and Human Services (HHS)
EXPIRED
Department of Health and Human
Services
Participating Organizations
National
Institutes of Health (NIH), (http://www.nih.gov/)
Components of Participating Organizations
National
Institute of Child Health and Human Development (NICHD), (http://www.nichd.nih.gov/)
Title: Reproductive Genetics and Epigenetics
(R21)
Announcement Type
This is a reissue of PA-04-049,
which was previously released January 8, 2004, and now is divided into separate
Funding Opportunity Announcements (FOAs) for R21, R03, and R01 funding
mechanisms.
NOTICE: Applications submitted in response to this FOA for Federal
assistance must be submitted electronically through Grants.gov (http://www.grants.gov) using the SF424
Research and Related (R&R) forms and SF424 (R&R) Application Guide.
APPLICATIONS MAY NOT BE SUBMITTED IN PAPER FORMAT.
This FOA must be read in conjunction with the application guidelines included with this announcement in Grants.gov/Apply for Grants (hereafter called Grants.gov/Apply).
A registration process is necessary before submission and applicants are highly encouraged to start the process at least four weeks prior to the grant submission date. See Section IV.
Program Announcement (PA) Number: PA-06-346
Catalog of Federal Domestic Assistance Number(s)
93.865
Key Dates
Release/Posted
Date: April 12, 1006
Opening
Date: May 2, 2006 (Earliest date an application may be submitted to
Grants.gov)
Letters of
Intent Receipt Date(s): Not Applicable
NOTE: On
time submission requires that applications be successfully submitted to
Grants.gov no later than 5:00 p.m. local time (of the applicant
institution/organization).
Application
Submission/Receipt Date(s): Standard dates apply, please see http://grants1.nih.gov/grants/funding/submissionschedule.htm
AIDS
Application Submission/Receipt Date(s): Not Applicable
Peer Review Date(s): Standard dates apply, please see http://grants1.nih.gov/grants/funding/submissionschedule.htm#reviewandaward
Council
Review Date(s): Standard dates
apply, please see http://grants1.nih.gov/grants/funding/submissionschedule.htm#reviewandaward
Earliest
Anticipated Start Date(s): Standard dates apply, please see http://grants1.nih.gov/grants/funding/submissionschedule.htm#reviewandaward
Additional Information to Be Available Date (URL Activation Date): Not Applicable
Expiration
Date: December 1, 2006
Due Dates for E.O. 12372
Not Applicable
Additional Overview
Content
Executive Summary
The purpose of this Funding Opportunity Announcement (FOA) issued by the National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), is to continue to support new studies on the genes, and genetic and epigenetic mechanisms influencing sex determination, fertility, reproductive health and reproductive aging, and other topics in Reproductive Genetics and Epigenetics. Studies submitted under this FOA are expected to identify and characterize the relevant genes, determine their function in normal human reproduction and reproductive development, identify functional partners or pathways and the nature of the interactions, and further our understanding of the consequences of mutations or dysregulation for human reproductive health. Studies of animal models are integral to this effort and are encouraged along with studies involving human subjects.
Table of Contents
Part I
Overview Information
Part II Full Text of Announcement
Section I. Funding Opportunity
Description
1. Research Objectives
Section II. Award Information
1. Mechanism of Support
2. Funds Available
Section III. Eligibility Information
1. Eligible Applicants
A. Eligible
Institutions
B. Eligible
Individuals
2.Cost Sharing or Matching
3. Other - Special Eligibility Criteria
Section IV. Application and Submission
Information
1. Request Application Information
2. Content and Form of Application Submission
3. Submission Dates and Times
A. Submission, Review and
Anticipated Start Dates
1. Letter of Intent
B. Sending an Application to the NIH
C. Application Processing
4. Intergovernmental Review
5. Funding Restrictions
6. Other Submission Requirements
Section V. Application Review
Information
1. Criteria
2. Review and Selection Process
A. Additional Review Criteria
B. Additional Review Considerations
C. Sharing Research Data
D. Sharing Research Resources
3. Anticipated Announcement and Award Dates
Section VI. Award Administration
Information
1. Award Notices
2. Administrative and National Policy
Requirements
3. Reporting
Section VII. Agency Contact(s)
1. Scientific/Research Contact(s)
2. Peer Review Contact(s)
3. Financial/ Grants Management Contact(s)
Section VIII. Other Information
- Required Federal Citations
Part II
- Full Text of Announcement
Section I. Funding Opportunity Description
1. Research Objectives
The
purpose of this Funding Opportunity Announcement (FOA) issued by the National
Institute of Child Health and Human Development (NICHD), National Institutes of
Health (NIH), is to continue to support new studies on the genes, and genetic
and epigenetic mechanisms influencing sex determination, fertility,
reproductive health and reproductive aging, and other topics in Reproductive
Genetics and Epigenetics. Studies submitted under this FOA are expected to
identify and characterize the relevant genes, determine their function in
normal human reproduction and reproductive development, identify functional
partners or pathways and the nature of the interactions, and further our
understanding of the consequences of mutations or dysregulation for human
reproductive health. Studies of animal models are integral to this effort and
are encouraged along with studies involving human subjects.
With the completion of the human genome project, the focus of genetic research must shift to functional genomics. NICHD encourages scientists interested in reproduction to lead the way in determining the genes and their mechanisms of action involved in the development of the gonads, reproductive ducts and genitalia, the processes of gametogenesis, normal and premature reproductive aging, and reproductive disorders such as infertility, cryptorchidism, endometriosis, and polycystic ovarian syndrome (PCOS). Studies on the genetic epidemiology of reproductive disorders might begin with the collection of large numbers of affected patients and their relatives for linkage analysis, association studies or quantitative trait loci (QTL) analysis. Studies using innovative statistical or technical methods are highly encouraged. We also encourage research into epigenetic mechanisms critical to reproduction, especially areas such as the establishment and maintenance of methylation patterns or imprinted loci in the early embryo, the timing, mechanisms and role of genomic methylation in gametogenesis, the effects of assisted reproductive therapy (ART) on imprinting and genomic methylation, and the reproductive determinants and consequences of X-chromosome inactivation.
Reproductive genetics is a broad research area, and the topics discussed and listed below are not meant to be exclusive areas of interest, but rather a sampling of the types of problems that this FOA intends to address.
Research Scope
(1) The Genetics of Sex Determination
Sex determination is the translation of the chromosomal sex (XX or XY) into the gender-appropriate internal and external reproductive structures. The initial events of sex determination are, therefore, genetically determined. Errors in the process can range in severity from complete sex reversal to gonadal dysgenesis or minor genital abnormalities. Sex determination, as an early embryological event, can help us address basic questions of the regulation 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 part of a larger pathologic syndrome, such as Frasier syndrome, Deny-Drash syndrome, or campomelic dysplasia, to name a few. The known genes involved in sex determination often act as growth and/or differentiation factors and there is mounting evidence that they may be important in tumorigenesis in the gonads as well as other tissues.
Despite the identification of the Y-chromosome gene SRY as the "testis determining factor" almost 15 years ago, the mechanisms and pathways of normal sex differentiation are still not well understood. In particular, although some downstream effects of SRY are known, such as cellular proliferation, Sertoli cell differentiation, and testis-specific vascularization, the direct transcriptional targets of SRY remain unknown. The factors regulating SRY expression remain unknown as well. While genes such as SOX-9, WT-1, DAX-1,
DMRT-1, GATA4, FOG2, and SF-1, among others, contribute to sex determination, the nature and timing of their interactions remain unclear, and there are clearly other unknown genes to be identified. A further level of complexity arises with gene dosage effects, such as XY sex reversal caused by duplication of Dax-1.
Sex determination can be divided into steps consisting of establishment of the bipotential gonad, formation of the primordial gonad, and differentiation of the gonad. Many of the sex determining genes act in multiple steps, but SRY mainly functions in shaping the primordial gonad into a testis. However, the classic view of SRY as a "switch" that confers maleness is an over-simplification as illustrated by the enormous potential for ambiguity in sex determination, and by evidence suggesting that steps in testis development that were once thought to be tightly coordinated, such as mesonephric cell migration and Leydig cell differentiation, or the formation of testis cords and the inhibition of male germ cell meiosis, can occur independently of each other. Additionally, ovarian development may not be the passive "default" process it was once thought to be. Estrogen may be necessary to maintain the ovarian phenotype, as mice unable to make estrogen (ArKO mice) or bind estrogen develop patches of Sertoli and Leydig cells within their ovaries postnatally.
Germ cells play a critical role in the formation of ovaries, although testes can form in their absence. The germ cells migrate into the gonad through the gut, through a process which has yet to be fully characterized. The presence of meiotic germ cells is critical for the formation and maintenance of ovarian follicles while, in contrast, in males the testis cords surround the germ cells and meiosis is inhibited. Germ cell migration and the progression into meiosis are not well understood.
There is clear evidence that the genes involved in sex determination have important roles beyond gonadal fate. Some, such as WT-1, are expressed in common embryonic precursors to different organ systems. Mutations in FOXL2, a gene deleted in polled intersex goats, cause the human syndrome BPES that often includes premature ovarian failure. The anti-mullerian hormone, known as Amh or MIS, causes regression of the female duct system in normal males, and in adult males, MIS has inhibitory effects on both Leydig cells and testosterone production. Such examples clearly demonstrate that the continued study of sex determination will not only benefit those born with gonadal dysgenesis or ambiguous genitalia, but will also advance our knowledge of the physiology of the adult reproductive system, and the development and regulation of other organ systems.
Specific topics of interest include, but are not limited to:
(2) Genes Regulating Fertility, Reproductive Health, 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 United States. 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 and surgical treatments for infertility caused by hormonal or structural defects. However, 30 percent of couples are infertile due to idiopathic or genetic causes, and they may suffer through failed conventional treatments before resorting to assisted reproductive technologies (ART) to conceive their biological children. Given the known and potential problems associated with the use of ART, it is essential that we focus our efforts on identifying and treating the underlying causes of infertility.
Studies of human infertility and studies using animal models have revealed many single gene mutations that cause infertility and new phenotypes continually appear in the literature. Each new gene teaches us more about the intricate pathways that contribute to normal fertility and may suggest leads for contraceptives. Epidemiological and family studies of human infertility are now feasible with the advent of genetic databases and new statistical techniques.
The most common identifiable cause of human male infertility is Klinefelter's syndrome, occurring in one in 400 live births. The Klinefelter's XXY genotype disrupts testis development and, in combination with high levels of meiotic non-disjunction, low sperm counts and infertility ensue. The Klinefelter's phenotype, along with data showing exclusive expression of several X-chromosome genes in the testes, suggests that the X-chromosome figures prominently in testis physiology. Clearly, loci on the Y-chromosome are also critical to male fertility. Deletions within the male specific region of the Y-chromosome, previously referred to as the non-recombining region, are also a common genetic cause of spermatogenic failure in men. Mutation of specific genes within the AZF (azoospermia factor) regions of the Y-chromosome, most notably DAZ, severely disrupts spermatogenesis. The recent mapping of the male specific region of the Y-chromosome suggests that gene conversion (non-reciprocal recombination), while conserving important testis gene function on the Y-chromosome through evolution, may also predispose to deletions that abolish spermatogenesis.
Less dramatic mutations can also render males infertile. Disruption of the action of hypothalamic hormones can delay or prevent puberty, leading to oligospermia or azoospermia. Mutations causing both the X-linked and autosomal dominant forms of Kallmann's syndrome (hypogonadotropic hypogonadism and anosmia), which is more common in males, were recently identified (KAL-1 and FGFR1, respectively). Similarly, mutation of the beta-subunit of the gonadotropin FSH also causes infertility by compromising spermatogenesis. Even when spermatogenesis proceeds smoothly, infertility can result if the chromatin is incorrectly packaged into the sperm head. Mutations that abolish the function of the transition proteins or the protamines that compact sperm chromatin cause infertility. The sperm mitochondrial genome also contributes to fertility. For example, absence of the common form of the POLG allele, encoding a mitochondrial DNA polymerase, is associated with infertility in men.
Genetic conditions in which the testes themselves are normal, but the male tract is affected, can render men infertile. Mutations in CFTR (the gene causing cystic fibrosis) can cause congenital bilateral absence of the vas deferens, seen in one percent of infertile men. Cryptorchidism is the most common defect of newborn boys, affecting two three percent. Strong evidence demonstrates a genetic component to cryptorchidism. Mutation of the genes encoding either INSL3 (insulin-like hormone) or its receptor GREAT/LGR8, compromises the transabdominal phase of testicular descent, causing cryptorchidism which, if uncorrected, will result in infertility. However, the known mutations explain only a minority of cases of cryptorchidism, suggesting the involvement of other genes and pathways.
The identification of genetic causes of female infertility lags behind, possibly because the female reproductive system is more complex than the male system. Finely tuned cyclic fluctuations in hormones coordinate the follicular development, ovulation, and uterine receptivity for implantation, the components that comprise a normal menstrual cycle. This complexity suggests that there are hundreds of genes, each contributing a small effect on female fertility.
Genes involved in regulating the hypothalamic-pituitary-ovarian axis are obvious candidates for female infertility and, while mutations have been reported in the genes encoding FSH-beta and the LH receptor, and the genes associated with Kallmann's syndrome have been identified, these mutations explain only a tiny proportion of cases of female infertility. However, work in highly prolific sheep has identified genes controlling ovulation rate and fertility, as well as ovarian development, which may lead to better understanding of infertility in women. In some breeds of ewes, naturally occurring mutations of genes encoding key players in the transforming growth factor beta signaling pathway increase ovulation rate and twinning. Conversely, homozygous mutation of the gene encoding the TGF signaling molecule BMP15 (GDF9B) causes sterility in the same breed of sheep. Such studies suggest new candidate molecules and pathways to study in human fertility.
The disruption of early embryonic development may be an under-estimated cause of infertility. Mammalian oocytes store products necessary for the very early stages of development, until the embryonic genome is activated. Deletion of maternal oocyte products such as MATER, DNMT1o, and Npm2 arrests embryo development and leads to female infertility or sub-fertility in knockout mice. It is not known if mutations in these genes, or insufficient levels of their products, are a cause of human infertility.
Reproductive diseases such as endometriosis and polycystic ovarian syndrome are common and can be quite debilitating. Recent research indicates genetic components to these disorders; identification of causative or modifying genes would be of enormous benefit. Both diseases are likely to involve complex interactions between gene products and environment rather than single major genes. Polymorphisms in the insulin gene, the gene CYP11a, and the androgen receptor gene have been associated with hyperinsulinemia and hyperandrogenism in PCOS. Similarly, alterations in the estrogen receptor gene, genes encoding products involved in detoxification, homeobox genes, and the LH-beta gene, have been associated with a small number of cases of endometriosis. Comparative genomic hybridization and gene chip studies of endometriosis have revealed candidate regions and patterns of altered gene expression, but no major genes as yet.
Because of the sharp decline in female fertility with age and the increasing number of women who opt to have children later in life, the incidence of infertility is growing. Data from animal models and some human syndromes indicate that the timing of reproductive aging, in a continuum from premature ovarian failure to early menopause and normal menopause, may have genetic components. The genes and mechanisms contributing to reproductive aging have not been well characterized. Given the social trend to delay starting a family and the concerns about the prolonged use of hormone replacement therapy for menopause, understanding the mechanisms of reproductive aging is a high priority.
Premature ovarian failure (POF), defined as the cessation of menstruation before the age of 40, affects approximately one percent of women. Most cases of POF are assumed to be genetic and insight into this condition may help us better understand the variation in normal ovarian aging as well. Mutations in the gene encoding the FSH receptor are a rare cause of POF. Women carrying the fragile X premutation have a greater risk for premature ovarian failure, although the mechanism is not known. Mutation in a forkhead transcription factor, FOXL2 (3q23), causes autosomal dominant POF due to follicle depletion in some women affected with the syndrome BPES. FOXL2 mutation results in ovarian phenotypes ranging from streak ovaries to otherwise normal ovaries that lack adequate follicles. Mice lacking Foxo3a, a distant relative of FoxL2, show early depletion of ovarian follicles and sterility shortly after sexual maturity. Other causative genes for POF in women, and perhaps protective genes or alleles, remain to be identified.
The accumulation of meiotic errors in aging oocytes contributes strongly to the age-related decrease in women's fertility and the increased risk for chromosomal abnormalities in children born to older mothers. This may be due to the unusual robustness of oocytes to proceed through meiosis despite flaws in the process; there are multiple examples of greater tolerance of meiotic defects in oogenesis as compared to spermatogenesis. For example, male germ cells are unable to progress through meiosis when the synaptonemal complex, which helps to hold homologous chromosomes together during meiosis, is compromised. While male mice bred to lack synaptonemal complex protein 3 are infertile, female SCP-3 knockout mice, though subfertile, are able to reproduce. Because the phenotype of subfertility due to embryo wastage becomes more severe with age, these mice may be a good model system not only for delineating the differences in meiosis in male and female gametes, but also for delineating the interactions between infertility and aging.
The phenomenon of reproductive aging in men, or decreased fertility with male age, is under debate and definitive studies are needed. Studies in old male rats demonstrate decreased fertility and an increased risk of siring abnormal offspring. Mutation rates appear to increase with age in male gametes and some genetic diseases, including both recessive X-linked and autosomal dominant conditions, demonstrate a paternal age effect, suggesting that the process of spermatogenesis does change with age in men. This is a phenomenon that needs further characterization and mechanistic study.
Specific topics of interest include, but are not limited to:
(3) Genomic Imprinting and X-Chromosome Inactivation
The wealth of gene sequence data generated by the Human Genome Project will significantly improve our ability to detect and treat genetic diseases. However, diseases caused by epigenetic defects, such as improper gene methylation or improper X-chromosome inactivation, clearly demonstrate that in addition to a normal gene sequence, the timing, specificity, degree of gene expression, and even the parental origin of an allele, are critical to normal human development and continued health. The epigenetic processes of imprinting and X-inactivation are intimately tied to reproduction, as the patterns are established during gametogenesis and embryogenesis, and they may in turn affect embryogenesis, gonadal/genital development, and fertility.
Imprinting is the phenomenon whereby one of the two autosomal alleles is preferentially expressed, dependent on its parental origin. Current estimates suggest that greater than one percent of all human genes are imprinted. Imprints are thought to be encoded by gene methylation patterns that differ between the maternally- and paternally-derived alleles. Parental imprints from the previous generation are erased in the germ cells at an early stage of development and new sex-specific imprints are established. This appears to occur before the onset of meiosis in male germ cells, but maternal imprints are established later, in growing oocytes arrested at the diplotene stage. Interestingly, the imprints are not all imposed together, as different genes are marked at various stages of oocyte growth. Although a genome-wide wave of demethylation occurs before implantation and de novo methylation re-establishes the pattern shortly after implantation, the core regions of the imprinted genes are somehow protected from these changes. Imprinting centers may play a role in the establishment and maintenance of the appropriate parental imprint, although the mechanism of such events remains unclear. Many imprinted loci encode anti-sense transcripts that have been implicated in the initiation of genomic imprinting, as well as X-chromosome inactivation.
Many key molecules regulating genomic methylation and transcriptional silencing have been identified. Methylation generally silences allele expression, as methyl-CpG-binding proteins such as MeCP2, bind to methylated DNA and recruit histone deacetylases. Hypoacetylated DNA is presumably inactive because it is conformationally inaccessible to the transcription machinery. The establishment and maintenance of DNA methylation are regulated by the DNA methyltransferases (Dnmt). Dnmt3A and Dnm3B function in de novo methylation, while Dnmt1 maintains methylation after each round of replication. Deficiency of Dnmt1 is lethal to embryos due to genome-wide demethylation. In contrast, the oocyte-specific form, Dnmt1o, seems to act only on certain genes and only at the eight-cell stage. Dnmt3L is required for the establishment of imprints during oogenesis, but is not necessary for the maintenance of paternal imprints during embryogenesis. BORIS, a paralog of CTCF, may participate in the erasure of parental methylation marks in the male germ line. More studies are needed to determine how the methylation and demethylation machinery correctly recognizes imprinted regions, discriminates between the maternal and paternal marks, and establishes or maintains the appropriate methylation patterns during gametogenesis and early embryogenesis.
Methylation of histones, in addition to DNA methylation, may regulate gene expression and the "read-out" of these types of methylation signals remains unclear. In mice lacking the polycomb group gene Eed, a subset of paternally repressed genes is improperly activated and expressed. Such data suggest that other trans-acting factors form an additional layer of regulation of the expression of imprinted genes.
Several human syndromes, such as Rett syndrome, ICF, Beckwith-Weidemann syndrome, Prader-Willi syndrome, and Angelman syndrome, are caused by defects in imprinting or in DNA methylation. Dysregulation of imprinted genes often manifests as abnormal growth of the fetus or placenta. One recently discovered example is the unknown locus on chromosome 19q13.4 that causes recurrent biparental complete hydatidiform molar pregnancies, as maternal alleles acquire paternal methylation patterns. Studies suggest that a failure of epigenetic reprogramming, as evaluated by methylation patterns, may underlie the extraordinarily high failure rate of cloning by nuclear transfer. The findings that cloned mouse embryos aberrantly express Dnmt1, while Dnmt1o fails to translocate to the nucleus, provide further support for this hypothesis. Culture conditions can also significantly and selectively alter the expression of imprinted genes, a finding that may be critical to human in vitro fertilization protocols. There is a trend among ART clinics to culture embryos for longer periods to enable selection of "higher quality" embryos; it is not clear if loss of imprinting occurs in such conditions and, if so, what effect it might have on the offspring. It seems likely that other more subtle phenotypes will be linked to defects in imprinting or DNA methylation/demethylation as well; exploration of these processes specifically in reproductive tissues is encouraged.
The inactivation of one X-chromosome in females is another type of gene silencing that acts as dosage compensation for the XX vs. XY genotype. 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 for fetal survival, as well as ovarian development.
There are two basic processes in X-inactivation: choice of which X-chromosome to inactivate, and implementation of the silencing. While recent studies show that X-inactivation has some mechanistic similarities to autosomal imprinting, X-chromosome inactivation in the embryo is usually random so that in each cell, the maternally- and paternally-derived X-chromosome have an equal probability of inactivation. The molecule Xist, an X-encoded untranslated RNA, is the master regulator of X-chromosome inactivation. Xist is expressed only from the X-chromosome destined to become inactive (X-I). The Xist transcripts coat X-I in cis and soon after, histone 3 is methylated on lysine 9 on the inactive X. The X-chromosome that is destined to remain active (X-A) is protected from Xist by Tsix, the Xist antisense transcript. On X-A, histone 3 is methylated on lysine 4; this differential methylation suggests that a histone code may regulate the transcriptional status of the X-chromosome. The DNA of the inactive X-chromosome is hypermethylated and this is functionally significant as Dnmt1 mutant embryos fail to maintain random X-chromosome inactivation. Other events that mediate the silencing of the Xist-coated X-chromosome remain unknown. Recent data also suggest that there is active selection of both X-I and X-A, rather than one chromosome's state being conferred by default.
Although the choice of which X-chromosome to inactivate is random in the embryo, it is imprinted in the extra-embryonic cells of mammals: the paternal X (Xp) chromosome is preferentially inactivated. The mechanisms for imprinted silencing of Xp in the extra-embryonic tissue and random X-chromosome inactivation in the embryo seem to be quite different. For example, Dnmt1 mutant embryos fail to maintain random X-chromosome inactivation in the embryo, but Xp is correctly inactivated in the extra-embryonic cells. Also, homozygous mutant eed mice initiate but fail to maintain imprinted Xp inactivation in the trophectoderm, but maintain normal random X-chromosome inactivation in the embryo itself, suggesting that eed functions only in maintenance of imprinted, but not random, X-chromosome inactivation.
Normal X-chromosome inactivation is essential to reproduction. Appropriate imprinted X-inactivation is critical to formation of the trophoblast and, ultimately, the placenta. Both heterozygous and homozygous Tsix knockout females are subfertile, with homozygous females showing a more drastic loss of fertility. Similar to imprinting defects in cloned embryos, cloned or in vitro embryos show disruption of dosage compensation of X-linked genes that may affect embryonic development.
The presence of skewed X-chromosome inactivation (XCI), usually defined as greater than 90 percent inactivation of a particular one of the pair of X-chromosomes, is increased in women with recurrent spontaneous abortion. In addition, women with skewed XCI and recurrent spontaneous abortion are more likely to have trisomic losses than women without XCI, but experiencing recurrent spontaneous abortion. Finally, deviations from random choice in X-chromosome inactivation can affect the relative expression of X-linked genes, many of which act in reproduction.
Transcriptional silencing of the X-chromosome (as well the Y-chromosome) occurs in males as well, just before meiotic prophase in spermatogenesis. The mechanism of male X-chromosome inactivation is likely completely different from that in the female because Xist mutation does not prevent the silencing in males. This remains a very poorly understood area.
Specific topics of interest include, but are not limited to:
See Section VIII, Other Information - Required Federal
Citations, for policies related to this announcement.
Section
II. Award Information
1. Mechanism of Support
This funding opportunity
will use the NIH Exploratory/Developmental
Research Grant (R21) award mechanism.
As an applicant, you will be solely responsible for
planning, directing, and executing the proposed project.
This funding opportunity uses just-in-time concepts. It also uses the modular budget formats (see the Modular Applications and Awards section of the NIH Grants Policy Statement). Specifically, if you are submitting an application with direct costs in each year of $250,000 or less (excluding consortium Facilities and Administrative [F&A] costs), use the PHS398 Modular Budget component provided in the SF424 (R&R) Application Package and SF424 (R&R) Application Guide (see specifically Section 5.4, Modular Budget Component, of the Application Guide).
The R21 mechanism is intended to encourage new exploratory and developmental research projects and/or exploration of novel hypotheses and strategies. For example, such projects could assess the feasibility of a novel area of investigation or a new experimental system. These projects should be exploratory and novel, and distinct from the type of project supported through the traditional R01. For further information on the R21 mechanism, see: http://grants2.nih.gov/grants/funding/r21.htm.
Exploratory/developmental grant support is for new projects only; competing renewal (formerly competing continuation ) applications will not be accepted. Up to two resubmissions (formerly revisions/amendments") of a previously reviewed exploratory/developmental grant application may be submitted. See NOT-OD-03-041, May 7, 2003.
2. Funds Available
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 NIH Institutes and Centers (ICs) provide support for
this program, awards pursuant to this funding opportunity are contingent upon
the availability of funds and the receipt of a sufficient number of meritorious
applications.
The total
project period for an application submitted in response to this funding
opportunity may not exceed 2 years. Although the size of award may vary with
the scope of research proposed, it is expected that applications will stay
within the budgetary guidelines for an exploratory/developmental project;
direct costs are limited to $275,000 over an R21 two-year period. For example,
the applicant may request $100,000 in the first year and $175,000 in the second year. The
request should be tailored to the needs of the project, with no more
than $200,000 in direct costs allowed in any single year. Applicants may
request direct costs in $25,000 modules, up to the total direct costs
limitation of $275,000 for the combined two-year award period. NIH grants
policies as described in the NIH Grants Policy
Statement will apply to the applications submitted and awards
made in response to this Program Announcement funding opportunity.
F&A costs requested by consortium participants are not included in the direct cost limitation. See NOT-OD-05-004, November 2, 2004.
Section III. Eligibility Information
1. Eligible Applicants
1.A. Eligible Institutions
You may submit an
application(s) if your organization has any of the following characteristics:
1.B.
Eligible Individuals
Any
individual with the skills, knowledge, and resources necessary to carry out the
proposed research as the Project Director/Principal Investigator (PD/PI) 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 support.
2. Cost Sharing or Matching
This program
does not require cost sharing as defined in the current NIH
Grants Policy Statement.
3. Other-Special Eligibility Criteria
Applicants
may submit more than one application, provided each application is
scientifically distinct.
Section IV. Application and Submission Information
Registration and Instructions for Submission via Grants.gov
To download a SF424 (R&R) Application Package and
SF424 (R&R) Application Guide for completing the SF424 (R&R) forms for
this FOA, link to http://www.grants.gov/Apply/
and follow the directions provided on that Web site.
A one-time registration is required for institutions/organizations at both:
PD/PIs should work with their institutions/organizations to make sure they are registered in the NIH Commons.
Several additional separate actions are required before an applicant institution/organization can submit an electronic application, as follows:
1) Organizational/Institutional Registration in Grants.gov/Get Started
2) Organizational/Institutional Registration in the eRA Commons
3) Project Director/Principal Investigator (PD/PI) Registration in the NIH eRA Commons: Refer to the NIH eRA Commons System (COM) Users Guide.
Note that if a PD/PI is also an NIH peer-reviewer with an Individual DUNS and CCR registration, that particular DUNS number and CCR registration are for the individual reviewer only. These are different than any DUNS number and CCR registration used by an applicant organization. Individual DUNS and CCR registration should be used only for the purposes of personal reimbursement and should not be used on any grant applications submitted to the Federal Government.
Several of the steps of the registration process could take four weeks or more. Therefore, applicants should immediately check with their business official to determine whether their institution is already registered in both Grants.gov and the Commons. The NIH will accept electronic applications only from organizations that have completed all necessary registrations.
1.
Request Application Information
Applicants must download
the SF424 (R&R) application forms and SF424 (R&R) Application Guide for
this FOA through Grants.gov/Apply.
Note:
Only the forms package directly attached to a specific FOA can be used. You
will not be able to use any other SF424 (R&R) forms (e.g., sample forms,
forms from another FOA), although some of the "Attachment" files may
be useable for more than one FOA.
For further assistance contact GrantsInfo, Telephone
301-710-0267, Email: [email protected].
Telecommunications for the hearing impaired: TTY
301-451-5936.
2. Content and Form of
Application Submission
Prepare all applications using the SF424 (R&R) application forms and in
accordance with the SF424 (R&R) Application Guide
(MS
Word or PDF).
The SF424 (R&R) Application Guide is critical to submitting a complete and accurate application to NIH. There are fields within the SF424 (R&R) application components that, although not marked as mandatory, are required by NIH (e.g., the Credential log-in field of the Research & Related Senior/Key Person Profile component must contain the PD/PI’s assigned eRA Commons User ID). Agency-specific instructions for such fields are clearly identified in the Application Guide. For additional information, see Tips and Tools for Navigating Electronic Submission on the front page of Electronic Submission of Grant Applications.
The SF424 (R&R) application is comprised of data arranged in separate components. Some components are required, others are optional. The forms package associated with this FOA in Grants.gov/APPLY will include all applicable components, required and optional. A completed application in response to this FOA will include the following components:
Required
Components:
SF424
(R&R) (Cover component)
Research & Related Project/Performance Site Locations
Research
& Related Other Project Information
Research
& Related Senior/Key Person
PHS398 Cover
Page Supplement
PHS398
Research Plan
PHS398
Checklist
PHS398 Modular
Budget
Optional Components:
PHS398 Cover Letter
File
Research & Related
Subaward Budget Attachment(s) Form
Note: While both budget components are included in the SF424 (R&R) forms package, the NIH R21 uses ONLY the PHS398 Modular Budget. (Do not use the detailed Research & Related Budget.)
Foreign
Organizations
Several special
provisions apply to applications submitted by foreign organizations:
Proposed research should provide special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions in other countries that are not readily available in the United States or that augment existing U.S. resources.
3. Submission Dates and Times
See Section IV.3.A for
details.
3.A.
Submission, Review, and Anticipated Start Dates
Opening Date:
May 2, 2006 (Earliest date an application may be submitted to
Grants.gov)
Letters of
Intent Receipt Date(s): Not Applicable
Application
Submission/Receipt Date(s): Standard dates apply, please see http://grants1.nih.gov/grants/funding/submissionschedule.htm
AIDS
Application Submission/Receipt Date(s): Not Applicable
Peer Review Date(s): Standard dates apply, please see http://grants1.nih.gov/grants/funding/submissionschedule.htm#reviewandaward
Council
Review Date(s): Standard dates
apply, please see http://grants1.nih.gov/grants/funding/submissionschedule.htm#reviewandaward
Earliest
Anticipated Start Date(s): Standard dates apply, please see http://grants1.nih.gov/grants/funding/submissionschedule.htm#reviewandaward
3.A.1. Letter of Intent
A letter of intent is
not required for the funding opportunity.
3.B. Sending an
Application to the NIH
To submit an application
in response to this FOA, applicants should access this FOA via http://www.grants.gov/Apply and follow
steps 1-4. Note: Applications must only be submitted electronically
PAPER
APPLICATIONS WILL NOT BE ACCEPTED.
3.C.
Application Processing
Applications
may be submitted on or after the
opening date and must be successfully received by Grants.gov no later than 5:00 p.m. local
time (of the applicant
institution/organization) on the application submission/receipt date(s). (See Section
IV.3.A. for all dates.) If an application is not submitted by the receipt date(s) and time, the
application may be delayed in the review process or not reviewed.
Once an application package has been successfully submitted through Grants.gov, any errors have been addressed, and the assembled application has been created in the eRA Commons, the PD/PI and the Authorized Organization Representative/Signing Official (AOR/SO) have two business days to view the application image.
Upon receipt,
applications will be evaluated for completeness by the Center for Scientific
Review, NIH. Incomplete applications will not be reviewed.
There will be an
acknowledgement of receipt of applications from Grants.gov and the Commons. Information related to the
assignment of an application to a Scientific Review Group is also in the Commons.
The
NIH will not accept any application in response to this FOA that is essentially
the same as one currently pending initial merit review unless the applicant
withdraws the pending application. The NIH will not accept any application that
is essentially the same as one already reviewed. This does not preclude the
submission of an application already reviewed with substantial changes, but
such application must include an Introduction addressing the previous
critique. Note such an application is considered a "resubmission" for
the SF424 (R&R).
4. Intergovernmental Review
This initiative is
not subject to intergovernmental
review.
5. Funding Restrictions
All NIH
awards are subject to the terms and conditions, cost principles, and other
considerations described in the NIH Grants Policy
Statement.
Pre-Award Costs
are allowable. A grantee may, at its own risk and without NIH prior approval,
incur obligations and expenditures to cover costs up to 90 days before the
beginning date of the initial budget period of a new award if such costs: are
necessary to conduct the project and would be allowable under the grant, if
awarded, without NIH prior approval. If specific expenditures would otherwise
require prior approval, the grantee must obtain NIH approval before incurring
the cost. NIH prior approval is required for any costs to be incurred more than
90 days before the beginning date of the initial budget period of a new award.
The incurrence of pre-award costs in anticipation of a
competing or non-competing award imposes no obligation on NIH either to make
the award or to increase the amount of the approved budget if an award is made
for less than the amount anticipated and is inadequate to cover the pre-award
costs incurred. NIH expects the grantee to be fully aware that pre-award costs
result in borrowing against future support and that such borrowing must not
impair the grantee's ability to accomplish the project objectives in the
approved time frame or in any way adversely affect the conduct of the project.
See the NIH Grants Policy Statement.
6. Other Submission Requirements
The NIH
requires the PD/PI to fill in his/her Commons User ID in the PROFILE Project
Director/Principal Investigator section, Credential log-in field of the
Research & Related Senior/Key Person Profile component. The applicant
organization must include its DUNS number in its Organization Profile in the
eRA Commons. This DUNS number must match the DUNS number provided at CCR registration with Grants.gov. For additional information, see Tips and Tools for Navigating
Electronic Submission on the front page of Electronic Submission of Grant
Applications.
Renewal (formerly competing continuation or Type 2 ) applications are not permitted.
All application instructions outlined in the SF424 (R&R) application are to be followed, with the following requirements for R21 applications:
Note: While each section of the Research Plan needs to be uploaded separately as a PDF attachment, applicants are encouraged to construct the Research Plan as a single document, separating sections into distinct PDF attachments just before uploading the files. This approach will enable applicants to better monitor formatting requirements such as page limits. All attachments must be provided to NIH in PDF format, filenames must be included with no spaces or special characters, and a .pdf extension must be used.
Plan for Sharing
Research Data
The precise content
of the data-sharing plan will vary, depending on the data being collected and
how the investigator is planning to share the data. Applicants who are planning
to share data may wish to describe briefly the expected schedule for data
sharing, the format of the final dataset, the documentation to be provided,
whether or not any analytic tools also will be provided, whether or not a
data-sharing agreement will be required and, if so, a brief description of such
an agreement (including the criteria for deciding who can receive the data and
whether or not any conditions will be placed on their use), and the mode of
data sharing (e.g., under their own auspices by mailing a disk or posting data
on their institutional or personal website, through a data archive or enclave).
Investigators choosing to share under their own auspices may wish to enter into
a data-sharing agreement. References to data sharing may also be appropriate in
other sections of the application.
The reasonableness
of the data sharing plan or the rationale for not sharing research data will be
assessed by the reviewers. However, reviewers will not factor the proposed data
sharing plan into the determination of scientific merit or the priority score.
Sharing Research
Resources
NIH policy requires
that grant awardee recipients make unique research resources readily available
for research purposes to qualified individuals within the scientific community
after publication (NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part7.htm#_Toc54600131).
Investigators responding to this funding opportunity should include a plan for
sharing research resources addressing how unique research resources will be
shared or explain why sharing is not possible.
The adequacy of the resources sharing plan and any related data sharing plans will be considered by Program staff of the funding organization when making recommendations about funding applications. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each Non-Competing Grant Progress Report (PHS 2590). See Section VI.3., Reporting.
Section
V. Application Review Information
1. Criteria
Only the review
criteria described below will be considered in the review process.
2. Review and Selection Process
Applications
submitted for this funding opportunity will be assigned to the ICs on the basis
of established PHS referral guidelines.
Appropriate scientific review groups convened in
accordance with the standard NIH peer review procedures (http://www.csr.nih.gov/refrev.htm)
will evaluate applications for scientific and technical merit.
As part of the
initial merit review, all applications will:
Applications submitted in response to this funding opportunity will compete for available funds with all other recommended applications. The following will be considered in making funding decisions:
The NIH R21 exploratory/developmental grant is a mechanism for supporting novel scientific ideas or new model systems, tools, or technologies that have the potential to significantly advance our knowledge or the status of health-related research. Because the Research Plan is limited to 15 pages, an exploratory/developmental grant application need not have extensive background material or preliminary information as one might normally expect in an R01 application. Accordingly, reviewers will focus their evaluation on the conceptual framework, the level of innovation, and the potential to significantly advance our knowledge or understanding. Reviewers will place less emphasis on methodological details and certain indicators traditionally used in evaluating the scientific merit of R01 applications, including supportive preliminary data. Appropriate justification for the proposed work can be provided through literature citations, data from other sources, or, when available, from investigator-generated data. Preliminary data are not required for R21 applications; however, they may be included if available.
The goals of NIH supported research are to advance our understanding of biological systems, to improve the control of disease, and to enhance health. In their written critiques, reviewers will be asked to comment on each of the following criteria in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application.
Note that an 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 scientific health problem?
If the aims of the application are achieved, how will scientific knowledge or
clinical practice be advanced? What will be the effect of these studies on the
concepts, methods, technologies, treatments, services, or preventative
interventions that drive this field?
Approach: Are the conceptual or clinical framework, design, methods,
and analyses adequately developed, well integrated, well reasoned, and
appropriate to the aims of the project? Does the applicant acknowledge
potential problem areas and consider alternative tactics?
Innovation: Is the project original and innovative? For example: Does
the project challenge existing paradigms or clinical practice; address an
innovative hypothesis or critical barrier to progress in the field? Does the
project develop or employ novel concepts, approaches, methodologies, tools, or
technologies for this area?
Investigators: Are the investigators appropriately trained and well suited
to carry out this work? Is the work proposed appropriate to the experience
level of the PD/PI and other researchers? Does the investigative team bring complementary
and integrated expertise to the project (if applicable)?
Environment: Does the scientific environment in which the work will be
done contribute to the probability of success? Do the proposed studies benefit
from unique features of the scientific environment, or subject populations, or
employ useful collaborative arrangements? Is there evidence of institutional
support?
2.A.
Additional Review Criteria:
In addition to the above criteria, the following
items will continue to be considered in the determination of scientific merit
and the priority score:
Protection of Human Subjects from
Research Risk: The involvement of
human subjects and protections from research risk relating to their
participation in the proposed research will be assessed. See item 6 of the
Research Plan component of the SF424 (R&R).
Inclusion of Women, Minorities and
Children in Research: The adequacy
of plans to include subjects from both genders, all racial and ethnic groups
(and subgroups), and children as appropriate for the scientific goals of the
research will be assessed. Plans for the recruitment and retention of subjects
will also be evaluated. See item 7 of the Research Plan component of the SF424
(R&R).
Care and Use of Vertebrate Animals in
Research: If vertebrate animals are to
be used in the project, the five items described under item 11 of the Research
Plan component of the SF424 (R&R) will be assessed.
Biohazards: If materials or procedures are proposed that are
potentially hazardous to research personnel and/or the environment, determine
if the proposed protection is adequate.
2.B. Additional Review
Considerations
Budget and Period of Support: The reasonableness of the proposed budget
and the appropriateness of the requested period of support in relation to the
proposed research may be assessed by the reviewers. Is the percent effort
listed for the PD/PI appropriate for the work proposed? Is each budget category
realistic and justified in terms of the aims and methods?
2.C.
Sharing Research Data
Data Sharing Plan: The reasonableness of the
data sharing plan or the rationale for not sharing research data will be
assessed by the reviewers. However, reviewers will not factor the proposed data
sharing plan into the determination of scientific merit or the priority score.
The presence of a data sharing plan will be part of the terms and conditions of
the award. The funding organization will be responsible for monitoring the data
sharing policy.
2.D. Sharing
Research Resources
NIH policy requires that grant awardee recipients make
unique research resources readily available for research purposes to qualified
individuals within the scientific community after publication (See NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part7.htm#_Toc54600131).
Investigators responding to this funding opportunity should include a plan for
sharing research resources addressing how unique research resources will be
shared or explain why sharing is not possible.
Program
staff will be responsible for the administrative review of the plan for sharing
research resources.
The adequacy of the resources sharing plan and any
related data sharing plans will be considered by Program staff of the funding
organization when making recommendations about funding applications. The
effectiveness of the resource sharing will be evaluated as part of the
administrative review of each Non-Competing Grant
Progress Report (PHS 2590), See Section VI.3.,
Reporting.
3. Anticipated Announcement and Award Dates
Not
Applicable.
Section VI. Award Administration Information
1. Award Notices
After the peer
review of the application is completed, the PD/PI will be able to access his or
her Summary Statement (written critique) via the NIH eRA Commons.
If the application is under
consideration for funding, NIH will request "just-in-time"
information from the applicant. For details, applicants may refer to the NIH
Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards,
Subpart A: General.
A formal notification in the form of a Notice of Award
(NoA) will be provided to the applicant organization. The NoA signed by the
grants management officer is the authorizing document. Once all administrative
and programmatic issues have been resolved, the NoA will be generated via email
notification from the awarding component to the grantee business official.
Selection of an application for award is not an
authorization to begin performance. Any costs incurred before receipt of the
NoA are at the recipient's risk. These costs may be reimbursed only to the
extent considered allowable pre-award costs. See Section
IV.5., Funding Restrictions.
2.
Administrative and National Policy Requirements
All NIH grant and cooperative agreement awards include
the NIH Grants Policy Statement as part of the NoA. For these terms of
award, see the NIH
Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards,
Subpart A: General and Part
II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions
for Specific Types of Grants, Grantees, and Activities.
3. Reporting
When multiple years are involved, awardees will be
required to submit the Non-Competing Grant
Progress Report (PHS 2590) annually and financial statements as required in
the NIH
Grants Policy Statement.
Section VII. Agency Contacts
We
encourage your inquiries concerning this funding opportunity 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:
1. Scientific/Research Contacts:
Susan
Taymans, Ph.D
Reproductive Sciences Branch, Center for Population Research
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 8B01
Bethesda, MD 20892 -7510
Telephone: (301) 496-6517
FAX: (301) 496-0962
Email: [email protected]
2. Peer Review Contacts:
Not Applicable.
3. Financial or Grants Management Contacts:
Cecilia
E. Bruce
Grants
Management Branch
National Institute of Child Health and Human Development
6100
Executive Boulevard,
Room 8A17L
Bethesda, MD 20892-7510
Telephone:
(301) 496-1304
FAX: (301)
451-5510
Email: [email protected]
Section VIII. Other Information
Required Federal Citations
Use of Animals in Research:
Recipients of PHS support for activities involving
live, vertebrate animals must comply with PHS Policy on Humane Care and Use of
Laboratory Animals (http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf)
as mandated by the Health Research Extension Act of 1985 (http://grants.nih.gov/grants/olaw/references/hrea1985.htm),
and the USDA Animal Welfare Regulations (http://www.nal.usda.gov/awic/legislat/usdaleg1.htm)
as applicable.
Human Subjects Protection:
Federal regulations (45CFR46) require that
applications and proposals involving human subjects must be evaluated with
reference to the risks to the subjects, the adequacy of protection against
these risks, the potential benefits of the research to the subjects and others,
and the importance of the knowledge gained or to be gained (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm).
Data and Safety Monitoring Plan:
Data and safety monitoring is required for all types
of clinical trials, including physiologic toxicity and dose-finding studies
(Phase I); efficacy studies (Phase II); efficacy, effectiveness and comparative
trials (Phase III). Monitoring should be commensurate with risk. The
establishment of data and safety monitoring boards (DSMBs) is required for
multi-site clinical trials involving interventions that entail potential risks
to the participants (NIH Policy for Data and Safety Monitoring, NIH Guide for
Grants and Contracts, http://grants.nih.gov/grants/guide/notice-files/not98-084.html).
Sharing Research Data:
Investigators submitting an NIH application seeking
$500,000 or more in direct costs in any single year are expected to include a
plan for data sharing or state why this is not possible (http://grants.nih.gov/grants/policy/data_sharing).
Investigators should seek guidance from their
institutions on issues related to institutional policies and local IRB rules,
as well as local, State and Federal laws and regulations, including the Privacy
Rule. Reviewers will consider the data sharing plan but will not factor the
plan into the determination of scientific merit or the priority score.
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 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 funding opportunity 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.
Sharing of Model Organisms:
NIH is committed to support efforts that encourage
sharing of important research resources including the sharing of model
organisms for biomedical research (see http://grants.nih.gov/grants/policy/model_organism/index.htm).
At the same time the NIH recognizes the rights of grantees and contractors to
elect and retain title to subject inventions developed with Federal funding
pursuant to the Bayh Dole Act (see the NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/index.htm).
All investigators submitting an NIH application or contract proposal, beginning
with the October 1, 2004 receipt date, are expected to include in the
application/proposal a description of a specific plan for sharing and distributing
unique model organism research resources generated using NIH funding or state
why such sharing is restricted or not possible. This will permit other
researchers to benefit from the resources developed with public funding. The
inclusion of a model organism sharing plan is not subject to a cost threshold
in any year and is expected to be included in all applications where the
development of model organisms is anticipated.
Inclusion of Women And Minorities in Clinical
Research:
It is the policy of the NIH that women and members of
minority groups and their sub-populations must be included in all NIH-supported
clinical research projects unless a clear and compelling justification is
provided indicating 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 clinical research should read the "NIH Guidelines
for Inclusion of Women and Minorities as Subjects in Clinical Research (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html);
a complete copy of the updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.
The amended policy incorporates: the use of an NIH definition of clinical research;
updated racial and ethnic categories in compliance with the new OMB standards;
clarification of language governing NIH-defined Phase III clinical trials
consistent with the SF424 (R&R); and updated roles and responsibilities of
NIH staff and the extramural community. The policy continues to require for all
NIH-defined Phase III clinical trials that: a) all applications or proposals
and/or protocols must 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) investigators must report annual
accrual and progress in conducting analyses, as appropriate, by sex/gender
and/or racial/ethnic group differences.
Inclusion of Children as Participants in Clinical
Research:
The NIH maintains a policy that children (i.e.,
individuals under the age of 21) must be included in all clinical research,
conducted or supported by the NIH, unless there are scientific and ethical
reasons not to include them.
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 (http://grants.nih.gov/grants/funding/children/children.htm).
Required Education on the Protection of Human
Subject Participants:
NIH policy requires education on the protection of
human subject participants for all investigators submitting NIH applications
for research involving human subjects and individuals designated as key
personnel. The policy is available at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.
Human Embryonic Stem Cells (hESC):
Criteria for federal funding of research on hESCs can
be found at http://stemcells.nih.gov/index.asp
and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html.
Only research using hESC lines that are registered in the NIH Human Embryonic
Stem Cell Registry will be eligible for Federal funding (http://escr.nih.gov). It is the responsibility
of the applicant to provide in the project description and elsewhere in the
application as appropriate, the official NIH identifier(s) for the hESC
line(s)to be used in the proposed research. Applications that do not provide
this information will be returned without review.
NIH Public Access Policy:
NIH-funded investigators are requested to submit to
the NIH manuscript submission (NIHMS) system (http://www.nihms.nih.gov)
at PubMed Central (PMC) an electronic version of the author's final manuscript
upon acceptance for publication, resulting from research supported in whole or
in part with direct costs from NIH. The author's final manuscript is defined as
the final version accepted for journal publication, and includes all
modifications from the publishing peer review process.
NIH is requesting that authors submit manuscripts
resulting from 1) currently funded NIH research projects or 2) previously
supported NIH research projects if they are accepted for publication on or
after May 2, 2005. The NIH Public Access Policy applies to all research grant
and career development award mechanisms, cooperative agreements, contracts,
Institutional and Individual Ruth L. Kirschstein National Research Service
Awards, as well as NIH intramural research studies. The Policy applies to
peer-reviewed, original research publications that have been supported in whole
or in part with direct costs from NIH, but it does not apply to book chapters,
editorials, reviews, or conference proceedings. Publications resulting from
non-NIH-supported research projects should not be submitted.
For more information about the Policy or the
submission process please visit the NIH Public Access Policy Web site at http://PublicAccess.nih.gov/ and
view the Policy or other Resources and Tools including the Authors' Manual (http://publicaccess.nih.gov/publicaccess_manual.htm).
Standards for Privacy of Individually Identifiable
Health Information:
The Department of Health and Human Services (DHHS)
issued final modification to the "Standards for Privacy of Individually Identifiable
Health Information", the "Privacy Rule", on August 14, 2002. The
Privacy Rule is a federal regulation under the Health Insurance Portability and
Accountability Act (HIPAA) of 1996 that governs the protection of individually
identifiable health information, and is administered and enforced by the DHHS
Office for Civil Rights (OCR).
Decisions about applicability and implementation of
the Privacy Rule reside with the researcher and his/her institution. The OCR
Website (http://www.hhs.gov/ocr/)
provides information on the Privacy Rule, including a complete Regulation Text
and a set of decision tools on "Am I a covered entity?" Information
on the impact of the HIPAA Privacy Rule on NIH processes involving the review,
funding, and progress monitoring of grants, cooperative agreements, and
research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.
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 PA 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.
Loan Repayment Programs:
NIH encourages applications for educational loan
repayment from qualified health professionals who have made a commitment to
pursue a research career involving clinical, pediatric, contraception,
infertility, and health disparities related areas. The LRP is an important
component of NIH's efforts to recruit and retain the next generation of
researchers by providing the means for developing a research career unfettered
by the burden of student loan debt. Note that an NIH grant is not required for
eligibility and concurrent career award and LRP applications are encouraged.
The periods of career award and LRP award may overlap providing the LRP
recipient with the required commitment of time and effort, as LRP awardees must
commit at least 50% of their time (at least 20 hours per week based on a 40
hour week) for two years to the research. For further information, please see: http://www.lrp.nih.gov.
Weekly TOC for this Announcement
NIH Funding Opportunities and Notices
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