DEVELOPMENTAL MECHANISMS OF HUMAN MALFORMATIONS Release Date: October 15, 1999 RFA: HD-99-008 National Institute of Child Health and Human Development National Institute of Environmental Health Sciences Letter of Intent Receipt Date: February 1, 2000 Application Receipt Date: March 22, 2000 PURPOSE The National Institute of Child Health and Human Development (NICHD) and the National Institute of Environmental Health Sciences (NIEHS) invite new, innovative, multidisciplinary, and synergistic program project (P01) grant applications that integrate basic and clinical approaches to study the developmental biology and molecular genetics of human malformations. This RFA is designed to exploit the use of animal models to elucidate the molecular and genetic bases of human malformations. The purpose is to encourage applications that will capitalize on the latest knowledge of structural, functional, and comparative genomics, proteomics, and biotechnology to dissect and unravel the complex developmental biological processes, pathways, genetics, and molecular mechanisms responsible for human structural birth defects. The objective is to enhance our knowledge and understanding of normal and abnormal embryonic and fetal development, and of the etiology and pathogenesis of human malformations. Each program project application must include interrelated basic, translational, or clinical component projects addressing a common central theme, research focus, or objective. This strategy is intended to maximize the opportunities for translating the basic findings from animal studies into clinical applications in humans. This initiative was developed primarily in response to a 1998 NICHD-sponsored workshop focusing on the developmental biology and genetics of structural birth defects in animal models and humans. The RFA will serve as a major component of a high-priority NICHD strategic plan to address the important public health problem of human birth defects. It will also enhance the strategy of the President’s Task Force on Children’s Environmental Health and Safety Risks to prevent developmental disorders associated with environmental factors. The most important long-term goal of this RFA is to translate the advances in basic biomedical science into molecular and genetic diagnostic tests, safe and efficacious therapeutic interventions, and effective and economic strategies for preventing birth defects. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This RFA is related to one or more of the priority areas. Potential applicants may obtain "Healthy People 2000" at http://odphp.osophs.dhhs.gov/pubs/hp2000. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic 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. Foreign institutions are not eligible to apply. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators/Program Directors. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) program project grant (P01) award mechanism. Responsibility for the planning, direction, and execution of the proposed projects will be solely that of the applicant. The total project period for an application submitted in response to this RFA may not exceed five years. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. The P01 supports broadly based multidisciplinary research programs that have a well-defined central research focus or objective. An important feature is that the interrelationships among the individual projects will result in a greater contribution to the overall program goals than if each project were pursued independently. The program project grant requires a minimum of three interrelated individual research projects that contribute to the overall program objective. At least one component project must be translational or clinical in nature. The application may request support for certain common core resources. Complete guidelines for the NICHD Program Project Grant may be found at: http://www.nichd.nih.gov/funding/mechanism/p01_guide.cfm. See also, APPLICATION PROCEDURES, below. FUNDS AVAILABLE The NICHD intends to commit approximately $5 million and the NIEHS intends to commit approximately $1 million in total costs (direct plus Facilities and Administrative) in FY 2001 to fund new grants in response to this RFA. It is anticipated that approximately six new awards will be made (five by the NICHD and one by the NIEHS). An applicant may request a project period of three to five years, and a budget for direct costs of up to $750,000 in the first year, excluding facilities and administrative costs (F&A) on consortium/contractual arrangements. Applicants may request no more than $4 million in direct costs over the five-year award period. Because the nature and scope of the research proposed may vary, it is anticipated that the size of awards also will vary. Although this program is provided for in the financial plans of the NICHD and NIEHS, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of applications of outstanding scientific and technical merit. RESEARCH OBJECTIVES Background In the United States, birth defects are the leading cause of infant mortality, accounting for one in five infant deaths. It is estimated that more than 120,000 babies in the United States (about three to four percent of all live births) are born with major birth defects each year. Birth defects account for half of all pediatric hospital admissions and, next to accidents, are the leading cause of death in children. Moreover, the estimated lifetime cost of children born each year with any of 17 major birth defects costs the U.S. economy billions of dollars. Considering the great impact of structural birth defects on public health, socioeconomics, and family life, the Center for Research for Mothers and Children (CRMC), NICHD, convened two workshops to address this significant problem. The purpose was to develop a comprehensive program and strategy to support epidemiological, basic, translational, and clinical research on human congenital malformations. The ultimate goal of this strategy is to translate the research findings into improved diagnostic techniques, safe therapeutic interventions, and effective prevention strategies for human malformations. The workshops reviewed the current knowledge of structural birth defects, identified gaps in our understanding, and recommended and prioritized areas of future research. The first workshop, in October 1997, addressed the clinical and epidemiological aspects of human malformations. At the workshop, participants identified a timely opportunity and need to use molecular genetic approaches to study the genetic susceptibility and epidemiology of human malformations. In response, on May 25, 1999, the NICHD, NIEHS, and co-sponsoring Institutes and agencies, issued RFA HD-99-002, "Genetic Susceptibility and Variability of Human Malformations." Recommendations from the second NICHD workshop, held in July 1998, served as the basis of the present solicitation. This workshop focused on basic studies of genes, molecular mechanisms, and biological processes responsible for normal and abnormal early development in animal models and humans. Moreover, the workshop affirmed that conservation of genes during evolution and recapitulation during embryonic and fetal development make animal models indispensable for understanding normal and abnormal development in humans. After receiving an update on the progress of the Human Genome Project, the workshop participants reviewed specific genes, gene/environmental interactions, environmental factors, teratogens, and developmental processes that cause structural birth defects in animal models and humans. They explored how the genomic information emerging from the Human Genome Project can be exploited to study normal and abnormal early development. For example, they emphasized how structural, comparative, and functional genomic databases and genetic, physical, and functional maps are critical for identifying genes, polymorphisms, and genotype/phenotype relationships and for elucidating the pathogenesis of structural birth defects. Furthermore, the participants expressed how the revolutionary advances in biotechnology will provide the tools for discovering new genes, dissecting underlying molecular mechanisms, and unraveling the etiopathogenesis of many human malformations. While a number of diverse recommendations emerged from this workshop, one recommendation was to establish and support interdisciplinary and integrated bench-to-bedside basic and clinical research projects on human malformations. In addition to the second NICHD workshop, the current RFA was encouraged in 1998 by an NICHD-sponsored symposium on "Genomics in Birth Defects Research" and the report by the President’s Task Force on Children’s Environmental Health and Safety Risks entitled "An Initiative to Prevent Developmental Disorders Associated with Environment Factors." The program project mechanism was selected because it is ideal for combining multiple clinical and basic component projects with a central theme, focus, or objective, and for fostering interactions and collaborations between basic and clinical scientists. Furthermore, the nucleus of multidisciplinary scientists in each program project will provide a fertile environment for cross-training basic and clinical scientists. Research Scope The purpose of this RFA is to support new, innovative, multidisciplinary, interactive and synergistic program projects that integrate basic, translational, and clinical approaches to understand the developmental biology and genetic basis of congenital human malformations. Each program project must consist of at least three component projects and include both basic science and clinical component projects. At least one component project must be clinical or translational in nature. The component projects must share a common central theme, focus, or objective on a specific developmental defect or malformation that is genotypically, mechanistically, biologically, or phenotypically analogous or homologous in both animal models and humans. Any non-mammalian or mammalian animal model may be used, as long as it contributes to the common overall theme or objective of the program project. If the component projects do not share a common developmental gene, process, mechanism, pathway, or phenotype, the application will be considered non- responsive to this RFA. Of particular interest to the NICHD are applications to study embryonic developmental defects of generalized body patterning and localized dysmorphic anomalies of the skeletal, nervous, and visceral systems that lead to clinically significant and major congenital structural malformations. While applications focusing on developmental disorders that result in mental retardation and related neurobehavioral disabilities are of interest to the NICHD, they are outside the scope of this RFA. The NIEHS is especially interested in research projects that study the mechanisms and pathogenesis of how environmental exposure to physical and chemical agents alter embryonic and fetal development and result in human malformations. Prior to preparing an application, it is important to ascertain that the proposed research is within the mission and areas of interest of the NICHD or NIEHS. For clarification, the potential applicant is strongly encouraged to consult NICHD and NIEHS program staff listed under INQUIRIES, below, before submitting a Letter of Intent. The basic science component projects may include studies to: 1) identify and characterize the genes, gene products, mutations, polymorphisms, multigene and gene/environment interactions that play a role in normal and abnormal embryonic patterning and organogenesis, 2) elucidate the developmental biological processes and pathways, the biochemical, cellular, molecular, genetic mechanisms, and spatial and temporal gene expression patterns which are involved in dysontogenesis, and 3) examine how teratogens, nutritional deficiencies, and environmental factors disrupt or modify gene expression and basic developmental processes. The translational/clinical component projects may include studies to: 1) characterize and classify genotypes and phenotypes of human malformations that are comparable in the animal models being examined, 2) develop physical, genetic, and comparative maps for genes involved in human malformations, 3) identify the developmental genetic processes and molecular pathogenesis of human malformations utilizing animal models, and 4) develop innovative molecular genetic methods, technologies, and strategies to enhance the diagnosis and methods for intervention of the human malformations. Applicants are encouraged to incorporate the recent scientific advances in developmental biology and genetics in their projects and to utilize the many research resources, bioinformatic databases, and biotechnological tools in their research cores. The research cores should be structured to share work effort and research resources (e.g., biotechnology, high-throughput instrumentation, microarrays, oligonucleotide chips, animal model development, and technical assistance) among the research projects. The aim of the core is to enhance the progress, productivity, cost-effectiveness, and outcome of the research projects. Applications may include new and innovative approaches to investigate: 1) genetic defects, nutritional deficiencies, teratogens, or environmental chemicals or factors that perturb, modify, or alter gene expression during early development, 2) the identity and function of transcription and growth factors in normal and abnormal gastrulation, embryogenesis, organogenesis, and patterning, and 3) defective embryonic developmental processes and pathways that ultimately lead to malformations. Research projects responsive to this RFA include, but are not limited to, the following: o Investigations on the identity, characteristics, and mechanisms of growth factors and growth factor receptors that function in embryonic development and dysmorphogenesis of the skeletal, nervous, and visceral systems, o Studies of transcription factors regulating gene expression and temporal and spatial expression patterns during normal and abnormal embryonic development, o Studies of developmental genes, gene products, transcription factors, and growth factors that function and interact to regulate cell proliferation, cell differentiation, apoptosis, cell migration, and cell fate in embryonic development, o Examination of genes and molecular mechanisms and interactions that control normal and abnormal body axes and symmetry during development, o Studies to identify, map, and characterize genes that play a role in: signal transduction and biochemical pathways, cell fate determination, gastrulation, embryogenesis, organogenesis, body patterning and how developmental defects, mutations, or susceptible polymorphisms lead to malformations, o Investigations of pharmaceutical, nutritional, environmental, and teratogenic agents and factors that alter genes and developmental processes and pathways that result in dysmorphologies, o Investigations to characterize and classify genotype/phenotypes of hereditary human malformations and correlate them to homologs in animal models, o Efforts to define pleiotropic effects that genes and their modifiers have in the spatial and temporal development of embryonic and/or fetal anomalies, o Studies on the interaction between toxic and environmental factors and modifiers of gene expression, o Development and validation of new and/or improved animal models to study the genes, mutations, mechanisms, environmental factors, and developmental processes and pathways that cause human malformations, o Imaging and gene expression studies to investigate and monitor the developmental pathogenesis of dysmorphologies, o Investigations of the role of imprinting and epigenetic factors in the development of major congenital malformations, o Studies on nutritional factors (e.g., folic acid deficiency) and teratogens (e.g., retinoids and valproic acid) affecting gene/gene, gene/receptor, gene/modifier, and gene/teratogen interactions that lead to neural tube defects, o Examination of the role and developmental biology of neural crest cells in normal embryonic development and how defects in cell proliferation, differentiation, migration, and patterning may result in major structural birth defects, o Elucidation of the underlying genetic and molecular mechanisms that alter normal developmental processes in drug-induced (e.g., Accutane, Thalidomide) malformations, o Identification and characterization of polymorphisms/mutations of metabolic genes that function in the development of structural birth defects. The topics listed above are only examples, are not in priority order, and are not intended to be all-inclusive. Investigators are encouraged to explore and develop new, innovative projects and research cores that are consistent with the overall objectives of this RFA. SPECIAL REQUIREMENTS The Program Director for the overall grant and the principal investigator for each component project should plan to attend an annual NIH-sponsored two-day meeting in Bethesda, MD. This meeting will be attended by investigators supported through this RFA and through the earlier RFA on genetic susceptibility and variability of human defects. The meetings will provide an opportunity for these investigators to communicate, discuss the progress of their research, exchange ideas and information, share resources, and foster collaborations that are relevant to the research goals of the NICHD birth defects initiative. This requirement is designed to establish an interactive network of investigators who are interested in multidisciplinary approaches to enhancing our understanding of the epidemiology, etiology, pathogenesis, and developmental biology and genetics of structural birth defects. All applications should include a request for funds to support attendance of the Program Director and project principal investigators at the annual meetings, as well as a statement of agreement to participate in these meetings and to cooperate with investigators at other program project sites. 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 "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research," published in the Federal Register of March 28, 1994 (FR 59 14508- 14513) and in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994, and available at: http://grants.nih.gov/grants/guide/notice-files/not94-100.html. LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes a descriptive title of the proposed research, the name, address, e-mail, telephone and fax number of the Program Director, and the identities of other key personnel and participating institutions. Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows NICHD and NIEHS staff to estimate the potential review workload and avoid conflict of interest in the review. The letter of intent is to be sent by February 1, 2000 to Dr. Allan Lock at the address listed under INQUIRIES. APPLICATION PROCEDURES The research grant application form PHS 398 (rev.4/98) is to be used in applying for these grants. Applications kits are available at most institutional offices of sponsored research and may be obtained 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: [email protected], and on the Internet at: http://grants.nih.gov/grants/funding/phs398/phs398.html . Application Instructions Applicants for P01 grants must follow special application guidelines in the NICHD PROGRAM PROJECT (P01) GUIDELINES (June 1998) that is available from NICHD program staff listed under INQUIRIES. The guidelines are also available on the Internet at: http://www.nichd.nih.gov/funding/mechanism/p01_guide.cfm. These guidelines contain important information on the suggested format of applications and on review criteria. For the purposes of this RFA, each core must be utilized by two or more component projects at all times during the period of award. This is an exception to the NICHD P01 Guidelines stating that each core should be utilized by three or more component projects. Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. If so, a letter of agreement from either the GCRC Program Director or Principal Investigator could be included with the application. Submission Instructions The RFA label available in the PHS 398 (rev. 4/98) application form must be stapled to the bottom of the face page of the application and must display the number of this RFA, HD-99-008. A sample modified RFA label is available at http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. Submit the signed, typewritten original of the application, including the Checklist, plus three 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) At time of submission, two additional copies of the application and all five sets of any appendices should be sent to: Director Division of Scientific Review National Institute of Child Health and Human Development Executive Building, Room 5E03, MSC 7510 6100 Executive Boulevard Bethesda, MD 20892-7510 Rockville, MD 20852 (for express/courier service) Telephone: (301) 496-1485 FAX: (301) 402-4104 Applications must be received by March 22, 2000. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications previously reviewed, but such applications must include an introduction addressing the previous critique. NIH policy permits a component research project of a multi-project grant application to be concurrently submitted as a traditional individual research project (R01) application. If, following review, both the multi-project application and the R01 application are found to be in the fundable range, the investigator must relinquish the R01 and will not have the option to withdraw from the multi-project grant. This policy is intended to preserve the scientific integrity of a multi-project grant, which may be seriously compromised if a strong component project(s) is removed from the program. Investigators wishing to participate in a multi-project grant must be aware of this policy before making a commitment to the Program Director and applicant institution. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by CSR and for responsiveness to the RFA by the NICHD and NIEHS staff. Incomplete and/or non- responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NICHD in accordance with the review criteria stated below. As part of the initial merit review, a process may be used by the initial review group in which all applications receive a written critique and undergo a process in which only those applications with the highest scientific and technical merit will be discussed, assigned a priority score, and receive a second level review by the National Advisory Child Health and Human Development (NACHHD) Council or the National Advisory Environmental Health Sciences (NAEHS) Council. Applications will not be reviewed by a site visit team. Review Criteria For program projects, peer review of scientific and technical merit focuses on three areas: 1) review of the individual component projects, 2) review of the individual cores, and 3) review of the program as an integrated effort and the overall merit of the program. The review criteria to be used to evaluate applications submitted in response to this RFA are presented in APPENDIX II, GUIDELINES FOR REVIEWERS COMMENTS, of the NICHD PROGRAM PROJECT (P01) GUIDELINES (June 1998), available at: http://www.nichd.nih.gov/funding/mechanism/p01_guide.cfm. SCHEDULE Letter of Intent Receipt Date: February 1, 2000 Application Receipt Date: March 22, 2000 Peer Review Date: May 2000 Council Review: September/October 2000 Earliest Anticipated Start Date: December 1, 2000 AWARD CRITERIA Funding decisions will be based on the following: o Scientific and technical merit of the proposed program as determined by peer review, o Cost effectiveness of the proposed strategy, o Program priorities and program balance, o Promise that the proposed program will accomplish the goals of this RFA, o Availability of funds. INQUIRIES Written and telephone inquiries concerning this RFA are strongly encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Contact information for inquiries regarding both programmatic and fiscal issues may be found at: http://www.nichd.nih.gov/rfa/HD-99-008/HD-99-008.htm. AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.865 (Research for Mothers and Children, NICHD) and No. 93.113 (Biological Responses to Environmental Health Hazards, NIEHS). Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78- 410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74. 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, 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.

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