This Program Announcement expires on November 1, 2003, unless re-issued.
REPRODUCTIVE GENETICS
Release Date: October 25, 2000
PA NUMBER: PA-01-005 (see replacement PA-04-049)
National Institute of Child Health and Human Development
(http://www.nichd.nih.gov)
THIS PA 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 PA.
PURPOSE
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
genes.
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).
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 Program Announcement
(PA) 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 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:
http://grants.nih.gov/grants/guide/pa-files/PAR-99-126.html. 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
http://grants.nih.gov/grants/funding/modular/modular.htm.
RESEARCH OBJECTIVES
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)
tumorigenesis.
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
genes,
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
description,
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
well.
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
Reproduction
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
embryogenesis,
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
effects.
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
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
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html), a
complete copy of the updated Guidelines are available at
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm. 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.
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 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:
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 also may 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.
APPLICATION PROCEDURES
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
http://grants.nih.gov/grants/funding/phs398/phs398.html, and from the
Division of Extramural Outreach and Information Resources, National
Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-
7910, telephone 301-710-0267, E-mail: grantsinfo@nih.gov.
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
http://grants.nih.gov/grants/guide/notice-files/not98-030.html.
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
http://grants.nih.gov/grants/guide/pa-files/PAR-99-126.html.
These applications must be submitted according to the Modular
Grant application instructions included in the NICHD Small Grant program
announcement.
Modular Grant Application Instructions for Research Project Grant (R01)
Applications
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.
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 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:
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)
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)
REVIEW CONSIDERATIONS
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
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 also will 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 that they may be adversely affected by the project
proposed in the application.
AWARD CRITERIA
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
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
Email: TaymansS@mail.nih.gov
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
Email: ml70m@nih.gov
AUTHORITY AND REGULATIONS
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.
Weekly TOC for this Announcement
NIH Funding Opportunities and Notices
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