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Developmental mechanisms of human structural birth defects.

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.

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, the National Institute of Child Health and Development (NICHD), the National Institute of Environmenal Health Sciences (NIEHS), the National Institute of Dental and Craniofacial Research (NIDCR), and the U.S. Environmental Protection Agency (U.S. 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.

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: 1) 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; 2) Studies of transcription factors regulating gene expression and temporal and spatial expression patterns during normal and abnormal embryonic development; 3) Studies of developmental genes, gene products, transcription factors, and growth factors that function and interact to regulate cell proliferation, cell differentiation, apoptosis, call migration, and cell fate in embryonic development; 4) Examination of genes and molecular mechanisms and interactions that control normal and abnormal body axes and symmetry during development; 5) 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; 6) Investigations of pharmaceutical, nutritional, and teratogenic agents and factors that alter genes and developmental processes and pathways that result in dysmorphologies; 7) Investigations to characterize and classify genotype/phenotypes of hereditary human malformations and correlate them to homologs in animal models; 8) Efforts to define pleiotropic effects that genes and their modifiers have in the spatial and temporal development of embryonic and/or fetal anomalies; 9) 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; 10) Imaging and gene expression studies to investigate and monitor the developmental pathogenesis of dysmorphic features; 11) Investigations of the role of imprinting and epigenetic factors in the development of major congenital malformations; 12) 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 in neural tube or other structural defects; 13) 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; 14) Elucidation of the underlying genetic and molecular mechanisms that alter normal developmental processes in drug-induced (e.g., Accutane, Thalidomide) malformations; 15) 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.

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.

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/ dsr_p01_guide.htm.

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/noticefiles/NOT-OD-03-032.html.

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 he 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, 301-435-0714, e-mail: GrantsInfo@nih.gov.

The title and number of this PA must be typed on line 2 of the face page of the application form and the YES box must be checked.

Applications submitted in response to this PA 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.

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.

Contact: Lorette Javois, Developmental Biology, Genetics and Teratology Branch, Center for Developmental Biology and Perinatal Medicine, NICHD, 6100 Executive Blvd, 4B01 MSC 7510, Bethesda, MD 20892-7510 USA, 301- 496-5541, fax: 301-480-0303, e-mail: javoisl@mail.nih.gov
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Title Annotation:Fellowships, Grants & Awards
Publication:Environmental Health Perspectives
Date:Mar 15, 2004
Words:2045
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