COMPARATIVE MOUSE GENOMICS CENTERS CONSORTIUM Release Date: December 16, 1999 RFA: ES-00-005 National Institute of Environmental Health Sciences Letter of Intent Receipt Date: May 12, 2000 Application Receipt Date: July 20, 2000 PURPOSE The National Institute of Environmental Health Sciences (NIEHS) invites applications for cooperative agreements (U01s) from groups of investigators who are capable of, and interested in, becoming components of the Comparative Mouse Genomics (CMG) Centers Consortium. The purpose of implementing this Consortium is to develop mouse models for studying the biological function of genetic variants of DNA repair and cell cycle control genes found in the human population. Mutant mice, protocols, assays, assessment criteria, and other materials and information generated in projects funded under this RFA will be made available to the wider biomedical community for further investigation or application. To accomplish this, the NIEHS will select, as components of the Consortium, groups of investigators whose scientific and technical expertise will enable them to derive the models, characterize them thoroughly, and validate them for various aspects of basic, clinical or applied research. The approaches used for generating, characterizing, and validating the mice will reflect the blend of experience and creativity of the CMG Consortium component groups, and will be originated by these investigators. They will contribute to the CMG Consortium their collective knowledge of mouse genetics, experimental genetic manipulation of mice and phenotypic and genotypic analyses of the resulting strains, genomics, animal husbandry, mouse and human pathology. Through formation of the CMG Consortium, the component groups will have access to resources, information, technologies, ideas, and expertise that are beyond the scope of any single research team. The goals of the CMG Consortium are: 1) to choose which models to derive de novo; 2) to choose which mouse models to characterize fully for their relevance to environmental health; and 3) to define the standards by which to validate the models for their relevance to human disease. The activities of the CMG Consortium will be coordinated with: (1) the National Center for Research Resources (NCRR)-Sponsored Mutant Mouse Regional Resource Centers (See RFA: RR 99-001, https://grants.nih.gov/grants/guide/rfa-files/RFA-RR-99-001.html), (2) the facilities established in response to RFA MH-99-007 AMouse Mutagenesis and Phenotyping: Nervous System and Behavior (see https://grants.nih.gov/grants/guide/rfa-files/RFA-MH-99-007.html), and (3) RFA HD-99-007 AMouse Mutagenesis and Phenotyping: Developmental Defects@ (see https://grants.nih.gov/grants/guide/rfa-files/RFA-HD-99-007.html ). The NCRR centers are being developed as regional distribution facilities capable of husbandry, cryopreservation, phenotypic characterization, genetic quality control, and maintenance of a mouse resource database. Further information about NIH initiatives on mouse genomics and genetics resources is available at the following Internet site: http://www.nih.gov/science/models/mouse. 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 Request for Applications (RFA), Comparative Mouse Genomics Centers Consortium, is related to the priority area of environmental health. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474- 0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202 512-1800) http://odphp.osophs.dhhs.gov/pubs/hp2000. ELIGIBILITY REQUIREMENTS Cooperative agreement (U01) 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, eligible agencies of the Federal government, and small businesses. Applications may represent a single institution, or may involve several institutions or organizations. Applications will not be accepted from foreign institutions, however, foreign institutions may establish sub-contract arrangements with domestic applicant institutions. Applications from minority individuals, women, and persons with disabilities as principal investigators are encouraged. MECHANISM OF SUPPORT The administrative and funding instrument to be used for this program will be a cooperative agreement (U01), an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIEHS scientific and/or programmatic involvement with the awardee is anticipated during performance of the activity. Under the cooperative agreement, the NIEHS purpose is to support and/or stimulate the recipient's activity by involvement in, and otherwise working jointly with, the award recipient in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Details of the responsibilities, relationships and governance of the study to be funded under cooperative agreement(s) are discussed later in this document under the section "Terms and Conditions of Award.@ Grants funded under this program must be interdisciplinary efforts bringing together investigators from different scientific disciplines. In order to be funded, each applicant must successfully meet the requirements as stated below: o Applicants must include expertise in transgenic technologies, mouse genetics and pathology, genomics, biostatistics, and at least two researchers with scientific expertise in the biology of the genes and gene products targeted for study (DNA repair and/or cell cycle control genes). o Applicants must include an administrative core to include: an information transfer activity, a Steering Committee liaison activity, and a technology transfer activity. FUNDS AVAILABLE The NIEHS anticipates making up to five U01 awards for project periods of five years. U01 application budgets may not exceed $700,000 direct costs in the first budget period. Should an applicant plan to include subcontracts to other institutions or organizations, only the direct costs associated with the subcontracts will be used to tally the direct costs that apply toward the cap of $700,000. For further budget information, see the "APPLICATION PROCEDURES" section. The NIEHS intends to commit $5 million dollars (Total Costs, including facilities and administrative costs) to fund applications in response to this RFA. The number of U01 awards and level of support depend upon receipt of a sufficient number of U01 applications of high scientific merit. Although this program is provided for in the financial plans of the NIEHS, U01 awards pursuant to this RFA are contingent upon the availability of funds for this purpose in fiscal year 2001. The anticipated award date is April 1, 2001. It is possible that new applications in other categories of genes (i.e., apoptosis and cellular differentiation, signal transduction mechanisms, and drug metabolizing enzymes) may be supported in future years, depending upon the success and the needs of the CMG Consortium, and the availability of funds. RESEARCH OBJECTIVES Background In March 1998, the NIH Director convened an External Advisory Group on Priority Setting for Mouse Genomics and Genetics Resources. The full report of this meeting can be obtained from the NIH web site (http://www.nih.gov/welcome/director/reports/mgenome.htm). Following some of the recommendations of this group, the NIEHS proposes the establishment of Comparative Mouse Genomics (CMG) Centers Consortium to address specifically the functional analysis of human genes associated with human-exposure diseases. The NIEHS Environmental Genome Project (see http://www.niehs.nih.gov/envgenom/home.htm) is founded on the sound scientific concept that the genetic makeup of an individual person is major factor in human disease resulting from exposure to environmental agents. The project long-term goal is to characterize specific genetic variations, or polymorphisms, that contribute to either resistance or susceptibility to environmentally induced diseases. NIEHS is collaborating with other NIH institutes in the discovery of single nucleotide polymorphisms in approximately 500 genes that might be relevant to understand human diseases resulting from exposure to environmental agents. NIEHS has decided to concentrate on studying the biological significance of the genetic variants in five categories of genes: DNA repair, cell cycle control, drug metabolizing enzymes, apoptosis and differentiation, and signal transduction mechanisms responsible for the regulation of the other categories of genes. To understand the functional significance of human polymorphic variants in the environmental responsive genes (ERG), the NIEHS will support the development of new research centers, to produce novel transgenic and knockout mouse models which will mirror specific human ERG polymorphic variants found in the general population. For the purposes of responding to this RFA, a research group will focus its activities on the development of novel models in DNA repair and/or Cell Cycle Control genes. Objectives and Scope Although many mice have been designed or engineered to ask specific mechanistic questions about the functions of single genes, the constraints of limited time and funding often do not permit an in-depth, comprehensive analysis and characterization of their phenotype and genotype. The NIH supports many individual projects that involve the derivation or study of mice that develop specific diseases. However, at the present time, the NIH does not support a coordinated, collaborative effort to produce highly accurate mouse models of environmentally induced human diseases, particularly for the early design, derivation, characterization, and validation phases of model building, and to ensure that the models and the data relevant to them are readily available to the research community for further investigation or application. The intent of this initiative is to assemble from U01 grants, a cross-disciplinary, multi-institutional Consortium whose component teams of investigators will derive or refine mouse models of environmentally-relevant human diseases, provide a comprehensive analysis of their phenotype and genotype, and validate them for their use by the research community for a variety of investigations. The CMG Consortium should improve access to information, resources, ideas, expertise, and technology beyond the scope of any single group, and should impact the entire scientific community. The CMG centers, working under the umbrella of a consortium, will function as centralized facilities for: o Comparative alignment of human-mouse sequence analyses. o Development of cloning-sequencing-vector construction strategies. o Production of transgenic and knockout animals and maintenance of breeding colonies. o Development, characterization, maintenance, and distribution of ES cell lines. o Identification of mouse lines suitable for tissue-specific and inducible mutagenesis. o Validation of the Cre-Lox system, and other novel approaches for targeted mutagenesis. o Development and distribution of relevant databases and other materials. A plan to make these animals and materials available to the scientific community must be included in the application. The transgenic and knockout mice expressing specific genes produced by the CMG Consortium might be used by the scientific community-at large to study disease sequelae due to specific insults, including: exposure to environmental agents, viruses, nutritional factors, pharmacological drugs, and other physical and chemical stresses. This comparative genomics strategy of using transgenic technologies to study human gene function has a high potential to be successful due to the increasingly detailed knowledge of functional homologies of proteins encoded by mouse and human genes. The CMG Consortium, when implemented from the component funded U01 grants, will through its Steering Committee: o set the priorities for the models which should be derived, o select those which should be comprehensively characterized and refined, o determine the parameters by which the models will be validated (standards for pathology, genotype, phenotype, etc.), o identify technological impediments for accurate model design, o select strategies for implementation or development to surmount them, o determine when a model is sufficiently characterized and validated so that the model itself, and all available accompanying data, can be distributed to the research community for individual investigator-initiated projects. To implement this initiative, the NIEHS will select up to five multi-disciplinary teams. Each team will be a self-assembled group of collaborating investigators (at one or several sites) with specific expertise in transgenic technology development and scientific knowledge in DNA repair and/or cell cycle control genes. It is anticipated that an applicant team will incorporate an appropriate mix of expertise, including, but not limited to: transgenic technologies, mouse genetics and genomics, mouse pathology; animal husbandry, and mouse models of human disease, computational and structural biology, bioinformatics, statistics, and expertise on the cellular and molecular biology of the genes and gene products chosen for investigation. SPECIAL REQUIREMENTS FOR THE RFA I. Definitions ARBITRATION PANEL: A panel that is formed to review any scientific or programmatic disagreement (within the scope of the U01 award), between U01 awardees and the NIEHS. The panel will be composed of three members: one selected by the Steering Committee (without NIEHS staff voting), or by an individual U01 awardee in the event of an individual disagreement; a second member selected by the NIEHS; and, the third member selected by the two prior selected members. AWARDEE: The institution to which a cooperative agreement (U01) is awarded. COOPERATIVE AGREEMENT (U01): An "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIEHS scientific and/or programmatic involvement with the awardee is anticipated during performance of the activity. Under the cooperative agreement, the NIEHS purpose is to support and/or stimulate the recipient's activity by involvement in, and otherwise working jointly with, the award recipient in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. CONSORTIUM: The Comparative Mouse Genomics Centers Consortium, which will have as its components the funded U01 grants. MOUSE TASK FORCE: A committee of NIEHS/NIH staff. The task force will meet regularly to review the progress of the Consortium, and to recommend to the NIEHS Program Director new scientific and technological advances that could enhance the goals of the Consortium. Non-government experts may be added to the Task Force to enhance the scientific expertise of the group. NIEHS PROGRAM DIRECTOR: A scientist administrator of the NIEHS extramural staff. The NIEHS Program Director will provide normal stewardship for the U01 grants awarded under this RFA, as well as have substantial scientific and programmatic involvement to assist, guide, coordinate, and participate in the conduct of the Consortium activities. The NIEHS Program Director will evaluate and implement the advice and recommendations of the Steering Committee for allocating NIH support. PRINCIPAL INVESTIGATOR (PI): The investigator who is designated by the applicant organization to direct the project to be supported by the U01 grant in response to this RFA. The PI will assume responsibility and accountability to the applicant organization officials and to the NIEHS for the performance and proper conduct of the research supported by the U01 in accordance with the terms and conditions that are stated in the RFA. The PI will coordinate the activities of the U01 with the Consortium, and will be one of two investigators from the U01 to serve as a voting member of the Steering Committee. STEERING COMMITTEE: This committee will be the main governing body of the Consortium. Its voting members will include the PI and an additional senior investigator from each U01, and up to three members of the Mouse Task Force. The Steering Committee will meet twice a year. The initial planning meeting will take place in the Research Triangle Park, NC, with subsequent meetings at a location that the Steering Committee selects and with which the NIEHS concurs. NIEHS/NIH representation on the Steering Committee will never make up a majority of the total number. II. Special Application Format The PHS 398 application must be used for this RFA, and the format must be modified as described under "APPLICATION PROCEDURES." III. Terms and Conditions of Award The following terms and conditions will be incorporated into the U01 award statement, and will be provided to the PI and the awardee institutional official at the time of award. These special Terms of Award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS Grant Administration Regulations at 45 CFR Parts 74 and 92, and other HHS, PHS, and NIH Grant Administration policy statements. [Part 92 applies when state and local governments are eligible to apply as a "domestic organization."] 1. The administrative and funding instrument used for the applicants to this program is a cooperative agreement (U01), an "assistance" mechanism (rather than an "acquisition" mechanism) in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during performance of the activity. Under the cooperative agreement, the NIH purpose is to support and/or stimulate the recipient's activity by involvement in and otherwise working jointly with the award recipient in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Consistent with this concept, the dominant role and prime responsibility for the activity resides with the awardee(s) for the project as a whole, although specific tasks and activities in carrying out the studies will be shared among the awardees and the NIEHS through the Steering Committee. 2. Awardee Rights and Responsibilities The PI will coordinate project activities scientifically and administratively at the awardee institution and at the other sites that may be supported by sub-contracts to this award. The PI of a U01 grant will have primary authority and responsibility to define objectives and approaches, and to plan, conduct, analyze, and publish results, interpretations, and conclusions of studies conducted under the terms and conditions of the cooperative agreement award. The PI will assume responsibility and accountability to the applicant organization officials and to the NIEHS for the performance and proper conduct of the research supported by the U01 in accordance with the terms and conditions of the award. o The PI, and another senior investigator from the U01, will serve, as voting members of the Steering Committee, and will attend the Steering Committee meetings. o The PI will be responsible for accepting and implementing the goals, priorities, procedures, and policies agreed upon by the Steering Committee. o The PI of a U01 will be responsible for close coordination and cooperation with the other components of the Consortium, the Steering Committee, and with the NIEHS staff. o The PI will submit periodic progress reports in a standard format, as agreed upon by the Steering Committee. o Awardees will retain custody of, and have primary rights to, the data developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies. Investigators conducting biomedical research frequently develop unique research resources. The policy of the PHS is to make available to the public the results and accomplishments of the activities that it funds. o All awardees must adhere to PHS policy for the distribution of unique research resources produced with PHS funding that was published in the NIH Guide for Grants and Contracts (NIH Guide, Vol. 25, No. 23, July 12, 1996), and is available at the following Internet address: https://grants.nih.gov/grants/guide/notice-files/not96-184.html Awardees specific plans for distribution of data and mouse models, produced as a result of their participation in this Consortium, will be incorporated into the Terms and Conditions of the Awards. The NIEHS reserves the right to require the transfer of appropriate mouse stocks, related reagents, and pertinent data that are generated as the result of participation in research supported under these awards to an eligible third party, in order to preserve the mouse models and data about them and/or to continue the research. Third parties supported under these awards must be informed of this right. Effective conduct of the Consortium goals will require considerable electronic communication of data and other information among the Consortium components and between the components and the NIEHS. Awardees are responsible for developing or enhancing their Internet communication tools to ensure effective communication among the different components that form the U01 grant (such as, sub-contracts, individual core facilities at the institution), the Consortium members, and with NIEHS. 3. NIEHS Extramural Staff Responsibilities The NIEHS Program Director will provide normal stewardship for the U01 awards under this RFA, as well as have substantial scientific and programmatic involvement to assist, guide, coordinate, and participate in the conduct of the Consortium activities. The NIEHS Program Director will coordinate and facilitate the Consortium programs, will attend and participate in all meetings of the Consortium Steering Committee, and will provide liaison between the Steering Committee, the Consortium, and the NIEHS/NIH. The Program Director will also coordinate the activities of the Consortium with the activities of the other facilities established under the Trans-NIH mouse genetics and genomics initiatives. The NIEHS Program Director will regularly consult with the Mouse Task Force on the scientific progress of the Consortium. The Mouse Task Force members will have access to progress reports and other relevant information submitted by U01 awardees. The NIEHS Program Director will assist the Steering Committee in developing and drafting operating policies and policies for dealing with recurring situations that require a coordinated action. The NIEHS Program Director will review the scientific progress of individual U01 grants, and review them for compliance with the operating policies developed by the Steering Committee. The Program Director may recommend withholding support, re-allocating support among awardees, and suspension or termination of a U01 award for lack of scientific progress or failure to adhere to policies established by the Steering Committee. NIEHS/NIH staff with relevant scientific expertise, or who manage research grant programs that relate scientifically to the goals of the Consortium will form the Mouse Task Force. The Group will meet regularly to review the progress of the Consortium, and to recommend to the NIEHS Program Director scientific developments and opportunities that may enhance the achievement of the Consortium goals. 4. Collaborative Responsibilities Steering Committee The representatives from the U01 grants that comprise the Consortium and representatives from the Mouse Task Force will be responsible for forming a Steering Committee as defined below. An arbitration system, as detailed below, will be available to resolve disagreements between the NIEHS Program Director and the members of the Steering Committee. The Steering Committee will be the main governing board of the Consortium. It will function to set priorities for model derivation, define the parameters for model validation, identify technological impediments to success and strategies to overcome them, and decide when models should be made available to the research community for individual investigator-initiated projects. The Steering Committee will be composed of the PI and a Co-PI or other senior investigator from each U01 and up to three members of the Mouse Task Force. The two investigators from each U01 and the members of the Mouse Task Force will each have one Steering Committee vote. The chairperson, who will be someone other than an NIEHS/NIH staff member, will be selected by the Steering Committee. The NIEHS Program Director is not a member of the Steering Committee, but will facilitate creation of the group and will attend all meetings. NIH staff may not serve as the Committee chair. The Steering Committee may, when it deems it to be necessary, invite additional, non-voting scientific advisors to the meetings at which research priorities and opportunities are discussed. The NIEHS reserves the right to augment the scientific or consumer expertise of the Consortium when necessary. There will be two Steering Committee meetings annually. The initial planing meeting will be organized by NIEHS, but subsequent meetings will be organized by the Steering Committee. The committee=s chair will schedule the meetings and will be responsible for developing meeting agendas (in collaboration with the Program Director), chairing the meetings, and producing Steering Committee=s reports. The first meeting of the Consortium will be a Planning Meeting, which will take place in the Research Triangle Park, NC very shortly after award of the U01 grants. At the Planning Meeting, the Steering Committee will be formed and select a chairperson from among the members who represent the U01 awardees. At the Planning Meeting, the Steering Committee may: o draft a charter to detail policies and procedures, a process for monitoring compliance with the policies and procedures, and a process for recommending that the NIEHS Program Director act on evidence of non-compliance of any Consortium component with Steering Committee policies; o agree upon the terms of the charter; o discuss the models and approaches that were proposed in the U01 applications, and any relevant new information, and set initial priorities for the models to be derived and for new technologies to be developed; o discuss and set initial genotypic and phenotypic parameters required to characterize the models and to define their comparability to human diseases; o discuss and set initial standards for validating the models for further biological studies. o discuss and set procedures for recommending to the Program Director, themes or scientific areas for solicitation of pilot projects from Consortium members, and establish guidelines for providing peer review of such pilot studies. At their first meeting each year, the Steering Committee may formulate plans for any workshops or symposia to be held. It will discuss and recommend to the Program Director areas or themes for pilot projects. The pilot projects will be peer reviewed following the procedures established by the Steering Committee, and awards will be made with funds set aside for this program. At the second and subsequent meetings, the Steering Committee will: 1) refine the Consortium scientific objectives, 2) define the characterization and validation strategies, and 3) identify available models with sufficient promise for further testing, or define those human diseases for which models must be created de novo. At any time during the Consortium project, the Steering Committee may examine the characterization and validation data for models derived by the Consortium components, and decide when a model is sufficiently validated that it may be distributed to the research community for further investigations or applications. The Steering Committee may recommend one or several workshops a year, or at different frequencies, to which non-Consortium participants may be invited to enable the Consortium to explore scientific or technological innovation that occurs during the course of the project. These meetings will serve to inform the research community of the progress made toward derivation or refinement of models, their characterization and validated uses, and any technological advances related to design and derivation of mouse models. The organization of the workshops and symposia will be the responsibility of the Consortium members. NIEHS may provide supplemental funds to the selected host institution, after the receipt of an appropriate application and reviewed by the Steering Committee. Applicants must budget for travel and per diem expenses for Steering Committee meetings. In the first year, applicants should plan for two investigators, the principal investigator and an additional senior investigator, to attend a Planning Meeting and two Steering Committee meetings. In the second and subsequent years, applicants should plan for the PI and another investigator to attend two Steering Committee meetings per year. Applicants must budget for travel and per diem expenses for participation in Consortium workshops and symposia. Applicants should plan that at least five investigators will attend a workshop or symposium every year in years two through five. The Steering Committee may establish subcommittees. The NIEHS Program Director and the other NIEHS/NIH staff who are Steering Committee members may serve on subcommittees, as they deem appropriate. 5. Arbitration Process Any disagreement that may arise on scientific/programmatic matters (within the scope of the U01 award), between U01 awardees and the NIEHS may be brought to arbitration. An arbitration panel will be composed of three members: one selected by the Steering Committee (without NIH representatives voting), or by the individual U01 awardee in the event of an individual disagreement; a second member selected by the NIEHS; and, the third member selected by the two prior selected members. For U01 awardees, this special arbitration procedure in no way affects the awardee's right to appeal an adverse action that can otherwise be appealed in accordance with the PHS regulations at 42 CFR Part 50, Subpart D and HHS regulation at 45 CFR Part 16. 6. Yearly Milestones and Evaluations Awardees will finalize yearly milestones at the time of their awards. The awardees= milestones will be provided to the Steering Committee. It is expected that the milestones will be adjusted annually at the award anniversary dates, both to incorporate a group=s scientific accomplishments and progress in the field in general, as well as to reflect the recommendations of the Steering Committee. In accord with the procedures described above, NIH may withhold or reduce funds for projects that substantially fail to meet their milestones or to maintain their research activities as state-of-the-art. Specific issues related to cooperative agreements must also be addressed as follows: Plan to Share Research Resources and Intellectual Property Rights NIH is interested in ensuring that the research resources developed through this RFA become readily available to the research community. Applicant institutions should present their intellectual property policies and practices. A description of plans for handling intellectual property resulting from the studies or for commercialization of any discoveries should be included in the application. This is expected to include an elaboration of the applicant=s anticipated plans to generate, or not generate, patents and/or exclusive or non-restrictive licensing of biomaterials and other patentable subject matter created with funds provided under this RFA. This plan is also expected to include disclosure of any pre-existing intellectual property rights, including options to for-profit research sponsors, that are associated with biomaterials and data that might be generated. The initial review group will make an administrative comment on the adequacy of the proposed plan for sharing and data access. NIEHS Program Staff will consider the adequacy of the plan in determining whether the grant shall be awarded. The sharing plan as approved, after negotiation with the applicant when necessary, will be a condition of the award. It is expected that this plan include all elements of the guidelines developed by NIH and the Department of Energy (DOE) to address the special needs of genome research. These guidelines call for material and information from genome research to be made available within six months of the time the data or materials are collected, and are available at: http://www.nhgri.nih.gov:80/Grant_info/Funding/Statements/. Where appropriate, awardees may work with the private sector to make unique resources available to the biomedical research community at a reasonable cost. Applicants are reminded that the awardee institution is required to disclose each subject invention to NIH within two months after the inventor discloses it in writing to the awardee institutional office responsible for patent matters. The awarding Institute reserves the right to monitor awardee activity in this area to ascertain if patterns or patent applications are adversely affecting the goals of this RFA. RESEARCH INVOLVING HUMAN SUBJECTS The primary objective of this RFA is to derive mouse models for environmental health research. Therefore, there may be instances in which applicants must collect or use pathology specimens derived from human subjects, or clinical or epidemiological data from projects involving human subjects, to inform the design of the models or to derive the standards that validate them as models of human diseases. In those instances, the NIH policies below apply and must be addressed in the application. 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 sub-populations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is 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", which were published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994, and are available at the following Internet address: https://grants.nih.gov/grants/guide/notice-files/not94-100.html INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that children (i.e., individuals under the age of 21) must be included in all human subject 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 was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following Internet address: https://grants.nih.gov/grants/guide/notice-files/not98-024.html and https://grants.nih.gov/grants/funding/children/children.htm. LETTER OF INTENT Prospective applicants are asked to submit by May 12, 2000, a letter of intent that includes: 1) a descriptive title of the proposed research; 2) the name, mailing address, telephone number, and email address of the Principal Investigator, 3) identities of other key personnel and participating institutions, and 4) the number and title of this RFA. Although a letter of intent is not required, is not binding, and does not enter into the review of subsequent applications, the information allows NIEHS staff to estimate the potential review workload and to avoid conflict of interest in the review. The letter of intent is to be sent (by mail, FAX, or email) to: J. Patrick Mastin, Ph.D. Scientific Review Administrator Scientific Review Branch Office of Program Operations Division of Extramural Research and Training National Institute of Environmental Health Sciences P. O. Box 12233, 111 Alexander Drive Research Triangle Park, North Carolina 27709 Tel. 919-541-1446 Fax: 919-541-2503 E-mail: mastin@niehs.nih.gov APPLICATION PROCEDURES Applicants for U01 grants must use the research grant application form PHS 398 (rev. 4/98), with the modified format that is described below. Application 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, Email: GrantsInfo@nih.gov. 1. General Application Format Instructions Administrative Core It is the intent of this RFA to support cutting edge research activities integrated into an interdisciplinary program. To ensure this goal, NIEHS requires the establishment of an Administrative Core. The Administrative Core will provide supportive structure sufficient to ensure accomplishment of the following: o planning and coordination of research activities, o fiscal and resource management planning, o information dissemination planning, o technology transfer planning. This core will provide leadership, ensure the integration of the program, and serve as a resource to the program in administrative matters. It is anticipated that this core will be composed of the principal investigator, a co-principal investigator, and an administrative staff. One individual would be assigned the responsibility for information transfer and dissemination. This individual would be the point of contact for NIEHS staff for coordinating written documents about the program. To further support the program=s goal in technology transfer, NIEHS recommends that the program designate an individual to promote technology transfer for the program. The responsibilities of this person would be to seek opportunities for applying research findings with appropriate audience. This may exist as a formal technology transfer activity, where the person would coordinate with the institution=s established office of technology transfer, or less formal arrangements where the individual would seek opportunities for partnership in advancing the science from the laboratory into application. The principal investigator will be the liaison between the program, the Steering Committee, and the NIEHS. The responsibilities of the principal investigator and co-principal investigator are detailed elsewhere in this document. Research Plan An integrated application, presenting a comprehensive and cross-disciplinary team approach, should be prepared in response to this RFA. The form PHS 398 should be modified as follows. The "Research Plan", sections a. to d., should be divided into four parts. The number of pages allowed for the "Research Plan" is increased from 25 to 40 pages; budget pages, budget justifications, and letters from collaborators and consultants and their biosketches are not included in this limit. For U01 applicants who do not request funds to support the activities in a particular part of the application, the applicants should indicate the source of funds (institutional, R01, P01, P30, etc.) that permit them to accomplish the project goals. The U01 applications should also have individual budgets for any sub-contracts proposed. The sub-contract budget should be a separate page, and the sub-contract indirect costs should be calculated and listed in the usual place as part of the direct costs in the composite budget. However, only the direct costs associated with each sub-contract will count toward the direct cost cap of $700,000 on the budget for the first year. The total costs for the U01 applications are not capped. Part 1. INFRASTRUCTURE. In this part of the "Research Plan", applicants should detail the specialized or unique facilities, fundamental infrastructure, research expertise, and core resources and services that are available to support the planned mouse model derivation, characterization, and validation. If facilities at more than one institution are required, applicants should thoroughly describe them, and obtain the appropriate assurances. The roles and expertise of all key personnel, collaborators, and consultants who are associated with this part of the application should be well documented; letters from collaborators and consultants and their biosketches should directly follow this part of the application. Part 2. MODEL DERIVATION. In this part of the "Research Plan," applicants should describe their rationale for the design and derivation of a new mouse model or models, or for altering and improving an existing model or models, based on their experience with mouse models of human disease, and their knowledge of basic and clinical research. Applicants should clearly explain their choice of genes to study. However, the models presented in the applications that are funded will be reviewed by the Steering Committee to determine which ones the Consortium will use. Applicants should describe the extent to which they plan to characterize any models they derive or refine; the methods that they will use to characterize the models; the rationale for choices of methods; and, how generally applicable the methods are, or will be, for all mouse models. In this part as well, applicants are expected to identify the standards they will apply to validate a model or models; the rationale for the choices; how generally applicable the validation standards are, or will be, for all mouse models; and, the purpose(s) for which they anticipate their models may be used. The roles and expertise of all key personnel, collaborators, and consultants who are associated with this part of the application should be thoroughly documented; letters from collaborators and consultants and their biosketches should directly follow this part of the application. Applicants must include expertise in transgenic technologies, mouse genetics and pathology, genomics, biostatistics, and at least two researchers with scientific expertise in the biology of the genes and gene products targeted for study (DNA repair and/or cell cycle control genes). Part 3. NEW TECHNOLOGY. In this part of the "Research Plan," applicants should define new technological approaches they will use, or any technology that they propose to develop, to achieve the goals of model derivation or refinement, characterization, and validation. The roles and expertise of all key personnel, collaborators, and consultants who are associated with this part of the application should be thoroughly documented. Letters from collaborators and consultants and their biosketches should directly follow this part of the application. Part 4. INTERACTIONS WITH OTHER CONSORTIUM COMPONENTS. In this part of the "Research Plan," applicants should describe how they believe their unique blend of experience can contribute to the collective efforts of the Consortium. They should identify potential pilot projects for research or technology development that they believe should be goals of the Consortium after it has been assembled from the U01 components. Applicants should not plan to budget any funds for collective Consortium pilot projects. During the second and subsequent years of the program, Consortium members will be able to submit applications for pilot studies to be funded from the set aside funds. Pilot project funds will be used to pursue scientific goals, such as high-risk technology development, that should be joint efforts pursued by the Consortium. At its first meeting every year, the Steering Committee will recommend to the Program Director scientific areas or themes for solicitation of pilot projects for that year. The pilot projects submitted by Consortium members will be peer reviewed following procedures established by the Steering Committee, and those judged to be highly meritorious will be funded from the set aside funds. The number of pilot projects to be awarded each year will be determined by the quality to the applications and the availability of funds for that purpose. In this part of the "Research Plan," applicants should describe their experience with, and capability for, Internet-based communication, and their ideas about how to facilitate electronic communication and other interactions among the Consortium components and the NIEHS. Applicants should state their willingness to collaborate and share data freely with the other Consortium components, to participate in planning and attending workshops and symposia, to serve on the Steering Committee and be bound by its decisions, particularly those which relate to setting priorities for model development and the standards for characterization and validation, and to be able and willing to share data and communicate with each other and the NIEHS in an Internet environment. Applicants should also describe how they would comply with the involvement of the NIEHS Program Director, and how they will fulfill the responsibilities of Consortium components to work together cooperatively. Additional Materials to Include in the Application Applicant institutions should submit in an APPENDIX their intellectual property policies and practices. A description of the plans to share materials and data, as well as plans for handling intellectual property resulting from the studies or for commercialization of any discoveries, should be included in this section. The RFA label available in the PHS 398 (rev. 9/95) application form must be affixed to the bottom of the face page of the application. 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, "Comparative Mouse Genomics Centers Consortium", and number, RFA ES-00-005 must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA number must be typed on the label as well. The sample RFA label is available at: https://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to allow for this change. Please note this is in pdf format. U01 applicants should submit a typewritten, signed original of the application, including the checklist, and 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 the time of submission, two additional signed photocopies of the application must also be sent to: J. Patrick Mastin, Ph.D. Scientific Program Administrator Scientific Review Branch Office of Program Operations Division of Extramural Research and Training National Institute of Environmental Health Sciences P. O. Box 12233, 111 Alexander Drive, EC-24 Research Triangle Park, North Carolina 27709 Applications must be received by July 20, 2000. If a U01 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 U01 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 a substantial revision of an application already reviewed, but such an application must follow the guidance in the PHS Form 398 application instructions for the preparation of revised applications, including an introduction addressing the previous critique. REVIEW CONSIDERATIONS General Considerations All U01 applications will be judged on the basis of the scientific and technical merit of the proposed project and the documented ability of the investigators to meet the "RESEARCH OBJECTIVES" of the RFA as presented in the four components of the Research Plan. Although the technical merit of the proposed protocol is important, it will not be the sole criterion for evaluation of a study. Other considerations, such as the multi-disciplinary nature of the studies, the appropriateness of the proposed Administrative Core, and the adequacy of the proposed plan for sharing and data access will be part of the evaluation criteria. Review Method Upon receipt by the Center for Scientific Review (CSR), U01 applications will be reviewed for completeness; incomplete applications will be returned to the applicant without further consideration. Complete applications will be reviewed for responsiveness by NIEHS staff. If an application is not responsive to the RFA, NIEHS staff will contact the applicant to inform him/her of that decision and will return the application. 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 NIEHS in accordance with the review criteria stated below. There will be no site visits. As part of the initial merit review, a process will be used by the initial review group in which applications 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 the applications under review, will be discussed, and assigned a priority score. All applications will receive a second level review by the National Advisory Environmental Health Sciences Council. Review Criteria The criteria to be used in the evaluation of grant applications are listed below. To put those criteria in context, the following information is contained in instructions to the peer reviewers. The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. The reviewers will comment on the following aspects of the application in their written critiques 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 by the reviewers 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 a 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. Applicants are encouraged to submit and describe their own ideas about how best to meet the goals of the Consortium, and are expected to address issues identified under "SPECIAL REQUIREMENTS FOR THE RFA." The peer review group will comment on each of the four sections of the Research Plan (Infrastructure, Model Derivation, New Technology, and Interactions with Other Consortium Components). The peer review group will assess the merit of the applications and related factors, including: 1. Significance: Do the model or models proposed for derivation/characterization/validation address an important need for the environmental health research community. What is the immediacy of the research opportunity? Over the project period, is there potential for the group to develop models other than those specified in the application? 2. Approach: Are the conceptual framework, design, methods, and analyses adequately developed and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? Can these approaches be used to derive mouse models for other diseases in addition to those proposed? Are the parameters chosen to characterize the model(s) sufficient and appropriate? Are these parameters generally applicable to all mouse models? Are the standards chosen to validate the model(s) for its relevance to a human disease adequate? Are these standards generally applicable to all mouse models? 3. Innovation: Does the project employ novel concepts, approaches or method? Is the project original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? Will the approaches advance the field of mouse transgenics or other model development? 4. Investigators: Are the principal investigator and his/her collaborators appropriately trained and well suited to carry out this work? To what extent do these investigators have the necessary complementary skills? Have collaborations been established or consultants identified to provide the appropriate depth and breadth of scientific expertise required for the project? Will this team of investigators contribute unique skills to the overall Consortium? Factors considered to be important for review include demonstrated expertise in transgenic technologies, mouse genetics, genomics, and pathology, as applied to the design and derivation of mouse models of human disease; a multi- disciplinary team of collaborators; substantial interactions among collaborating researchers; demonstration of appropriate facilities and resources; willingness to share data and reagents freely. In addition, the reviewers will take into consideration the demonstrated expertise of the applicant group in the biology of the gene and gene products chosen for investigation. For example, a group proposing development of models involving DNA repair genes, should demonstrate substantial expertise in the field of DNA repair, including, but not limiting to, having a minimum of two researchers with current external funding (preferable from NIH) and current peer review publications. 5. Environment: Are the facilities for mouse maintenance and experimentation appropriate to support the endeavor? 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 and incorporate the best use of collaborative arrangements? Is there evidence of institutional support? Additional Considerations 6. Interactions: Are there adequate plans for effective interaction and coordination between Consortium components and the NIEHS? Do the investigators state their willingness to collaborate extensively and share information fully? Do the investigators state their willingness to abide by the priorities and policies agreed upon by the Steering Committee? Have the applicants proposed sound strategies for communication among themselves, with the other Consortium components, and with the NIEHS? 7. Budget: Does the apportionment of the budget among fundamental infrastructure, model development, characterization, and validation, and technology development indicate that the applicants understand the requirements of managing this sort of model-building enterprise? AWARD AND SELECTION CRITERIA The NIEHS intends to choose the programs which will collectively provide for the Consortium the most creative approaches to mouse model design, and the range of research experience, technology, and resources to ensure that the models that are validated as appropriate for various aspects of research are derived rapidly. U01 applications recommended by the National Advisory Environmental Health Sciences Council (NAEHSC) will be considered for award based upon: (a) scientific and technical merit, (b) importance of the proposed models for enhancing NIEHS mission, (c) the adequacy of the proposed plans for sharing resources and data access, and (d) the availability of funds. SCHEDULE Letter of Intent Receipt: May 12, 2000 Application Receipt Date: July 20, 2000 Review by NAEHSC: February 2001 Earliest Award Date: April 1, 2001 INQUIRIES Due to the unusual application format and complexity of this RFA, the NIEHS encourages potential applicants to take the opportunity to clarify any issues or questions. Written and telephone inquiries concerning the RFA are welcome. Direct inquiries regarding programmatic issues to: Jose M. Velazquez, Ph.D. Scientific Program Administrator Chemical Exposures and Molecular Biology Branch Office of Program Development National Institute of Environmental Health Sciences P.O. Box 12233, 111Alexander Drive Research Triangle Park, NC 27709 Telephone: (919)541-4998 FAX: (919) 316-4606 Email: Velazqu1@niehs.nih.gov Direct inquiries regarding fiscal matters to: Ms. Laura Williams Grants Management Specialist Grants Management Branch Office of Program Operations National Institute of Environmental Health Sciences P. O. Box 12233, 111 Alexander Drive Research Triangle Park, North Carolina 27709 Telephone: (919) 541-7629 FAX: (919) 541-2860 Email: Willia27@niehs.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No.93.113,93.114, and 93.15. 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 Parts 52 and 45 CFR Part 74 [and Part 92 when applicable for State and Local governments]. 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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