This Program Announcement expires on May 15, 2004, unless reissued. THE ZEBRAFISH AS AN ANIMAL MODEL FOR DEVELOPMENT AND DISEASE RESEARCH Release Date: May 16, 2001 PA NUMBER: PA-01-095 Trans-NIH Zebrafish Coordinating Committee ( National Institute of Child Health and Human Development (NICHD, National Cancer Institute (NCI, National Center for Research Resources (NCRR, National Eye Institute (NEI, National Human Genome Research Institute (NHGRI, National Institute on Aging (NIA, National Institute on Alcohol Abuse and Alcoholism (NIAAA, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS, National Institute on Deafness and Other Communication Disorders (NIDCD, National Institute of Dental and Craniofacial Research (NIDCR, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK, National Institute on Drug Abuse (NIDA, National Institute of Environmental Health Sciences (NIEHS, National Institute of General Medical Sciences (NIGMS, National Institute of Mental Health (NIMH, National Institute of Neurological Disorders and Stroke (NINDS, 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. This Program Announcement replaces PA-98-074. PURPOSE The purpose of this Program Announcement (PA) is to solicit applications as part of a National Institutes of Health (NIH) initiative to increase our support of the zebrafish as an animal model for development, organ formation, behavior, aging, and disease research. This PA is a reissuance of PA-98-074, which was published in the NIH Guide for Grants and Contracts, Vol. 5, No. 22 on May 21, 1998. This effort stems from an NIH initiative with participation of the Institutes and Centers listed above, working though the Trans-NIH Zebrafish Coordinating Committee (TZCC, under the co-chairmanship of NICHD and NIDDK. Since its formation in 1997, the committee has played an active role as an advocate for the zebrafish as an important model for development, organ formation, behavior, aging, and disease research. 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 "Healthy People 2010" at 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. Applications from new investigators are particularly encouraged. MECHANISM OF SUPPORT This PA will use the National Institutes of Health (NIH) individual research project grant (R01) award mechanism. Because the nature and scope of the research proposed in response to this PA may vary, it is anticipated that the size of awards will also vary. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. Although this PA is the result of a trans-NIH initiative, awards will be made through the Institute or Center whose mission is most closely related to the proposed work. Through TZCC, each funding component will share with the other committee members findings of research supported as a result of this PA. All investigators funded under this initiative will be expected to work together cooperatively so that the information learned will be of maximum usefulness to the community. For all competing applications requesting up to $250,000 direct costs per year, specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being examined by NIH. Complete and detailed instructions and information on Modular Grant applications can be found at Applications that request more than $250,000 in any year must use the standard PHS 398 (rev. 4/98) application instructions. RESEARCH OBJECTIVES Background The TZCC continues to play an active role as an advocate for the zebrafish model. The committee’s initial efforts resulted in RFA DK-98-006, entitled Genomic Resources for the Zebrafish, and continued with a Program Announcement, PA-98-074, entitled The Zebrafish as an Animal Model for Development and Disease Research. On May 10-11, 1999, the TZCC sponsored a workshop entitled Genomic and Genetic Tools for the Zebrafish. At this workshop, which expanded upon the Non-mammalian Models Workshop held on February 16-17, 1999, zebrafish researchers were asked to help prioritize the short- and long-term needs of the community. One result of the workshop was the recommendation that more genetic screens in the zebrafish need to be supported by the NIH. RFA-HD-00-004, entitled Mutagenesis Screens/Phenotyping Tools for Zebrafish, addressed, in part, this and some of the other recommendations made by workshop participants. Due to the response of the community to this RFA, a follow-up PA (PA-01-070, was recently released to provide an umbrella under which to continue NIH efforts to support mutagenesis screening and development of phenotyping tools for zebrafish. Since there has a been a continued interest in the further development of this animal model, the original Program Announcement, PA-98- 074, The Zebrafish as an Animal Model for Development and Disease Research, is being reissued here under the same title. Vertebrate development has been characterized extensively using the methods of classical embryology, molecular biology, and biochemistry. However, mutational analysis in vertebrates has lagged behind such investigations in invertebrates. As experimentation in Drosophila melanogaster and Caenorhabditis elegans has established, mutational studies are a powerful tool to determine the events that result in patterning and morphogenesis of the embryo. When combined with genetic combinatorial analyses, mutational analyses can identify specific genes that act during embryonic development, provide insight into how they function, and clarify the pathways in which they participate. Studies that compare results from these invertebrate systems with those obtained in vertebrates have established that there is remarkable evolutionary conservation in the genetic programs that determine embryo formation, including such early patterning events as formation of the embryonic axes, but also including later events such as development of eye, heart, and other organs. Although invertebrate systems are extremely powerful and numerous aspects of development are conserved, many aspects of patterning and morphogenesis of the vertebrate embryo are distinct and cannot be studied in invertebrates. The vertebrate embryo has many features not present in other models, including the substantially different organization and greater complexity of the nervous system, and the fact that some vertebrate organs have no clear cognates in the simpler invertebrates. Thus, understanding human development will require application of experimental approaches to the formation of the vertebrate embryo. Some assessment of mutations that affect development has been possible in the mouse, but the mouse embryo is inaccessible in utero throughout much of its development. Consequently, mutational studies in this species have been limited largely to defects in post-natal maturation. While reverse genetics (e.g., knock- outs) have been useful in the mouse model, the substantial costs of maintaining large mouse colonies have limited the applicability of forward genetic approaches, which will have a profound impact on our understanding of development. As a vertebrate, the zebrafish, Danio rerio, is more closely related to humans than are yeast, worms or flies. It has a number of valuable features as a model organism for study of vertebrate development. Many features of zebrafish development have been characterized, including early embryonic patterning, early development of the nervous system, and aspects of cell fate and lineage determination. The embryos are transparent and accessible throughout development. In live embryos, the same specific cell or even cellular processes can, in many cases, be identified from individual to individual, affording a high level of precision in characterizing the effect of developmental or genetic perturbation. Techniques for ablation and transplantation of individual cells have been used to explore questions about induction and cell fate, and continue to be refined. There are also a growing number of molecular markers to facilitate developmental studies. Because of their relatively short reproductive cycle, the large number of progeny that can be produced, and the relatively small space needed to maintain large numbers of offspring, the zebrafish is an efficient vertebrate model system for genetic analysis. It is possible to generate haploid progeny, which are viable to the point where many recessive embryonic phenotypes can be identified, and also homozygous diploid progeny that carry only maternal (or paternal) genetic information. A genetic map of approximately two - three centimorgan resolution is available, and mutations can be readily placed on the map. Positional cloning of genes identified by mutation has recently been accomplished. Finally, there are several promising methods for transformation and insertional mutagenesis which are now being developed. A number of mutagenesis screens have been performed to date and the transparent embryos examined for defects in overall embryonic pattern, morphogenesis or organ formation. These screens have identified a substantial number of mutations that affect the formation of organ systems, including defects in the nervous system, skeletal muscle, craniofacial region, kidney and endocrine organs, cardiovascular and gastrointestinal systems, and the sensory cells of lateral line systems, which are important to auditory and vestibular function. For most of these mutations, the gene defect has not yet been identified. It is likely that many of these mutations affect genes relevant to human development and aging and disease processes such as neurodegeneration and cancer. The zebrafish offers the opportunity of using classical genetics to define gene functions. Scope The NIH is interested in helping to develop and support tools to improve the ability of model organisms to elucidate the genetic and molecular mechanisms that regulate normal and abnormal biological processes. The zebrafish is one such model that holds tremendous promise to increase our understanding of vertebrate biology. The principle objective of this PA is to continue to promote the zebrafish as an animal model for the study of development, organ formation, behavior, aging, and disease research. Applications for investigator-initiated research projects that will use state-of-the-art methods, and that will develop any necessary new technologies to address well-defined hypothesis-driven research questions will be appropriate for this PA. The goals of this PA are to encourage new and innovative research and approaches using the zebrafish to identify the genes and elucidate the molecular and genetic mechanisms responsible for normal and defective development, organ formation, behavior, aging, and disease. Each of the participating Institutes and Centers has specific interests in using the zebrafish as a model system to better understand particular processes, organs or diseases. In addition, some may be interested in supporting development of methods, either general techniques or techniques that may particularly apply to their areas of interest. The participating NIH Institutes and Centers have provided a brief outline of their interests as they relate to the goals of this PA. These brief mission statements are intended to give some understanding of the breadth of the biomedical areas of interest in development of this model and are listed below in alphabetical order. Participating Institutes have included examples of research topics that are appropriate for this PA, however, they are not to be considered as exclusive or limiting. Institute and Center Statements of Interest NCI: Generation and study of zebrafish models to identify and place genes in functional pathways that affect growth and development, in particular, genes/pathways that, when altered, result in uncontrolled or cancerous growth. Identification of key sites within these pathways that could be exploited for cancer therapeutic discovery purposes. NCRR: The NCRR supports research projects that broaden the utility of the zebrafish model for cross-cutting biomedical research that is not encompassed within a single NIH Institute or Center. Interests include, but are not limited to, development of new methods for mutagenesis and/or phenotypic characterization that would be of use in research on a wide range of diseases or organs, particularly if these methods could be applied to other animal models as well as the zebrafish. NEI: Fundamental mechanisms underlying all aspects of eye development, function, and disease, including development of the retina and lens, optic nerve axon guidance, and the neural circuitry producing eye movements and oculomotor behaviors. NHGRI: Proposals for the development of high throughput, widely applicable technologies or methodologies to examine gene function on a genomic scale. This could include initial development of high throughput or large-scale methods for examining gene expression, development of tools for comprehensive mutational analysis, or genome-scale identification of regulatory regions. NIA: Basic research on the genetic and molecular basis of aging and longevity. Generation and analysis of late-age onset or long-lived mutants that can be used to identify, clone, and characterize genes involved in normal and pathological aging. Cellular and molecular function of genes expressed, for example, in the aging nervous system, cardiovascular, immune, and musculoskeletal systems. Such genes include, but are not limited to, those involved in neurodegenerative disorders, neuroplasticity, cell death, damage and repair of DNA and proteins, and oxidative metabolism, and maintenance of differentiated cell function. NIAAA: Mechanistic studies of ethanol-induced teratogenesis, behavioral impairments, and organ damage. NIAMS: Mutations that have the potential to illuminate the development and function of the vertebrate musculoskeletal system and skin. The musculoskeletal system includes muscle, bone, articulated joints, cartilage, tendon, and ligament. Priority will be given to the establishment of collaborations between investigators with expertise in the zebrafish and investigators with expertise in the musculoskeletal systems and skin of mammals and humans. NICHD: Identification, cloning, and characterization of the genes important in normal development as well as those mutant genes that cause developmental defects. Elucidation of the cellular, biochemical, molecular, and genetic mechanisms underlying normal and defective development. This includes, but is not limited to, the study of general mechanisms of pattern formation and cell lineage, neural crest development, cell specification, differentiation, migration, and fate in early development of many organs/systems such as limb, nervous system, immune system, and heart. NIDA: Identification of mechanisms underlying tolerance, sensitization, and addiction to drugs of abuse such as nicotine, amphetamine, cocaine, opiates, barbiturates, and hallucinogens. Identification of genetic suppressors and enhancers of the teratological effects of drugs of abuse on behavior and the nervous system. Processes involved in the development of brain regions mediating the hedonic properties of drugs of abuse. NIDCD: Identification and cloning of genes involved in the normal and disordered development of hearing, balance, smell, and taste sensory systems. Elucidation of the cellular, molecular, and biochemical mechanisms governing the proliferative, plastic, and regenerative capacities of these sensory cells and tissues. NIDDK: Research on diabetes, particularly studies on pancreatic beta cell function and development, obesity and mechanisms underlying satiety, other endocrine and metabolic diseases, hematologic disorders, and diseases of the digestive system, liver, kidney, and urinary tract. Studies aiming to clarify the cellular and molecular events that dictate tissue and organ formation in all these systems are considered of relevance. These studies could include, but need not be limited to, studies to develop cell lines from any of the tissues or organs of interest, studies to characterize normal or abnormal function of tissues or organs of interest, methods to screen and identify additional mutations in these systems, studies to define the molecular mechanisms that dictate cell-specific gene expression in relevant cell types. NIDCR: All aspects of normal and abnormal craniofacial development, including genetics, complex origins of craniofacial disorders, cell lineages and differentiation, cell signaling and gene regulation, embryonic patterning, imaging, biomimetics, and new technologies for high-throughput genetic and protein screens. NIEHS: Studies to examine the mechanism whereby environmental factors/agents alter any aspect of development. This includes the screening for mutants that ameliorate the toxicity of environmental agents, and the subsequent identification and characterization of the genes and pathways involved in their action. Characterization of the interactions among genetics, environmental agents, and time during development that lead to structural or functional abnormalities. Studies to examine the mechanistic pathways involved in developmental exposure to environmental agents and subsequent increased susceptibility to adult onset disease (developmental imprinting). Development of a mechanistically based model for testing environmental agents for developmental toxicity. NIGMS: Basic biomedical research that addresses fundamental biological mechanisms such as those that underlie gene regulation, chromosome organization and mechanics, cell growth and differentiation, pattern formation, sex determination, morphogenesis, cell cycle control, behavior, the genetics of complex traits, and the application of mathematical models to complex biological systems. NIMH: Investigations that examine molecular, cellular, and biochemical bases of genetic mutations affecting neurogenesis, biological rhythms, learning, memory, and other cognitive functions and behaviors of the nervous system. These studies include, but are not limited to, development of screening methods for such mutations, identification, isolation, mapping, and functional analyses of the genes underlying mutations. NINDS: Research on the development and function of the nervous system. Possible projects include, but are not limited to, studies of neurogenesis, nervous system patterning, cell lineage, cell migration, programmed cell death, axon pathfinding and regeneration, myelination, and cognitive, motor and sensory function. Analyses of mutants that may serve as models for neurological disorders are also encouraged. The areas of interest listed above are not presented in any order of priority, they are only examples of areas of research to consider. Applications representing areas of interest to more than one Institute or Center will be assigned to multiple Institutes or Centers for funding consideration. Applicants are encouraged to propose work in other areas that are related to the objectives and scope of this PA. 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, 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: 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 the Institute program staff before submitting the application, i.e., as plans for the study are being developed. Furthermore, applicants must obtain agreement from program staff that the Institute will accept the application for consideration for award. Finally, applicants must identify, in a cover letter sent with the application, the program 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. Additional information about this policy may be found in the NIH Guide for Grants and Contracts, March 20, 1998 at: SPECIFIC INSTRUCTIONS FOR MODULAR GRANT 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 Institute staff. 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 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 all 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: ( -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. 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) REVIEW CONSIDERATIONS Applications will be assigned on the basis of established PHS referral guidelines. Upon receipt, applications will be reviewed for completeness by the Center for Scientific Review (CSR). Incomplete applications will be returned to the applicant without further consideration. Applications will be evaluated for scientific and technical merit by an appropriate scientific review group convened in accordance with the standard NIH peer review procedures. As part of the initial merit review, all applications will receive a written critique and 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 or board. 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 assigning the overall score, weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative, but is essential to move a field forward. (1) Significance: Does this study 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? (2) 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? (3) 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? (4) 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)? (5) 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 accordance with NIH policy, all applications also will be reviewed with respect to the following: o The reasonableness of the proposed budget and duration in relation to the proposed research. o The adequacy of the proposed protection of human, animals, or the environment, to the extent they may be adversely affected by the project proposed in the application. AWARD CRITERIA Factors that will be used to make award decisions are as follows: o Scientific and technical merit of the proposed project as determined by peer review, o Cost effectiveness of the proposed strategy, o Promise of the proposed program to accomplish the goals of this PA and address the needs of the participating Institutes and Centers as regards their interest in the zebrafish as a model organism, o Program priorities and program balance, o Availability of funds. INQUIRIES Potential applicants are strongly encouraged to contact program staff with any questions regarding the responsiveness of their proposed project to the goals of this PA. Written and telephone inquiries concerning this PA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. A complete listing of contacts for both programmatic and fiscal/administrative inquiries may be found at: AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance Nos. 93.865, 93.396, 93.306, 93.867, 93.839, 93.172, 93.866, 93.273, 93.846, 93.173, 93.121, 93.847, 93.848, 93.849, 93.279, 93.113, 93.862, 93.242, 93.853. 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 Parts 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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