PA-04-052: DEVELOPMENTAL MECHANISMS OF HUMAN STRUCTURAL BIRTH DEFECTS

Department of Health
and Human Services (HHS)

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DEVELOPMENTAL MECHANISMS OF HUMAN STRUCTURAL BIRTH DEFECTS RELEASE DATE: January 28, 2004 PA NUMBER: PA-04-052 (Reissued as PA-07-419) EXPIRATION DATE: February 15, 2007, unless reissued Department of Health and Human Services (DHHS) PARTICIPATING ORGANIZATION: National Institutes of Health (NIH) (http://www.nih.gov) COMPONENT OF PARTICIPATING ORGANIZATION: National Institute of Child Health and Human Development (NICHD) (http://www.nichd.nih.gov/) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.865 THIS PA CONTAINS THE FOLLOWING INFORMATION o Purpose of this PA o Research Objectives o Mechanism of Support o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements o Where to Send Inquiries o Submitting an Application o Peer Review Process o Review Criteria o Award Criteria o Required Federal Citations PURPOSE OF THIS PA The purpose of this PA is to support new, innovative, multidisciplinary, interactive, and synergistic program projects that integrate basic, translational, and clinical approaches to understanding the developmental biology and genetic basis of congenital human malformations. Each program must consist of at least three component projects. At least one 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 nonresponsive to this PA. RESEARCH OBJECTIVES Background Annually, about four percent of all live births in the United States involve babies with significant structural birth defects (more than 150,000 babies). Next to accidents, birth defects are the leading cause of death in children; they account for half of all pediatric hospitalizations. In terms of the economic costs, billions of dollars are spent over the lifetimes of children born with any of 17 major, severe, nonfatal birth defects. In sum, structural birth defects have a great impact on public health, socioeconomics, and family life. A high priority goal of NICHD's strategic plan is to address the problem of human structural birth defects. The clinical and epidemiological aspects of human malformations were addressed at a workshop in 1997. As a result of that workshop, NICHD, NIEHS, NIDCR, and the EPA issued RFA HD-99-002, "Genetic Susceptibility and Variability of Human Malformations." That initiative funded several R01s and established a basis for a network of investigators focused on the use of molecular genetic approaches to the study of genetic susceptibility and epidemiology of human malformations. A second workshop was held in 1998 and its recommendations served as the basis for RFA HD-99-008, "Developmental Mechanisms of Human Malformations", from which NICHD and NIEHS funded several P01s. An important feature of those P01s was the emphasis on integrating basic, translational, and clinical research. Combined with the R01s funded under the first initiative, these projects expanded the network of researchers focused on the study of structural birth defects. By issuing this PA, "Developmental Mechanisms of Human Structural Birth Defects," the NICHD plans to increase the number of basic scientists and clinicians involved in this network. Now that the sequencing of the human genome is complete, it is time to capitalize on the rapid advances being made in functional genomics and proteomics. Broadening the base of PIs involved in this research effort will promote the translation of these advances from the bench to the bedside. Scope The purpose of this PA 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 congenital human malformations. Of particular interest to the NICHD are applications proposing to study embryonic developmental defects of generalized body patterning and localized anomalies of the skeletal, nervous, and visceral systems that lead to clinically significant 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 PA. 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 dysmorphogenesis; and 3) examine how teratogens and nutritional deficiencies 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 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, as well as their modification by environmental agents; and 3) defective embryonic developmental processes and pathways that ultimately lead to malformations. Research projects responsive to this PA 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, 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 Development and validation of new and/or improved animal models to study the genes, mutations, mechanisms, and developmental processes and pathways that cause human malformations; o Imaging and gene expression studies to investigate and monitor the developmental pathogenesis of dysmorphic features; 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 or other structural 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 PA. Research Cores 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 cores is to enhance the progress, productivity, cost-effectiveness, and outcome of the research projects. MECHANISM OF SUPPORT This PA will use the NIH Program Project Grant (P01) award mechanism. 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 P01 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. As an applicant you will be solely responsible for planning, directing, and executing the proposed project. Guidelines for the NICHD Program Project (P01) Grant may be found at http://www.nichd.nih.gov/funding/mechanism/p01_guide.cfm. ELIGIBLE INSTITUTIONS You may submit an application if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic institutions/organizations o Foreign institutions are not eligible to apply INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research 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 programs. 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. In addition, this meeting will be attended by investigators supported through the two previous RFAs (HD-99-002, Genetic Susceptibility & Variability of Human Malformations, and HD-99-008, Developmental Mechanisms of Human Malformations). The meeting will provide an opportunity for all the 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. A data-sharing plan must be included as outlined in the recent NIH Guide notice http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-032.html. WHERE TO SEND INQUIRIES We encourage your inquiries concerning this PA and welcome the opportunity answer questions from potential applicants. Inquiries may fall into two areas: scientific/research and financial or grants management issues: o Direct your questions about scientific/research issues to: Lorette Javois, Ph.D. Developmental Biology, Genetics and Teratology Branch, Center for Developmental Biology and Perinatal Medicine National Institute of Child Health and Human Development 6100 Executive Blvd., 4B01 MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 496-5541 FAX: (301) 480-0303 Email: javoisl@mail.nih.gov o Direct your questions about financial or grants management matters to: Annette Hanopole Grants Management Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, 8A17, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 435-6975 FAX: (301) 402-0915 Email: hanopola@mail.nih.gov SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). Applications must have a Dun and Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the Universal Identifier when applying for Federal grants or cooperative agreements. The DUNS number can be obtained by calling (866) 705-5711 or through the web site at http://www.dunandbradstreet.com/. The DUNS number should be entered on line 11 of the face page of the PHS 398 form. The PHS 398 is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: GrantsInfo@nih.gov. The title and number of this program announcement must be typed on line 2 of the face page of the application form and the YES box must be checked. APPLICATION RECEIPT DATES: Applications submitted in response to this program announcement will be accepted at the standard application deadlines, which are available at http://grants.nih.gov/grants/dates.htm. Application deadlines are also indicated in the PHS 398 application kit. SPECIFIC INSTRUCTIONS FOR APPLICATIONS REQUESTING $500,000 OR MORE PER YEAR: Applications requesting $500,000 or more in direct costs for any year must include a cover letter identifying the NIH staff member within one of NIH institutes or centers who has agreed to accept assignment of the application. Applicants requesting more than $500,000 must carry out the following steps: 1) Contact the IC program staff at least six weeks before submitting the application, i.e., as you are developing plans for the study; 2) Obtain agreement from the IC staff that the IC will accept your application for consideration for award; and, 3) Identify, in a cover letter sent with the application, the staff member and IC who agreed to accept assignment of the application. This policy applies to all investigator-initiated new (type 1), competing continuation (type 2), competing supplement, or any amended or revised version of these grant application types. Additional information on this policy is available in the NIH Guide for Grants and Contracts, October 19, 2001 at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html. SENDING AN APPLICATION TO THE NIH: 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) APPLICATION PROCESSING: Applications must be mailed on or before the receipt dates described at http://grants.nih.gov/grants/funding/submissionschedule.htm. The CSR will not accept any application in response to this PA 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 a substantial revision of an application already reviewed, but such application must include an Introduction addressing the previous critique. Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within eight weeks. PEER REVIEW PROCESS Applications submitted for this PA will be assigned on the basis of established PHS referral guidelines. An appropriate scientific review group 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: o Undergo a selection process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed and assigned a priority score o Receive a written critique o Receive a second level review by the appropriate national advisory council or board. REVIEW CRITERIA Applications assigned to NICHD will be evaluated for scientific and technical merit according to the review criteria outlined in the NICHD Program Project (P01) Grant Guidelines (http://www.nichd.nih.gov/funding/mechanism/p01_guide.cfm). ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following items will 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 criteria included in the section on Federal Citations, below.) 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 Inclusion Criteria in the sections on Federal Citations, below.) CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to be used in the project, the five items described under Section f of the PHS 398 research grant application instructions (rev. 5/2001) will be assessed. ADDITIONAL REVIEW CONSIDERATIONS SHARING RESEARCH DATA: Applicants requesting more than $500,000 in direct costs in any year of the proposed research are expected to include a data sharing plan in their 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 priority score. BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. AWARD CRITERIA Applications submitted in response to a PAR will compete for available funds with all other recommended applications. The following will be considered in making funding decisions: o Scientific merit of the proposed project as determined by peer review o Availability of funds o Relevance to program priorities REQUIRED FEDERAL CITATIONS 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). SHARING RESEARCH DATA: Starting with the October 1, 2003 receipt date, 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, 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 the scientific merit or the priority score. 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 - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (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 new PHS Form 398; 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 RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy 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 and 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 that is available at 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 proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, 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 (see 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. PUBLIC 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 public 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 PA 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. 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). Those who must comply with the Privacy Rule (classified under the Rule as covered entities ) must do so by April 14, 2003 (with the exception of small health plans which have an extra year to comply). 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.

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