These forms are available at most 
institutional offices of sponsored research, on the Internet at, 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:  

Applicants planning to submit an investigator-initiated new (type 1), 
competing continuation (type 2), competing supplement, or any amended/revised 
version of the preceding grant application types requesting $500,000 or more 
in direct costs for any year are advised that they must contact NICHD program 
staff before submitting the application, i.e., as plans for the study are 
being developed. Furthermore, the applicant must obtain agreement from NICHD 
staff that NICHD will accept the application for consideration for award. 
Finally, the applicant must identify, in a cover letter sent with the 
application, the staff member and Institute who agreed to accept assignment 
of the application.

This policy requires an applicant to obtain agreement for acceptance of both 
any such application and any such subsequent amendment. Refer to the NIH 
Guide for Grants and Contracts, March 20, 1998 at

Application Instructions for NICHD Small Grant (R03) Applications

The small grant (R03) research mechanism should be used for support of pilot 
studies and/or exploration of novel hypotheses and strategies that are sound 
and justifiable, but not sufficiently developed for the R01 mechanism.  A 
description of the NICHD Small Grants Program and complete application 
instructions are available from the program contact listed under INQUIRIES 
and on the Internet at   
These applications must be submitted according to the Modular 
Grant application instructions included in the NICHD Small Grant program 

Modular Grant Application Instructions for Research Project Grant (R01) 

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.

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 PHS398 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.

4 of the PHS 398.  It is not required and will not be accepted with 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 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: 

- 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 title and number of the program announcement must be typed on line 2 of 
the face page of the application form and the YES box must be marked.

For R01 applications, submit a signed, typewritten original of the 
application, including the Checklist, and five signed photocopies in one 
package to: 

BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

For R03 applications, submit a signed, typewritten original of the 
application, including the Checklist, and three signed photocopies in one 
package to:

CENTER FOR SCIENTIFIC REVIEW, at address listed above.

At the time of submission, two additional copies of the R03 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 Boulevard, Room 5E03, MSC 7510
Bethesda MD 20892-7510
Rockville MD 20852 (for express/courier service)


Applications will be assigned on the basis of established PHS referral 
guidelines. Upon receipt, applications will be reviewed for completeness by 
the NIH Center for Scientific Review (CSR).  Applications that are complete 
will be evaluated for scientific and technical merit by an appropriate peer 
review group convened in accordance with NIH peer review procedures. 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, generally the top half of applications under 
review, will be discussed, assigned a priority score, and receive a second 
level review by the appropriate national advisory council. 

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 the assignment of the 
overall score, weighting them as appropriate for each application. Note that 
the application does not need to be strong in all categories 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.

o  Significance:  Does the proposal 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?

o  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?

o  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?

o  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)?

o  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 

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 also will be 

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 that they may be adversely affected by the project 
proposed in the application.


Applications will compete for available funds with all other recommended 
applications.  The following will be considered in making funding decisions:  
Quality of the proposed project as determined by peer review, availability of 
funds, and program priority.


Inquiries are encouraged.  The opportunity to clarify any issues or questions 
from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Susan Taymans, Ph.D.
Reproductive Science Branch, Center for Population Research
National Institute of Child Health and Human Development
6100 Executive Blvd., Room 8B01, MSC 7510
Bethesda, MD  20892-7510
Telephone:  (301) 496-6517
FAX:  (301) 496-0962

Direct inquiries regarding fiscal matters to:

Mary Ellen Colvin
Grants Management Branch
National Institute of Child Health and Human Development
6100 Executive Blvd., Room 8A17J, MSC 7510
Bethesda, MD 20892-7510 
Telephone:  (301) 496-1304 
FAX:  (301) 402-0915 


This program is described in the Catalog of Federal Domestic Assistance No. 
93.864.  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 Part 
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 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, and 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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