Part I Overview Information


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 (R03)

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 R03, R21, and R01 grant 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-06-347

Catalog of Federal Domestic Assistance Number(s)
93.865

Key Dates
Release/Posted Date:  April 12, 2006
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#reviewandawardCouncil 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 funding opportunity  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 Small Research Grant (R03) award mechanism.  The applicant will be solely responsible for planning, directing, and executing the proposed project.

This FOA 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). All applications submitted in response to this FOA must use the modular budget format. Specifically, since 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).

Competing renewal (formerly “competing continuation”) applications will not be accepted for the R03 grant mechanism. Small grant support may not be used for thesis or dissertation research. Up to two resubmissions (formerly “revisions/amendments") of a previously reviewed small grant application may be submitted. See NOT-OD-05-046, April 29, 2005.  

For specific information about the R03 programs, see: http://grants.nih.gov/grants/funding/r03.htm

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.

A project period of up to two years and a budget for direct costs of up to two $25,000 modules, or $50,000 per year, may be requested (i.e., a maximum of $100,000 over two years in four modules of $25,000 each). Commensurate F &A costs are allowed.

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 Directory/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 301-435-0714, Email: GrantsInfo@nih.gov.

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 R03 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#reviewandawardCouncil 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 Guide (MS Word or PDF are to be followed, with the following requirements for R03 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 (See the NIH Grants Policy Statement  http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm#_Toc54600131). Investigators responding to this funding opportunity should include a sharing research resources plan 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 R03 small grant is a mechanism for supporting discrete, well-defined projects that realistically can be completed in two years and that require limited levels of funding.  Because the research plan is restricted to 10 pages, a small grant application will not have the same level of detail or extensive discussion found in an R01 application. Accordingly, reviewers should evaluate the conceptual framework and general approach to the problem, placing 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 from investigator-generated data. Preliminary data are not required, particularly in applications proposing pilot or feasibility studies.

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

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 SF 424 (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 SF 424 (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 SF 424 (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/archive/grants/policy/nihgps_2003/index.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 will be considered by Program staff of the funding organization when making recommendations about funding applications. Program staff may negotiate modifications of the data and resource sharing plans with the awardee before recommending funding of an application. The final version of the data and resource sharing plans negotiated by both will become a condition of the award of the grant. 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.”

Model Organism Sharing Plan:   Reviewers are asked to assess the sharing plan in an administrative note. The sharing plan itself should be discussed after the application is scored. Whether a sharing plan is reasonable can be determined by the reviewers on a case-by-case basis, taking into consideration the organism, the timeline, the applicant's decision to distribute the resource or deposit it in a repository, and other relevant considerations. For the R03 mechanism, the presence or adequacy of a plan should not enter into the scoring of the application.

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/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: Taymanss@mail.nih.gov 

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: brucec@mail.nih.gov

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/archive/archive/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.



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NIH Funding Opportunities and Notices


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