MUTANT MOUSE REGIONAL RESOURCE CENTERS Release Date: January 22, 1999 RFA: RR-99-001 - (Reissued as RFA-RR-09-003) P.T. National Center for Research Resources Letter of Intent Receipt Date: February 23, 1999 Application Receipt Date: March 25, 1999 PURPOSE In response to recommendations of the NIH meeting on "Priority Setting for Mouse Genomics and Genetics Resources" and to pressures created by the great increase in the numbers of genetically altered mice used by the biomedical research community, the National Center for Research Resources (NCRR) invites applications for cooperative agreements (U42) to support Mutant Mouse Regional Resource Centers (MMRRCs). These Centers will enhance the availability of, and help to ensure the quality of, genetically altered mice. The MMRRCs will be coordinated and linked electronically, and will include a coordinated database characterizing the animals. Each MMRRC will be capable of maintaining and providing animals, cryopreserving, storing and reconstituting embryos, and of supporting these activities with the necessary administrative and quality control infrastructure. Because of their regional nature, responsiveness to specific needs, and interrelatedness, these Centers will help ensure the continued supply of characterized mutant mice in an efficient and cost effective manner. 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), MUTANT MOUSE REGIONAL RESOURCE CENTERS, is related to the priority areas of immunology, reproductive biology, atherosclerosis, carcinogenesis, and infectious diseases. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0) or "Healthy People 2000" (Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-512-1800). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT The administrative and funding instrument to be used for this program will be an "Animal (Mammalian and Nonmammalian) Model, and Animal and Biological Materials Resource Cooperative Agreement" (U42), an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NCRR scientific and/or programmatic involvement with the awardees is anticipated during the performance of the activity. Under the cooperative agreement, the NCRR's purpose is to support and/or stimulate the recipient's activity by involvement in, and otherwise working jointly with the award recipient in a partnership role, but it is not to assume direction, primary responsibility, or a dominant role in the activity. Details of the responsibilities, relationships and governance of the activities to be funded under cooperative agreements are discussed later in this document. The NCRR anticipates two or three cooperative awards for MMRRCs with budgets that may not exceed $750,000 each in direct costs in the first year. In addition, it is anticipated that one award will be made for an Informatics Coordinating Center (ICC) with a budget that may not exceed $450,000 in direct costs in the first year. FUNDS AVAILABLE The NCRR anticipates making awards for two or three MMRRCs and one ICC for project periods of up to five years. Approximately $3.0 million total costs is expected to be set aside for funding these activities in the initial year. The number of awards and the level of support will depend upon receipt of a sufficient number of applications of high scientific merit. Although this program is provided for in the financial plans of the NCRR, awards pursuant to this RFA are contingent upon the availability of funds for this purpose in fiscal year 1999. The anticipated award date is September 30,1999. At the present time, the NCRR has not determined whether or how this solicitation will be continued beyond the present RFA. RESEARCH OBJECTIVES Background Advances in the technologies that allow investigators to create transgenic and targeted mutant mice, which have proven to be extremely powerful biomedical research tools, have led to an explosive expansion in the use of these genetically altered animal research models. Large numbers of new mutant mouse strains are being developed and characterized by investigators from around the world. These animal models are often made available to other investigators for collaborative or independent biomedical research uses, but often the demands for distribution and maintenance of mice are beyond the physical and/or financial resources of the initial investigator. This may impose undesirable limits on the scientific exploitation of potentially valuable animal models. In addition, unique mouse strains may become unavailable or disappear. Objectives and Scope In response to the critical nationwide need for making mutant mice available to the biomedical research community, the NCRR will establish a cooperative network of MMRRCs. The MMRRCs must have three basic characteristics. First, each MMRRC must have research components to generate new information that is relevant to the resource. Second, each MMRRC must serve the needs of investigators in a variety of research areas where work is sponsored by NIH categorical Institutes. If the mouse user community targeted is very narrow scientifically or limited to the applicant institution, support for the resource should be sought from the appropriate NIH categorical Institute. Third, each MMRRC must be willing to make mice available to investigators on a local, regional, and national basis. It is expected that some of the costs specifically associated with the establishment, improvement, or expansion of supply and long-term mouse resource maintenance should be recovered from users through a charge schedule acceptable to the NIH. The MMRRCs will be responsible for: o Support for the establishment and maintenance of animal facilities, both barrier and traditional, for the husbandry of various hybrid and inbred strains and for genetically selected or altered lines of mice; o Cryopreservation capabilities, storage facilities, and expertise for the reconstitution of cryopreserved embryos and gametes; o Phenotypic characterization of induced mutants with regard to development, function and pathology, including surveillance for infectious and environmental factors in animals and in germplasm; o Genetic quality control. Facilities and expertise to analyze the genetic integrity of stocks being maintained, imported and exported must exist on site; o Maintenance of a local electronic database for live animals and for cryopreserved germplasm. The local database must be connected through an integrated network with all of the other institutional MMRRCs and with the ICC; o An administrative structure responsible for directing all of the activities at the MMRRC and for cooperative interactions with other institutional MMRRCs and with the ICC. The Informatics Coordinating Center (ICC) will be responsible for designing and developing the necessary software, installing an electronic network linking the MMRRCs, and maintaining the database. The ICC database should be updated continuously and must include the live mouse and cryopreserved germplasm inventory at each MMRRC. The coordinated management of these inventories in a cost and resource efficient manner is the prime objective of the ICC. SPECIAL REQUIREMENTS The cooperative agreements (U42s) will require cooperation between the NCRR representative (NCRR Program Administrator) and the Principal Investigators (PIs) of the individual projects in order to assure smooth interactions among cooperating organizations. The NCRR Program Administrator will assist in coordinating the activities of the awardees and in facilitating exchange of information. TERMS AND CONDITIONS OF AWARD The following terms and conditions will be incorporated into the U42 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."] The administrative and funding instrument to be used for this program will be an "Animal (Mammalian and Nonmammalian) Model, and Animal and Biological Materials Resource Cooperative Agreement" (U42), an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NCRR scientific and/or programmatic involvement with the awardees is anticipated during the performance of the activity. Under the cooperative agreement, the NCRR's purpose is to support and/or stimulate the recipient's activity by involvement in, and otherwise working jointly with the award recipient in a partnership role, but it is not to assume direction, primary responsibility, or a dominant role in the activity. Details of the responsibilities, relationships and governance of the activities to be funded under cooperative agreements are discussed later in this document. 1. COLLABORATIVE RESPONSIBILITIES Coordinating Committee(CC) The NCRR Program Administrator and awardees are responsible for forming a CC as defined below. The CC is responsible for reviewing the plans for development of the MMRRCs proposed in the individual applications of awardees. They will develop uniform procedures for quality control in mouse husbandry and in the maintenance of animal facilities, shipping and receiving animals and germplasm, cryopreservation and reconstitution of embryos and gametes, phenotypic characterization, gametic quality control, maintenance of a local electronic database, and administrative direction and reporting procedures. The CC will also review and approve the operating procedures proposed by individual awardee organizations in order to ensure that they are compatible with the overall goals of the RFA. The CC is also responsible for selecting members and coordinating the activities of the MMRRC Advisory Panel (AP) as described below. The CC will initially consist of the Principal Investigator of each MMRRC and the ICC with the NCRR Program Administrator. Additional members can be added by action of the CC. The structure of the CC should be established at the first meeting as noted below. The Chair of the CC will be responsible for coordinating the Committee activities, for preparing meeting agendas, and for scheduling and chairing meetings. The NCRR Program Administrator attends and participates in all meetings of the CC and should be informed of any major interactions. The CC must prepare an annual progress report which will include individual reports from each awardee. Each awardee is responsible for timely preparation of this report. At its initial meeting, the Committee will elect a chairperson (who may not be the NCRR Program Administrator). The CC will determine whether additional CC representation is required. Depending on availability of appropriate expertise, the MMRRCAP described below could be constituted as a sub-committee of the CC. The CC will meet three times in the first year to map strategies, to develop operating procedures and to evaluate progress. The initial meeting will be held as soon as possible after funding. Two additional meetings will be held during the first year of operation and there will be at least two meetings per year thereafter. Meetings may be held at any of the participating organizations or at another convenient location. These meetings are aimed at coordinating the activities of the participating laboratories, establishing new policies and priorities, and reviewing progress. The NCRR Program Administrator will participate in the discussions at these meetings. The NCRR Program Administrator, as a member of the CC, will assure that operating policies are acceptable to the NCRR. An arbitration system, as detailed below, will be available to resolve disagreements between awardees and NCRR staff. Mutant Mouse Regional Resource Center Advisory Panel (MMRCAP) The MMRRCAP is responsible for reviewing and approving requests from investigators both to have mutant strains accepted and to decide which individual MMRRC is the most appropriate site. The decisions as to whether to accept live animals or cryopreserved germplasm and whether to maintain live animals or only cryopreserved germplasm will also be determined by the MMRRCAP. The composition of the MMRRCAP will be determined by the CC. Members must have appropriate expertise in molecular genetics which might include clinicians, laboratory researchers, statisticians or other experts that the CC determines are needed. The NCRR Program Administrator is a member (but not the Chairperson)of the MMRRCAP. Members of the CC may also serve on the MMRRCAP but may not be in the majority. 2. AWARDEE RIGHTS AND RESPONSIBILITIES o Awardees will have primary and lead responsibilities for the project as a whole, including selection and maintenance of mutant mouse strains, mouse husbandry, gamete and embryo cryopreservation and revitalization, microbiological and genetic monitoring, data quality control and reporting to the ICC, research to enhance the resource, preparation of publications, as well as collaboration with the other awardees with assistance from the NCRR Program Administrator. o Awardees must comply with the operating policies and procedures developed by the CC. o The ICC will serve as the central repository and distribution center for electronic data on all strains of mutant mice maintained in the MMRRCs. Data on the numbers and locations of live mice, including their ages and sex, plus the numbers and locations of cryopreserved embryos and gametes must be submitted electronically by the MMRRCs to the ICC in a timely manner using procedures and computer software developed by the ICC. An electronic inventory of the mouse resources will be maintained and constantly updated by the ICC. The ICC will design and maintain a public web site to advertise the availability of mutant mice and to indicate the procedures for requesting these resources. All requests from the research community for live mice and cryopreserved material will be directed to the ICC, which will be responsible for authorizing the distribution from the appropriate MMRRC. The ICC will follow the policy guidelines developed by the CC and by the MMRRCAP. Upon request, the ICC will report to the CC or MMRRCAP on the details of policy implementation, and will aid these groups in their decision making. 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. All awardees must adhere to PHS policy for the distribution of unique research resources produced with PHS funding that was published in NIH Guide for Grants and Contracts (NIH Guide, Vol. 25, No. 23, July 12, 1996), and is available at the following Internet address: http://grants.nih.gov/grants/guide/notice-files/not96-187.html. o Effective conduct of the MMRRC goals will require considerable electronic communication of data and other information among the MMRRC and ICC participants. Awardees are responsible for assuring that the activities supported under the cooperative agreement will not be adversely affected by Year 2000 problems as detailed in "Notice Regarding the Year 2000 Computer Problem" that was published in the NIH Guide for Grants and Contracts, April 3, 1998, and is available at the following Internet address: http://grants.nih.gov/grants/guide/notice-files/not98-046.html 3. NCRR PROGRAM ADMINISTRATOR RESPONSIBILITIES o The NCRR Program Administrator will coordinate and facilitate the programs supported by these cooperative agreements, will attend and participate as a voting member in all meetings of the CC and MMRRCAP, and will provide liaison between them and the NCRR. o The NCRR Program Administrator will ensure that there is effective communication between the MMRRCs and the ICC. o The NCRR Program Administrator will assist the CC in developing and drafting operating policies and procedures for dealing with recurring situations that require coordinated action, e.g. standardized cryopreservation techniques, genetic and microbiological monitoring. o The NCRR Program Administrator may review the operations of individual U42 grants for compliance with the operating policies developed by the CC, and may recommend withholding of support, suspension, or termination of an award for lack of progress or failure to adhere to policies established by the CC. 4. ARBITRATION PROCEDURES An arbitration panel of external consultants will be created as needed to resolve any irreconcilable differences of opinion related to scientific/programmatic matters between the NCRR Program Administrator and the CC with respect to implementation of a proposed operating policy. The panel will include one member selected by the CC, one member selected by the NCRR, and a third member chosen by the other two members of the arbitration panel. These special arbitration procedures in no way affect the awardee's right to appeal an adverse determination in accordance with PHS regulations at 42 CFR Part 50, subpart D and HHS regulations at 45 CFR Part 16. LETTER OF INTENT Prospective applicants are asked to submit, by February 23, 1999, a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and 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 a subsequent application, the information that it contains will allow NCRR staff to estimate the potential review workload and avoid conflict of interest in the review. The letter of intent is to be sent to: Neal B. West, Ph.D. Comparative Medicine area National Center for Research Resources 6705 Rockledge Drive, Room 6030 Bethesda, MD 20892-7965 Telephone: (301) 435-0744 FAX: (301) 480-3819 APPLICATION PROCEDURES To promote the development of a collaborative program among the award recipients, a number of issues need to be addressed in the applications. Applicants must include their specific plans for responding to the "Terms and Conditions of Award" section. Applicants should state their willingness to collaborate and share data freely with the other MMRRCs and with the ICC, to serve on the CC and to be bound by its decisions, and to be able and willing to share data and communicate with each other and with the NCRR in an internet environment. Applicants should also describe how they will comply with the decisions of the CC, and how they will fulfill the responsibility of the MMRRC components to work together cooperatively. Applicants should detail the specialized or unique facilities, fundamental infrastructure, research and mouse husbandry expertise, and core resources and services that are available to support the planned MMRRC, and should propose any additional equipment, specialized caging, and personnel requirements needed to participate in the cooperative group. If facilities at more than one institution are required, applicants should thoroughly describe them and obtain the appropriate assurances. Applicants for the ICC should describe the personnel and the computer hardware and software available, and should propose additional needs related to the proposed cooperative group activities. The roles and expertise of all key personnel, collaborators, and consultants who are associated with the application should be well documented. Each applicant should describe their plans for interfacing with the CC and MMRRCAP and should propose their views on how the CC and MMRRCAP activities should be carried out in the context of the Collaborative Responsibilities described above. Applicants should submit budget requests that include travel to required CC meetings and/or telephone conferences. The MMRRCAP will meet with the CC at least once yearly and each MMRRC and the CC should include travel funds for one MMRRCAP member in their budget requests. The research grant application form PHS 398 (rev. 5/95) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research and from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/435-0714, Email: email@example.com. Application kits are also available at: http://grants.nih.gov/grants/funding/funding.htm and from the program administrator listed under INQUIRIES. The RFA label available in the PHS 398 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 and number 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 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 copies of the application must be sent to: Neal B. West, Ph.D. Comparative Medicine area National Center for Research Resources 6705 Rockledge Drive, Room 6030 Bethesda, MD 20892-7965 BETHESDA, MD 20817 (for express/courier service) Applications must be received by March 25, 1999. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by CSR and responsiveness by the NCRR. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NCRR in accordance with the review criteria stated below. 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 the applications under review, will be discussed, assigned a priority score, and receive a second level by the National Research Resources Advisory Council. Review Criteria Applicants are encouraged to submit and describe their own ideas about how to meet the Objectives and Scope described above for the cooperative network of MMRRCs. The review group will assess the scientific merit of the applications and related factors, including: Significance Does this resource address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of the resource-related studies on the concepts or methods that drive this field? 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? Innovation Does the project employ novel concepts, approaches or methods? Is the project original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? Will the approaches proposed advance the field of mouse resource development? Investigators Are the investigators 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? 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 or employ useful collaborative arrangements? Is there evidence of institutional support? The Informatics Coordinating Center will be supported by a separate U42 grant that may or may not be located at a site that has animal facilities. The review criteria described above will still be applied with the exception of the requirement for mouse facilities under Environment. The initial review group will also examine the provisions for the protection of animal subjects and the safety of the research environment. AWARD CRITERIA Applications recommended by the National Research Resources Advisory Council will be considered for award based upon scientific merit as determined by peer review, availability of funds, and programmatic priorities including the geographical distribution of the applicants. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. An Applicant Information Meeting (AIM) to assist applicants unfamiliar with the requirements for "Animal (Mammalian and Nonmammalian) Model, and Animal and Biological Materials Resource Cooperative Agreement" (U42) applications and to clarify any issues or questions from potential applicants will be held at 1 P.M. on February 23, 1999 in Bethesda, MD. For additional information regarding the AIM, call (301) 435-0744. A summary of the presentations and issues discussed will be provided upon request for those unable to attend. Direct inquiries regarding programmatic issues to: Neal B. West, Ph.D. Comparative Medicine area National Center for Research Resources 6705 Rockledge Drive, Room 6030 Bethesda, MD 20892-7965 Telephone: (301) 435-0744 FAX: (301) 480-3819 Email: firstname.lastname@example.org Direct inquiries regarding fiscal matters to: Joellen M. Harper Office of Grants Management National Center for Research Resources One Rockledge Centre, Room 6086 Bethesda, MD 20892-7965 Telephone: (301) 435-0844 FAX: (301) 480-3777 Email: JH41M@NIH.GOV AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.306. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR 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 tobacco products. In addition, Public Law 103-277, 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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