This Program Announcement expires on November 1, 2003, unless re-issued. REPRODUCTIVE GENETICS Release Date: October 25, 2000 PA NUMBER: PA-01-005 (see replacement PA-04-049) National Institute of Child Health and Human Development (http://www.nichd.nih.gov) THIS PA USES THE MODULAR GRANT AND JUST IN TIME CONCEPTS. IT INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS PA. PURPOSE The National Institute of Child Health and Human Development (NICHD) invites qualified researchers to submit new applications for research projects that address issues in reproductive genetics. The purpose of this initiative is to support new studies on the genes and genetic mechanisms influencing sex determination, human fertility, the role of differential expression of parental alleles (i.e., genomic imprinting and X-inactivation) in reproduction, and other topics in reproductive genetics. The studies targeted by this program announcement are expected to identify and characterize the relevant genes, determine their function in normal human reproduction and reproductive development, identify functional partners and the nature of their interactions, and further our understanding of the multiple adverse health consequences of mutations or dysregulation of these genes. As the human genome project nears its goal, the coding sequence of all the human genes is becoming available and the focus of research must shift from gene identification to functional genomics. Studies using innovative statistical or technical methods, such as quantitative trait locus (QTL) analysis or gene chip technology, are highly encouraged. NICHD encourages researchers interested in reproduction to lead the way in determining the functional role of genes involved in the development of the gonads and external genitalia, gametogenesis, infertility, endometriosis, polycystic ovarian syndrome (PCOS) and premature ovarian failure (POF), and reproductive aging. Studies on the genetic epidemiology of reproductive disorders, such as those listed above, must begin with the collection of large affected families for classic linkage studies, and/or QTL analysis. We also encourage research into epigenetic mechanisms crucial in embryonic development, such as the establishment and maintenance of imprinting patterns, the role of methylation in gametogenesis, the implications of imprinting for assisted reproductive technologies (ART), and the reproductive determinants and consequences of X-inactivation (or the escape from X-inactivation). HEALTHY PEOPLE 2010 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of Healthy People 2010, a PHS- led national activity for setting priority areas. This Program Announcement (PA) is related to one or more of the priority areas. Potential applicants may obtain Healthy People 2010 at http://www.health.gov/healthypeople. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, for-profit and non- profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT This Program Announcement will use the National Institutes of Health (NIH) Research Project Grant (R01) and Small Grant (R03) award mechanisms. Supplements to existing NIH grants also will be considered. Information and application instructions for the NICHD Small Grant Program are available in the NIH Guide for Grants and Contracts at: http://grants.nih.gov/grants/guide/pa-files/PAR-99-126.html. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for an application submitted in response to this PA may not exceed five years. Specific application instructions have been modified to reflect MODULAR GRANT and JUST-IN-TIME streamlining efforts being examined by the NIH. Complete and detailed instructions and information on Modular Grant applications can be found at http://grants.nih.gov/grants/funding/modular/modular.htm. RESEARCH OBJECTIVES Reproductive genetics is a broad research area, and the topics listed below are not meant to be exclusive areas of interest, but rather a sampling of the types of problems this program announcement is intended to address. The Genetics of Sex Determination Sex determination is the translation of the chromosomal sex (XX or XY) into the development of the gender-appropriate internal and external reproductive structures. The initial events of sex determination are, therefore, genetically determined. Errors in the process are fairly common and can range in severity from complete sex reversal to minor genital abnormalities. Sex determination, as an early embryological event, is a dynamic morphological process that can help us address basic questions of gene expression, cell-fate determination, and hormone signaling. Approximately one in 1,000 newborns has some abnormality of genital and/or gonadal development. In many cases, gonadal dysgenesis is one part of a larger pathologic syndrome. Examples include Frasier syndrome, Denys-Drash syndrome, campomelic dysplasia, Perrault syndrome, and Rutledge lethal multiple congenital anomaly syndrome. The genes involved in sex determination often act as growth and/or differentiation factors, and there is mounting evidence that they may be important in gonadal (or other tissue) tumorigenesis. The mechanisms involved in normal sex differentiation are not yet well defined and, while many genes are known to contribute to the process, the nature and timing of their interactions remain unclear. Studies of sex-reversed XX males revealed that the vast majority has a small piece of the Y chromosome fused to one X chromosome. Investigation of that Y translocation led to the identification of the testis-determining SRY gene. In the absence of SRY, the embryo will develop along the default or female pathway. However, the view of SRY as a switch that confers maleness is overly simplistic, as illustrated by the enormous potential for ambiguity in the sex determination process. Other autosomal genes, such as SOX-9 and WT-1, play critical roles in normal sex determination. Another sex-determining gene, Dax-1, has different effects based on the level of its expression. A functional loss of Dax-1 causes X-linked congenital adrenal hypoplasia and hypogonadotropic hypogonadism in affected males surviving to adolescence. However, duplication of Dax-1 causes dosage sensitive sex reversal despite the presence of functional SRY. Therefore, a functional copy of Dax-1 is not necessary for normal testis formation, but a double dose of Dax-1 disrupts testis formation. There is mounting evidence that the genes involved in sex determination do not cease to be important once the sexual phenotype is established. These genes may be expressed in common embryonal precursors to different organ systems, or have a broad expression pattern in many cell lineages. Many have pleiotropic effects and somatic mutations may predispose to tumor formation. For example, malignant gonadoblastomas develop in approximately 30 percent of XY females. Speculation that defects in the genes crucial to sex determination may also cause tumorigenesis is consistent with the fact that many encode growth and differentiation factors that affect cell proliferation. Such examples clearly demonstrate that the continued study of sex determination will benefit not only those born with gonadal dysgenesis, but also will advance our knowledge of the development and regulation of other organ systems. Specific topics of interest include, but are not limited to: o Identification of the target genes regulated by SRY and other related genes, o Clarification of the functional interactions between the known sex determination genes, o Cloning of genes at other chromosomal regions associated with sex reversal (human regions 2q31, 9p, 10q25, and 22q13) and discovering their function, this may entail collection of affected families and careful phenotypic description, o Human epidemiological studies, including the collection of families affected with gonadal dysgenesis, o Creation of new animal models, especially transgenic and knock-out mice, to precisely characterize the functions of sex-determination genes. Genes Regulating Fertility and Reproductive Aging Infertility is a major public health problem in our country, affecting 10-15 percent of couples, or about 2.5 million couples in the U.S. The annual cost of services to diagnose and combat infertility is now estimated at over one billion dollars. In recent years, great advances have been made in medical or surgical treatments for infertility due to hormonal and structural defects. However, these treatments do not benefit the 30 percent of couples who are infertile due to idiopathic or genetic causes. These couples may suffer through failed conventional treatments before resorting to assisted reproductive technologies (ART) to conceive their biological children. Given the problems inherent in the use of ART, it is imperative that we focus our efforts on identifying and treating the underlying causes of infertility. The most common identifiable genetic cause of human male infertility is Klinefelter’s syndrome, occurring in one in 400 live births. The causative XXY genotype results in failure of normal testicular development and infertility due to low sperm count. Another frequent cause of male infertility is mutation in the gene encoding the beta subunit of luteinizing hormone, an important factor in the spermatogenesis pathway. Recently, scientists found that a point mutation in a specific Y chromosome gene, USP9Y, can abolish spermatogenesis, leading to male infertility. USP9Y lies in the AZFc region of the Y chromosome, deletions of this region are responsible for 20 percent of all cases of infertility caused by a low sperm count. Another Y chromosome gene, Ube1y, may represent the spermatogenesis factor Spy that is deleted in some infertile men. The situation in females is more complex. Finely tuned cyclic fluctuations in hormones coordinate the follicular development, ovulation, and uterine preparation for implantation that comprise a normal menstrual cycle. This complexity suggests that there are hundreds of genes, each contributing a small effect on female fertility. Perhaps because of this complexity, little is known about the genetics of female infertility. Recently, however, one gene controlling ovulation rate and fertility in sheep was identified. This naturally occurring mutation in BMP15 (a member of the TGFbeta superfamily, also known as GDF9B) increases ovulation rate and twinning in heterozygotes, but causes sterility in homozygotes because follicles fail to mature beyond the primary stage. The human ortholog of ovine BMP15 maps to human Xp11.2- 11.4, making it a candidate for premature ovarian failure, primary and secondary amenorrhea, and twinning in humans. Polycystic ovarian syndrome (PCOS) is the most common female reproductive endocrine pathology, affecting approximately five percent of all premenopausal women. PCOS ovaries contain multiple immature follicles that are rarely ovulated. Genetic studies of PCOS are strongly suggestive of a role of the follistatin gene, with weaker evidence for disruptions of the CYP11A gene. Other, as yet unknown, genes probably contribute to PCOS as well. Endometriosis causes pelvic pain and infertility in 10-15 percent of women. There is increasing evidence that endometriosis is inherited as a complex trait, with multiple genes contributing to the eventual phenotype. Specific polymorphisms in the estrogen receptor gene, and in the detoxification system genes NAT2 and GSTM1, have been linked to endometriosis. A recent study found altered expression of HOX genes in the endometrium of affected women. Finally, a mutation in the gene encoding the beta subunit of LH was found in two women with endometriosis. Genome-wide studies have detected loss of material from chromosomes 1p and 22q in endometriotic lesions, but candidate genes have not been identified. The incidence of infertility is growing due to the increasing number of women who opt to have children later in life, and the sharp decline in female fertility with age. The genes and mechanisms contributing to reproductive aging have not been well characterized. The accumulation of chromosomal errors in oocytes contributes to age-related declines in female fertility: the majority of oocytes in women over 35 years old have defects in the second phase of meiosis. Such chromosomally aberrant oocytes fail to produce viable embryos. Further studies are necessary to follow up on recent findings in reproductive aging, such as the association of the fragile X pre-mutation with the incidence of familial premature ovarian failure. The cessation of ovarian function before the age of 40 occurs in about one percent of the general population of women. However, 16 percent of women carrying the fragile X pre-mutation experienced premature ovarian failure. Specific topics of interest include, but are not limited to: o Identifying the genes responsible for azoospermia/oligospermia in the AZF regions of chromosome Y, and elucidating their functions, o Investigations of the possible association between the use of ART, especially for cases of azoospermia/oligospermia, and resulting chromosomal aberrations or birth defects (especially of the gonads or genitourinary tract), and studies of the fertility of ART offspring, o Genetics of reproductive disorders, such as PCOS and endometriosis, including genetic epidemiology and family studies, o The role of the second X chromosome in the Klinefelter’s phenotype, especially infertility, o The mechanisms responsible for the accumulation of meiotic errors in aging oocytes, and identification of factors that impede or advance the process. Role of Differential Inheritance and Expression of Parental Alleles in Reproduction The wealth of gene sequence data generated by the Human Genome Project will significantly improve our ability to treat human genetic diseases. However, diseases caused by epigenetic defects, such as imprinting and X-inactivation, clearly demonstrate that the timing, specificity, and degree of gene expression, and even the parental origin of the gene, are critical to normal human development and continued health. These processes are intimately tied to reproduction, because the patterns are established during gametogenesis and implantation. In addition, defects in these processes may affect gametogenesis, embryogenesis, gonadal/genital development, and fertility. Imprinting refers to the phenomenon whereby only one of the two autosomal alleles is expressed and the other remains inactive, depending on its parental origin. The mechanisms responsible for establishing and maintaining imprinting are under intensive investigation. Imprints are believed to be encoded by gene methylation patterns that differ between the maternal and paternal alleles. Parental imprints from the previous generation are erased in the germ cells at an early stage of development, and then new sex-specific imprints are established, through mechanisms that remain to be elucidated. In embryogenesis, a genome-wide wave of demethylation occurs during pre- implantation, and de novo methylation of CpG islands re-establishes the pattern shortly after implantation. However, the methylation of core differential methylation regions of imprinted genes is somehow protected from both of these changes. Imprinting centers, DNA sequences in close proximity to imprinted genes, may establish the parental imprint in the germ line and maintain it post-zygotically, although the mechanism and timing of such events remain unclear. Recently, many key molecules regulating genomic methylation and transcriptional silencing have been identified. The DNA methyltransferase DNMT1 maintains methylation after each round of DNA replication. Deficiency of DNMT1 is embryonic lethal due to genome-wide demethylation, dysregulating gene expression. Methyl-CpG-binding proteins, such as MeCP2, bind to methylated DNA and recruit histone deacetylases. Hypoacetylated DNA is presumably inactive because its tightly compacted configuration renders it inaccessible to the transcriptional machinery. In addition to maintaining methylation, DNMT1 also functions in transcriptional repression through direct association with histone deacetylases. Other DNA methyltransferases, DNMT3A and DNMT3B, are the de novo methyltransferases that restore methylation following the wave of demethlyation in early embryonic development. It is not known if these molecules participate in establishing imprints in germ cells. Two human syndromes, Rett Syndrome and ICF (immunodeficiency, centromere instability, and facial anomalies) are known to result from defects in the DNA methylation process. Rett syndrome is a relatively rare X-linked dominant disorder of inappropriate gene activation due to a mutation in MeCP2. ICF is the first human genetic disorder known to involve constitutive abnormalities of genomic methylation patterns. In ICF, inactivation of DNMT3B specifically in lymphocytes results in immunodeficiency that is lethal before adulthood. It seems likely that other phenotypes will be linked to dysfunction in the methylation/deacetylation pathway, exploration of these pathways specifically in reproductive tissues is encouraged. Recent findings show that culture conditions can significantly and selectively alter the expression of imprinted genes in embryonic mice, a finding that may be critical to human in vitro fertilization protocols. There is an increasing trend among ART clinics to culture embryos for longer periods of time to ensure implantation of higher quality embryos. It is not known if loss-of-imprinting occurs under such conditions and, if so, if it is harmful to the resulting embryos. Likewise, the imprinting effects of ICSI and the use of male gametes that are not fully mature, remain to be studied. Another type of gene silencing is dosage compensation, or the inactivation of one X chromosome in females. This inactivation is usually random so that in each cell, the paternal and maternal X have an equal probability of inactivation. Some critical X-linked genes escape inactivation and are expressed from both copies of the X chromosome. Turner Syndrome, resulting from a 45, X karyotype, clearly demonstrates the importance of genes on the second X chromosome in normal ovarian development and fertility. In addition, some studies suggest phenotypic differences associated with the parental origin, or imprinting, of the one X chromosome. Genes on Xp22.3, the pseudo-autosomal region, normally escape inactivation. Gene deletions at this locus result in short stature, mental retardation, X- linked ichthyosis, and Kallmann’s syndrome. In this syndrome, loss of function of the X-linked KAL1 gene disrupts migration of the LHRH-secreting cells to the hypothalamus during embryonic development, resulting in hypogonadotropic hypogonadism, anosmia, ataxia, unilateral renal agenesis, and in males, genital abnormalities including micropenis, cryptorchidism, and testicular atrophy. The specific genes involved, and their particular roles, are unknown. Recent studies show that extreme skewing of X-inactivation can have either protective or negative effects on a variety of conditions. For example, normal mothers of girls with Rett syndrome may have the MECP mutation, but are protected from its consequences by almost 100 percent inactivation of the X chromosome carrying the mutation. On the other hand, extreme skewing of X- inactivation may also be associated with recurrent spontaneous abortion in otherwise healthy women. Intermediate phenotypes may in some cases be a result of skewed but incomplete inactivation of a mutation-bearing X chromosome. This suggests that X-inactivation and skewing may have significant effects on X-linked reproductive phenotypes. Elucidation of the basic mechanisms of imprinting, gene silencing, and X- inactivation will be crucial to clarifying the differential temporal, spatial, and developmental expression of genes involved in reproduction, this knowledge is indispensable in translating the raw human genetic code into a blueprint for human reproductive health. Specific topics of interest include, but are not limited to: o Genes and mechanisms important in erasing and re-establishing genomic imprinting and genome-wide methylation during gametogenesis and embryogenesis, o The effects of various manipulations of gametes or fertilized eggs, especially those commonly used in assisted reproductive therapies, on gene methylation patterns or the differential expression of parental alleles, o Evidence for defects in imprinting or methylation patterns in abnormal reproductive phenotypes including effects on gametogenesis, fertility, implantation, or gonadal/genital development, o The effects of targeted deletion of DNA methyltransferases, deacetylases, or associated molecules, in gametes and reproductive tissues, o Elucidation of the genetic influences on the differential survival and phenotypes of girls with Turner Syndrome, o Clarification of the genes and genetic mechanism(s) responsible for normal and skewed X chromosome inactivation, o Studies of the association between skewed X-inactivation and various reproductive manifestations, whether having protective or deleterious effects. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH-supported biomedical and behavioral research projects involving human subjects unless a clear and compelling rationale and justification are provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," published in the NIH Guide for Grants and Contracts on August 2, 2000 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html), a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm. The revisions relate to NIH defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable, and b) all investigators to report accrual, and to conduct and report analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific or ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects," published in the NIH Guide for Grants and Contracts, March 6, 1998, and available at: http://grants.nih.gov/grants/guide/notice-files/not98-024.html. Investigators also may obtain copies of these policies from the program staff listed under INQUIRIES. Program staff also may provide additional relevant information concerning the policy. URLS IN NIH GRANT APPLICATIONS OR APPENDICES All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (revised 4/98) and will be accepted at the standard application deadlines as indicated in the application kit. These forms are available at most institutional offices of sponsored research, on the Internet at http://grants.nih.gov/grants/funding/phs398/phs398.html, and from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892- 7910, telephone 301-710-0267, E-mail: grantsinfo@nih.gov. Applicants planning to submit an investigator-initiated new (type 1), competing continuation (type 2), competing supplement, or any amended/revised version of the preceding grant application types requesting $500,000 or more in direct costs for any year are advised that they must contact NICHD program staff before submitting the application, i.e., as plans for the study are being developed. Furthermore, the applicant must obtain agreement from NICHD staff that NICHD will accept the application for consideration for award. Finally, the applicant must identify, in a cover letter sent with the application, the staff member and Institute who agreed to accept assignment of the application. This policy requires an applicant to obtain agreement for acceptance of both any such application and any such subsequent amendment. Refer to the NIH Guide for Grants and Contracts, March 20, 1998 at http://grants.nih.gov/grants/guide/notice-files/not98-030.html. Application Instructions for NICHD Small Grant (R03) Applications The small grant (R03) research mechanism should be used for support of pilot studies and/or exploration of novel hypotheses and strategies that are sound and justifiable, but not sufficiently developed for the R01 mechanism. A description of the NICHD Small Grants Program and complete application instructions are available from the program contact listed under INQUIRIES and on the Internet at http://grants.nih.gov/grants/guide/pa-files/PAR-99-126.html. These applications must be submitted according to the Modular Grant application instructions included in the NICHD Small Grant program announcement. Modular Grant Application Instructions for Research Project Grant (R01) Applications The modular grant concept establishes specific modules in which direct costs may be requested as well as a maximum level for requested budgets. Only limited budgetary information is required under this approach. The just-in- time concept allows applicants to submit certain information only when there is a possibility for an award. It is anticipated that these changes will reduce the administrative burden for the applicants, reviewers, and NIH staff. The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants, with the modifications noted below. Modular Grant applications will request direct costs in $25,000 modules, up to a total direct cost request of $250,000 per year. (Applications that request more than $250,000 direct costs in any year must follow the traditional PHS398 application instructions.) The total direct costs must be requested in accordance with the program guidelines and the modifications made to the standard PHS 398 application instructions described below: o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments up to a maximum of $250,000) and Total Costs [Modular Total Direct plus Facilities and Administrative (F&A) costs] for the initial budget period. Items 8a and 8b should be completed indicating the Direct and Total Costs for the entire proposed period of support. o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD: Do not complete Form Page 4 of the PHS 398. It is not required and will not be accepted with the application. o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT: Do not complete the categorical budget table on Form Page 5 of the PHS 398. It is not required and will not be accepted with the application. o NARRATIVE BUDGET JUSTIFICATION: Prepare a Modular Grant Budget Narrative page. (See http://grants.nih.gov/grants/funding/modular/modular.htm for sample pages.) At the top of the page, enter the Total Direct Costs requested for each year. This is not a Form Page. Under Personnel, list ALL project personnel, including their names, percent of effort, and roles on the project. No individual salary information should be provided. However, the applicant should use the NIH appropriation language salary cap and the NIH policy for graduate student compensation in developing the budget request. For Consortium/Contractual costs, provide an estimate of Total Costs (Direct plus F & A) for each year, each rounded to the nearest $1,000. List the individuals/organizations with whom consortium or contractual arrangements have been made, the percent effort of key personnel, and the role on the project. Indicate whether the collaborating institution is foreign or domestic. The total cost for a consortium/contractual arrangement is included in the overall requested modular direct cost amount. Include the Letter of Intent to establish a consortium. Provide an additional narrative budget justification for any variation in the number of modules requested. o BIOGRAPHICAL SKETCH: The Biographical Sketch provides information used by reviewers in the assessment of each individual"s qualifications for a specific role in the proposed project, as well as to evaluate the overall qualifications of the research team. A biographical sketch is required for all key personnel, following the instructions below. No more than three pages may be used for each person. A sample biographical sketch may be viewed at: http://grants.nih.gov/grants/funding/modular/modular.htm. - Complete the educational block at the top of the Form Page, - List position(s) and any honors, - Provide information, including overall goals and responsibilities, on research projects ongoing or completed during the last three years, - List selected peer-reviewed publications, with full citations. o CHECKLIST: This page should be completed and submitted with the application. If the F&A rate agreement has been established, indicate the type of agreement and the date. All appropriate exclusions must be applied in the calculation of the F&A costs for the initial budget period and all future budget years. o The applicant should provide the name and telephone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. Submission Instructions The title and number of the program announcement must be typed on line 2 of the face page of the application form and the YES box must be marked. For R01 applications, submit a signed, typewritten original of the application, including the Checklist, and five signed photocopies in one package to: CENTER FOR SCIENTIFIC REVIEW NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) For R03 applications, submit a signed, typewritten original of the application, including the Checklist, and three signed photocopies in one package to: CENTER FOR SCIENTIFIC REVIEW, at address listed above. At the time of submission, two additional copies of the R03 application should be sent to: L. R. Stanford, Ph.D. Director, Division of Scientific Review National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 5E03, MSC 7510 Bethesda MD 20892-7510 Rockville MD 20852 (for express/courier service) REVIEW CONSIDERATIONS Applications will be assigned on the basis of established PHS referral guidelines. Upon receipt, applications will be reviewed for completeness by the NIH Center for Scientific Review (CSR). Applications that are complete will be evaluated for scientific and technical merit by an appropriate peer review group convened in accordance with NIH peer review procedures. As part of the initial merit review, all applications will receive a written critique and may undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed, assigned a priority score, and receive a second level review by the appropriate national advisory council. Review Criteria The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments reviewers will be asked to discuss the following aspects of the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in the assignment of the overall score, weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. o Significance: Does the proposal address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? o Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? o Innovation: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? o Investigator: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the Principal Investigator and other researchers (if any)? o Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements ? Is there evidence of institutional support? In addition to the above criteria, in accordance with NIH policy, all applications also will be reviewed with respect to the following: o The adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects also will be evaluated. o The reasonableness of the proposed budget and duration in relation to the proposed research. o The adequacy of the proposed protection for humans, animals or the environment, to the extent that they may be adversely affected by the project proposed in the application. AWARD CRITERIA Applications will compete for available funds with all other recommended applications. The following will be considered in making funding decisions: Quality of the proposed project as determined by peer review, availability of funds, and program priority. INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Susan Taymans, Ph.D. Reproductive Science Branch, Center for Population Research National Institute of Child Health and Human Development 6100 Executive Blvd., Room 8B01, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 496-6517 FAX: (301) 496-0962 Email: TaymansS@mail.nih.gov Direct inquiries regarding fiscal matters to: Mary Ellen Colvin Grants Management Branch National Institute of Child Health and Human Development 6100 Executive Blvd., Room 8A17J, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 496-1304 FAX: (301) 402-0915 Email: ml70m@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.864. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, and portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.


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