MOUSE MUTAGENESIS AND PHENOTYPING: NERVOUS SYSTEM AND BEHAVIOR Release Date: March 31, 1999 RFA: MH-99-007 P.T. National Institute of Mental Health National Institute of Neurological Disorders and Stroke National Institute on Aging National Institute on Deafness and Other Communication Disorders National Institute on Drug Abuse National Eye Institute National Institute on Alcohol Abuse and Alcoholism Public Briefing Date: June 21, 1999 Letter of Intent Receipt Date: August 2, 1999 Application Receipt Date: October 14, 1999 PURPOSE The purpose of this request for applications (RFA) is to establish facilities for large-scale mutagenesis and phenotyping of nervous system functions and complex behaviors in the laboratory mouse. Neuroscience-focused mutagenesis and phenotyping facilities established by this RFA are expected to serve as a national resource by producing a bank of mouse strains that harbor a wide range of mutations affecting murine nervous system function and behavior. Data and biomaterials produced in projects supported under this RFA will be made widely available to the scientific community. A companion RFA entitled, "Phenotyping the Mouse Nervous System and Behavior: MH-99-006," available at http://grants.nih.gov/grants/guide/rfa-files/RFA-MH-99-006.html, solicited applications that focused on the development of standardized criteria and high-throughput phenotyping assays to assess a comprehensive range of murine nervous system functions and complex behaviors. These assays will be widely distributed to the scientific community and available for application in projects supported under this RFA. The activities of facilities established under this RFA will be coordinated with those supported under RFA HD-99-007, "Mouse Mutagenesis and Phenotyping: Developmental Defects," available at http://grants.nih.gov/grants/guide/rfa-files/RFA-HD-99-007.html, and with those of future related facilities. Further information about NIH initiatives on mouse genomics and genetics resources are available at http://www.nih.gov/science/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 RFA - Mouse Mutagenesis and Phenotyping: Nervous System and Behavior - is related to one or more priority areas. Applicants may obtain a copy of "Healthy People 2000" at http://www.crisny.org/health/us/health7.html. 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. Applications will not be accepted from foreign institutions. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators (PIs). MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) cooperative agreement (U01) award mechanism, an "assistance" mechanism, which is distinguished from a regular research grant in that substantial scientific and/or programmatic interaction between NIH program staff and the awardees is anticipated. The cooperative agreement is used when participation by NIH staff is warranted to support and/or stimulate the recipient"s activity by involvement in or otherwise working jointly with the award recipient in a partner role, NIH staff will not assume direction, prime responsibility, or a dominant role in the activity. Details of the responsibilities, relationships, and governance of the studies funded under cooperative agreements are discussed later in this document under "Terms and Conditions of Award." If there are multiple facilities to be supported, each will be awarded as a separate U01. For administrative reasons all applications received in response to this solicitation will be initially assigned to NIMH. After discussions among the participating NIH Institutes, applications will be reassigned to the Institute(s) that is programmatically most appropriate. Because the scope of some of the research projects proposed in response to this RFA encompasses the interests of several Institutes, applications may receive dual assignments based on established PHS guidelines. Awards will be made and managed by NIMH and/or the other participating Institutes. FUNDS AVAILABLE This RFA is a one-time solicitation. It is anticipated that $5.5 million (including direct and indirect costs) will be available for this initiative in Fiscal Year 2000, during which it is anticipated that 2 to 4 awards will be made. The total project period for an application submitted in response to this RFA may not exceed 5 years. Awards pursuant to this RFA are contingent upon the availability of funds for this purpose. The amount of funding for this initiative may be increased if a large number of highly meritorious applications are received and if funds are available. Only applications that are found to be of the highest scientific merit will be considered for funding, and not all of the funding will be spent if there are not enough highly meritorious applications. Funding in future years will be subject to the availability of funds. For the purpose of accomplishing the goals of this RFA, the facility may include investigators at more than one site, and subcontracts may be included in the budget to support investigators at sites other than the awardee institution. RESEARCH OBJECTIVES Background With the impending elucidation of the complete sequence of both the mouse and human genomes, the next challenge will be to conduct large-scale functional analyses of these genomes to greatly enhance our understanding of mammalian biology. The laboratory mouse plays a pivotal role in human functional genomics, insofar as mouse strains carrying mutations have provided useful models for human diseases. Despite an apparent large collection of mouse mutations, the genetic bases of nervous system functions and complex behaviors are still poorly understood. This is in part true because there have not been systematic, large- scale efforts to identify mutations across the genome via systematic mutagenesis, and comprehensive phenotypic and genetic analyses of the resulting mouse strains. Creation of additional genomic and genetic resources to facilitate functional analysis of murine biology is of widespread interest, and will make the mouse an even more useful model for the research community. In order to help define and establish priorities for generating such resources, the NIH Director convened a meeting of a distinguished group of scientists in March 1998, and a follow-up meeting in October 1998. Summaries of the two meetings can be found at http://www.nih.gov/welcome/director/reports/mgenome.htm and http://www.nih.gov/welcome/director/reports/mgenom3.htm (links to these summaries, as well as all relevant information regarding NIH initiatives on mouse genomics and genetics resources, are available at http://www.nih.gov/science/mouse/). A recent article (J. Battey et al., Nature Genetics 21:73, 1999, available at http://www.nih.gov/science/mouse/reports/actionplan.html) summarizes a proposed action plan by NIH for implementation of these recommendations. Large-scale, genome-wide mutagenesis is a powerful approach for the analysis of gene function, and has historically played a major role in the evolution of our understanding of the biology of viruses, bacteria, fungi, the nematode, Caenorhabditis elegans, the fruit fly, Drosophila melanogaster, and most recently, the zebrafish, Danio rerio. In all three of the metazoan species so studied, genome-wide mutagenesis has made important contributions to our understanding of the development and cellular functions of the nervous system. Two routes, phenotype-driven and genotype-type driven, are currently being used to develop large-scale mutagenesis efforts. Phenotype-driven approaches typically utilize pseudo-randomly acting chemical agents such as N-ethyl-N- nitrosourea (ENU), procarbazine, or chloroambucil, to generate mice with phenotypes of interest. Recovery of novel phenotypes is a starting point from which the relevant genes and biochemical, anatomical and physiological pathways are subsequently elucidated. Although considerable effort is needed to find the genes underlying novel phenotypes in mice, this approach has been successfully used to identify genes encoding leptin, and novel genes involved in genetic deafness and circadian rhythms. This RFA will establish neuroscience-focused facilities for large-scale, efficient, whole-genome mutagenesis and phenotyping, in order to promote the systematic and comprehensive functional analysis of neurobiological and behavioral phenotypes in the mouse. Such facilities will create and maintain for distribution validated protocols for mutagenesis and phenotypic characterization, a collection of mutant mouse strains and databases containing phenotypic and genetic data on these strains. These resources will provide a platform from which hypothesis-driven research can be developed to gain a more comprehensive understanding of the molecular and genetic bases underlying nervous system function and complex behavior in mammals. Projects supported under this RFA will complement those supported under RFA HD-99-007, which will focus on genes that affect murine embryonic and post-embryonic development. Scope and Objectives Projects supported under this RFA will conduct genome-wide mutagenesis and high- throughput phenotyping of genetically altered mice. These mutant animals, along with embryos and/or sperm, will be made available for wide distribution to the scientific community. Each of the following areas are of primary importance and should be explicitly addressed in the application: o Utilization of a whole-genome approach to mutagenesis that is phenotype- driven, genotype-driven, or a combination of the two. The strategy must enable identification of both dominant and recessive mutations. o Initial, high-throughput characterization of mutant phenotypes relevant to nervous system function and behavior. o Focused phenotypic characterization of mutant mouse strains to screen for alterations in two or three domains of nervous system function and behavior (see below). o Development and maintenance of a database of all phenotypic data generated from mutants. o Maintenance and provision of animals, embryos, and/or sperm to:(1) one of the facilities supported under this RFA, which may receive supplemental funds under competitive peer-review to distribute these biomaterials to the wider scientific community after projects solicited under this RFA are funded, and/or (2) another NIH-designated facility (e.g., a National Center for Research Resources (NCRR)- sponsored Mutant Mouse Regional Resource Center as described in RFA RR-99-001 at http://grants.nih.gov/grants/guide/rfa-files/RFA-RR-99-001.html). o State-of-the-art procedures that will ensure distribution of pathogen-free mutant mice, embryos, and/or sperm. o A proposed sharing plan to insure that mutant mice, sperm, embryos, phenotyping assays, and phenotypic data for all mutant strains are widely available to the scientific community. o NIH expects to make a Determination of Exceptional Circumstances (DEC) to eliminate the potential for patents on mutant mice, sperm, and embryos. The application should include a proposed plan addressing if, or how, the PI and recipient institution will exercise their intellectual property rights regarding other patentable research resources not covered under the DEC, such as phenotyping assays, mutagenesis protocols, and instrumentation produced in projects funded under this RFA (these issues are addressed below under OTHER SPECIAL REQUIREMENTS). o A proposed plan to permit guest investigators not associated with the facility to make use of the facility to screen for, and/or to examine, alterations in nervous system function and behavior not otherwise being studied at the facility. Funding for such additional projects would come from other sources. Applications should utilize pre-existing high-throughput phenotyping assays and/or newly developed high-throughput assays (e.g., those developed in projects funded under RFA MH-99-006) to characterize mutant mouse strains. It is expected that each facility supported under this RFA will conduct screens of multiple phenotypic domains of nervous system functions or complex behaviors (see below). Each screen should include several assays that collectively measure multiple components of the phenotypic domain under investigation. Domains to be screened may include, but are not limited to, the following: o Complex traits related to normal or abnormal nervous system function and behavior, including but not limited to the following: emotion, attention, cognition, perception, concentration, sensation, learning, memory, reproductive and parenting behaviors, social behavior, circadian rhythms, grooming, impulse control, appetite, hedonic capacity, weight loss/gain, energy level, and peripheral sensory and autonomic nervous system function. o Neurological symptoms including ataxia, dystonia, seizures, paralysis, rigidity, tremor, cognitive impairment, motor tics, deficits in sensory, motor, and cognitive function following ischemic insult, neurotoxic insult, spinal cord injury, head injury, or nerve trauma. o Motor behavior, including measures of strength, motor control and coordination, and cognitive aspects of motor planning. o Acute and chronic sensitivity to neuropathic and inflammatory pain. o Visual phenotypes including, but not limited to, the following: retinal degeneration, cataract, cornea dystrophy, glaucoma, and abnormalities affecting sensory, plasticity and motor functions in the visual system. o Phenotypes that reflect alterations (i.e., impairment, distortion, or hypersensitivity) in sensory function including, but not limited to, the following: hearing and susceptibility to noise-induced hearing loss, balance and vestibular function, olfaction (including assays for neonatal function), vomeronasal function, and taste. o Behavioral traits related to alcohol ingestion, including but not limited to the following: alcohol drinking preference, alcohol-induced ataxia and locomotor activation, acute and chronic alcohol withdrawal, alcohol-induced conditioned place preference and conditioned taste aversion, operant responding for an alcohol reward, acute behavioral tolerance to alcohol, and alcohol-induced anxiolysis. o Phenotypes that undergo alterations with aging including, but not limited to, the following: learning, memory and cognition, sensory and motor function, sleep and circadian rhythms, glial structure and function, blood brain barrier structure and function, regional brain volume, susceptibility or resistance to neurodegeneration, neurotoxicity, and oxidative stress, and biochemical and physiological measures of nervous system function. o Behavioral traits related to the taking and seeking of drugs of abuse, which model aspects of drug addiction and co-morbid behaviors. These include, but are not limited to the following: drug preference, conditioned place preference, acquisition, maintenance, extinction, and reinstatement of drug taking behavior, narrowing of behavioral repertoires, and drug sensitization, tolerance, and withdrawal. o Behavioral abnormalities that model those found in mental disorders including, but not limited to, the following: attention-deficit hyperactivity disorder, autistic disorder, bipolar disorder, depression, eating disorders, obsessive- compulsive disorder, panic disorder, schizophrenia and other psychotic disorders, sleep disorders, and Tourette syndrome. o Behavioral, neurological, and sensory phenotypes limited to specific stages of development or to specific stages of the life span, such as neurodegenerative disorders in early development or aging. o High-throughput methods for the following: structural and functional characterization of the central and peripheral nervous systems in living animals through fMRI, PET, and other neuroimaging techniques or through evaluation of electrophysiological parameters, such as conduction velocity, EEG or long-term potentiation. SPECIAL REQUIREMENTS FOR COOPERATIVE AGREEMENTS I. Definitions ARBITRATION PANEL: A panel that would be formed to arbitrate scientific or programmatic disagreement, should any arise, between award recipients and NIH within the scope of the award. AWARDEE: The institution to which a cooperative agreement is awarded. COOPERATIVE AGREEMENT: An assistance mechanism in which there is anticipated substantial NIH programmatic involvement with the recipient organization during the performance of the planned activity. PRINCIPAL INVESTIGATOR (PI): The researcher who assembles the project, submits an application in response to this RFA, and assumes responsibility for the overall performance of the project. The PI will coordinate project activities scientifically and administratively. NIH PROGRAM DIRECTOR: A scientist of the NIH program staff who serves on a rotating basis to represent the 7 NIH Institutes sponsoring this RFA. The NIH Program Director has substantial scientific/programming involvement. NEUROSCIENCE STEERING COMMITTEE (NSC): A committee that is the main governing board of all of the mutagenesis and phenotyping facilities funded under this RFA, and the committee through which the NIH interacts and collaborates with the facilities. Membership includes the NIH Program Director(s), the PI of each awarded cooperative agreement, and three scientists with relevant expertise who are not affiliated with any of the funded projects. MOUSE GENOMICS & GENETICS SCIENTIFIC PANEL (MSP): A committee that is advisory to NIH. MSP ensures coordination among projects funded under this RFA and RFA HD- 99-007, and evaluates their progress in relation to the evolving goals for trans- NIH initiatives on mouse genetics and genomics. II. Terms and Conditions of Award The following Terms and Conditions will be incorporated into the award statement. The following 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 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies: 1. The administrative and funding instrument used for this program will be the U01, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH scientific and/or programmatic involvement with the awardees is anticipated during performance of the activities. Under the cooperative agreement, the NIH purpose is to support and/or stimulate the recipients" activities by involvement in and otherwise working jointly with the award recipients in a partnership role. The NIH purpose is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and NIH program staff. 2. PI Rights and Responsibilities The PI will coordinate project activities scientifically and administratively at the awardee institution. The PI will have primary responsibility for defining the details for the projects within the guidelines of this RFA, and for performing all scientific activities. The PI will agree to accept the close coordination, cooperation, and participation of the Program Director(s), Neuroscience Steering Committee (NSC), and Mouse Genomics & Genetics Scientific Panel (MSP) in those aspects of scientific and technical management of the project as described below. Specifically, the PI will: o Determine experimental approaches, design protocols, direct experiments, and work cooperatively to set project milestones, in consultation with NIH program staff and NSC. o Release data according to plans and publish results, as agreed upon by NIH program staff and NSC. o Submit periodic progress reports in a standard format, as agreed upon by NSC. o Accept and implement the common guidelines and procedures approved by NSC and MSP. o Share with other mutagenesis and phenotyping facilities mutants that may be of interest to those facilities, as directed by NSC and MSP. o Be aware of mutants that the other mutagenesis and phenotyping facilities are producing, and be prepared to accept them for initial screening and/or focused characterization, as directed by NSC and MSP. o Solicit the views of the broad neuroscience and behavioral research communities for the phenotypes and/or genotypes of interest. o Participate in NSC meetings (budget requests should include travel funds for the PI and other critical staff to attend NSC meetings in the metropolitan Washington, DC area at least twice per year). 3. NIH Program Staff Responsibilities The NIH Program Director(s) will have substantial scientific/ programmatic involvement during the conduct of this activity through technical assistance, advice, and coordination. This includes functioning as a peer with the PIs, facilitating the partnership relationship between NIH and the neuroscience- focused mutagenesis and phenotyping facilities funded under this RFA, helping to maintain the overall scientific balance in the program commensurate with new research and emerging research opportunities, and ensuring that the activities of the neuroscience-focused mutagenesis and phenotyping facilities are consistent with the missions of the participating Institutes. The role of NIH will be to facilitate and not to direct activities. It is anticipated that decisions will be reached by consensus of the PIs and that NIH staff will be given the opportunity to offer input to this process. One to two NIH Program Directors shall participate as members of NSC. NIH staff will have a total of one vote. In order to separate the functions of the Program Director(s) from scientific stewardship functions (e.g., review of annual progress report, decisions about permitting carryover, re-budgeting, administrative supplements, etc.) for each facility, the Project Officers for the facilities funded under this RFA will not serve on NSC as Program Director(s). Specifically, the NIH Program Director(s) will: o Provide relevant scientific expertise and overall knowledge. o Participate with other NSC members in the group process of setting research priorities and milestones, deciding optimal research approaches and protocol designs, and contributing to the adjustment of research protocols or approaches as warranted. The Program Director(s) will assist and facilitate the group process and not direct it. o Serve as administrative liaison to MSP, attending MSP meetings as a non-voting member, to help coordinate activities of facilities funded under this RFA with those funded under RFA HD-99-007 and other NIH mouse genomics and genetics initiatives. The Program Director(s) will also coordinate the activities of facilities funded under this RFA with other US and international efforts. o Provide information about ongoing NIH-supported research and resource collections. o Appoint the NSC Chair based on a recommendation from NSC committee members. o Attend NSC meetings as one voting member, and assist to develop operating guidelines, quality control procedures, and consistent policies for dealing with recurrent situations that require coordinated action. The Program Director(s) must be informed of all major interactions of members of NSC. The Program Director(s) will be responsible for preparing within 30 days a concise summary of each NSC meeting. o Serve as scientific liaison between the awardees and other NIH program staff. o Assist in promoting the mutagenesis facilities to the scientific community at large. o Assist in developing timetables for the wide distribution of biomaterials and data to the scientific community. o Coordinate the activities of facilities to ensure the efficient long-term storage and timely release of biomaterials and data to the wider scientific community. o Help determine the most appropriate mechanisms for storage and distribution of biomaterials and data to the scientific community, i.e., storage and distribution by one of the facilities funded under this RFA and/or by another NIH-funded facility. o Retain the option to recommend re-allocating NIH support among awardees, as scientific goals evolve. o Participate in data analyses and, where warranted, co-authorship of papers resulting from projects funded under this RFA. 4. Collaborative Responsibilities - NSC Functions All collaborative activities of awardees and NIH staff will occur through the activities of NSC, which will serve as the governing board of all the neuroscience-focused mutagenesis and phenotyping facilities funded under this RFA. NIH will interact and collaborate with the facilities through the NSC, which will include the PIs, the NIH Program Director(s), and three scientists (advisors) with relevant scientific expertise who are not affiliated with any of the facilities. These advisors will be appointed by the directors of the 7 NIH Institutes supporting this RFA, and may include PIs on projects funded under RFA MH-99-006. One of the advisors will be appointed to be the committee"s chair by the Program Director(s), after consideration of recommendations made by NSC. After appointment by the Program Director(s), the Chair of NSC will schedule the first NSC meeting. The Chair will be responsible for developing meeting agendas and chairing meetings. NSC will meet at least twice per year. Additional NSC members may be added by action of NSC. Other NIH staff may attend NSC meetings, when their expertise is required for specific discussions. The Program Director(s), each PI, and each advisor will have one vote each. NSC will coordinate the activities of the mutagenesis and phenotyping facilities and the exchange of information and biomaterials with the wider scientific community. While mutagenesis of multiple regions of varying size across the whole mouse genome will be conducted, it is expected that priorities for genomic regions and phenotypes of particular interest will be established by NSC. NSC will discuss scientific progress, make recommendations regarding how mutations should be obtained, analyzed, and collected, in order to be maximally valuable to all interested investigators. MSP recommendations will be addressed by NSC. 5. Mouse Genomics & Genetics Scientific Panel (MSP) MSP will coordinate activities among the facilities and resources participating in NIH"s mouse mutagenesis and phenotyping initiative, including this RFA and RFA HD-99-007. MSP will use its knowledge of the activities of all of the participating facilities to ensure adequate investigation, communication and sharing, and to avoid redundant activities. It will advise NIH with respect to the coordination of all activities that involve the mutagenesis, phenotyping, maintenance, and distribution of mutant mouse strains. MSP will evaluate and make recommendations regarding the coordination of the activities of the facilities that are funded by the mutagenesis and phenotyping initiatives, and other related activities that may be developed in the future. It will be the responsibility of MSP to make recommendations that will lead to exchanging mutants between facilities, sharing assay strategies, adopting common policies on data sharing, creating compatible databases, and other activities that will make these facilities of maximal utility to the scientific community. MSP will also set standards for data format and nomenclature, as well as develop common guidelines and procedures for deposition of the primary phenotypic data and for the preservation of mutant mouse strains. The committee will consist of about 10 scientists (advisors) who are not affiliated with any of the mutagenesis and phenotyping facilities, and are not members of the advisory committees of those facilities. They will be appointed by NIH. These advisors will be selected for their broad expertise in relevant topics such as, developmental biology, aging, neurobiology, behavior, mutagenesis, phenotyping, mouse genetics, husbandry, genomics, and database issues. MSP will meet at least once each year. A schedule for subsequent meetings will be prepared at the first meeting. NIH will select one member to be the committee chair, after considering MSP"s recommendations. The chair will schedule the first meeting, will be responsible for developing meeting agendas and chairing the meetings. Additional MSP members may be added by an action of the original MSP members. Program Director(s) will attend MSP as non-voting members and will act as a representative of NSC. Other NIH staff and NSC members may attend MSP meetings, when their expertise is required for specific discussions. 6. Milestones and Evaluations Applicants should define yearly milestones in their applications, and the selected awardees will have the opportunity to modify these milestones at the time of their awards. The awardees" milestones will be provided to NSC and MSP. It is expected that the milestones should 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 NSC and MSP recommendations. Following the evaluation of milestones, NIH program staff may recommend augmenting any project or reducing or withholding funds for any project that substantially fails to meet its milestones or to remain state-of-the-art. 7. Arbitration Process Any disagreements that may arise in scientific or programmatic matters within the scope of the award between recipients and the NIH may be brought to arbitration. This special arbitration procedure in no way affects the awardee"s right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations 42 CFR Part 50, Subpart D and HHS regulation at 45 CFR Part 16. An Arbitration Panel will help resolve both scientific and programmatic issues that develop during the course of work that restrict progress. The Arbitration Panel will be composed of three members: a designee of NSC chosen without the NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two (in the case of an individual disagreement, the first member is not chosen by NSC rather by the individual awardee). OTHER SPECIAL REQUIREMENTS Restricted availability of unique research resources, upon which further studies are dependent, can impede the advancement of research and delivery of medical care. The sharing of biomaterials, data, and software in a timely manner, on the other hand, has been an essential element in the rapid progress that has been made in the genetic analysis of mammalian genomes. PHS policy requires that investigators make unique research resources readily available for research purposes to qualified individuals within the scientific community when they have been published (PHS Grants Policy Statement in the July 12, 1996 issue of the NIH Guide to Grants and Contracts). Biomaterials (pathogen-free mutant animals, preserved sperm and embryos) and other patentable research resources (e.g., phenotyping assays, mutagenesis protocols, instrumentation) produced in projects funded by this RFA will be made available and distributed to the broader scientific community. For applications submitted in response to this RFA, three special requirements exist regarding research resources produced in the proposed project: (1) applicants are required to include a specific plan by which they will share research resources with the wider scientific community, (2) NIH expects to make a Determination of Exceptional Circumstances (DEC) to eliminate the potential for patents on mutant mice, sperm, and embryos, and (3) applicants are required to include a plan addressing if, or how, they will exercise their intellectual property rights while making available to the broader scientific community other patentable research resources (e.g., phenotyping assays, protocols, instrumentation, and methodologies) not covered under the DEC. Each is discussed in detail below. Plan to Share Research Resources To address the joint interests of the government in the availability of, and access to, the results of publicly funded research NIH requires applicants who respond to this RFA to propose detailed plans for sharing the research resources generated through the grant. It is expected that the resources to be shared include all materials developed in projects funded under the RFA, including but not limited to, the following: mutant animals, preserved embryos and sperm, phenotypic and genetic data, phenotyping assays, instrumentation, and mutagenesis protocols. For this purpose, it is NIHs opinion that dissemination of such data and materials via individual laboratories and Web sites is not sufficient, as it would force interested investigators to search several different data collections to make use of the results of this initiative. It is preferable that data, protocols, technologies, and biomaterials generated in grants funded under this RFA should be placed in common, public repositories and databases that are widely accessible by investigators in the scientific community. It is expected that the investigator"s data and biomaterials sharing plan will include the following elements: (1) establishment of and access to a comprehensive database containing detailed results from phenotyping screens, (2) access to mutants identified through high-throughput phenotyping, (3) access to preserved embryos and sperm for these mutants, (4) access to phenotyping assays not currently available to the wider scientific community that are used to characterize mutants, (5) access to mutants which have been screened but not found to have a phenotype of interest to investigators associated with this facility. This means that, before discarding rejected mice, the facility will specifically advertise their availability to the facility supported under RFA HD- 99-007, and other investigators in the wider scientific research community wishing to conduct screens of their own but who do not otherwise have access to mutagenesis facilities. If demand for these mice is great enough, the facility may have to develop priorities and rules for distribution, (6) elaboration of mechanisms and protocols to be followed to promote the wide distribution of resources to investigators in the scientific community, and (7) a distribution timeline. The initial review group will make an administrative comment on the adequacy of the proposed plan for sharing and data access. The adequacy of the plan will be considered by NIH program staff 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. Evaluation of renewal applications will include assessment of the effectiveness of research resource release. It is expected that this plan includes all elements of the guidelines developed by the 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/Grant_info/Funding/Statements/data_release.html. Adherence with this time frame is highly desirable. More rapid sharing is encouraged. Requests for exemptions or extensions will require compelling justification and will be fully evaluated through peer review and by NIH program staff. Where appropriate, awardees may work with the private sector to make unique resources available to the wider biomedical research community at a reasonable cost. Applicants may request funds to defray the costs of sharing resources, with adequate justification. Intellectual Property Rights NIH is interested in ensuring that the research resources developed through this RFA become readily available to the research community. To ensure unrestricted availability of mutant mice developed under this RFA, NIH expects to make a Determination of Exceptional Circumstances (DEC) pursuant to 37 CFR 401.3(a)(2) which will cover mutant animals, embryos, and sperm. The purpose of the DEC is to eliminate the potential for patents on mutant mice, embryos, and sperm to undermine the development of a widely available national resource that is the fundamental purpose of this RFA. With regard to other patentable research results, such as phenotyping assays, mutagenesis protocols, instrumentation, and methodologies, NIH requires applicants who respond to this RFA to develop and propose a plan addressing if, or how, they will exercise their intellectual property rights while making available to the broader scientific community research resources produced in projects funded under this RFA. This is expected to include an elaboration of the awardee"s anticipated plans to generate, or not generate, patents and/or exclusive or non-exclusive licensing of biomaterials and other patentable subject matter created in projects funded 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 may be generated. Note that this plan will NOT include mutant animals, embryos and sperm (for which the potential for patents will be eliminated pursuant to the DEC described above). This plan also is in addition to the plan for sharing and disseminating research resources described in the previous section. The initial review group will make an administrative comment on the proposed plan. The plan will be considered by NIH program staff in determining whether the grant shall be awarded. The plan as approved, after negotiation with the applicant when necessary, will be a condition of the award. Evaluation of renewal applications will include assessment of the awardee"s adherence to the proposed plan. Applicants are also 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 awardee institution personnel responsible for patent matters. The awarding Institute reserves the right to monitor awardee activity in this area to ascertain if patents or patent applications on phenotyping assays, protocols, instrumentation, methodologies or other patentable subject matter are adversely affecting the goals of this RFA. LETTER OF INTENT Prospective applicants are asked to submit by August 2, 1999 a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone and facsimile numbers of the PI, 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 and is not binding, it is highly encouraged. The information it contains will allow NIH program staff to estimate the workload and also to avoid potential conflicts of interest in the review. The letter of intent is to be sent to: Dr. Hemin R. Chin Division of Neuroscience & Basic Behavioral Science National Institute of Mental Health 6001 Executive Boulevard, Room 7190, MSC 9643 Bethesda, MD 20892-9643 Telephone: (301) 443-1706 FAX: (301) 443-9890 Email: [email protected] PUBLIC BRIEFING Prospective applicants are invited to attend a briefing on this RFA and on RFA HD-99-007 on June 21, 1999 at the NIH Campus in Bethesda, MD. Interested scientists should contact the NIH program staff contact listed under LETTER OF INTENT to obtain further information. At the public briefing NIH program staff will explain the purpose of these RFAs, provide detailed instructions about the application process, and answer questions. Potential applicant institutions are urged to send a representative to this briefing, both to gather information and to exchange ideas with other potential applicants. Anyone who cannot attend this briefing will be provided with any distributed materials and with a summary of the discussion. APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) 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) 710-0267, Email: [email protected]. It is also available at http://grants.nih.gov/grants/funding/phs398/phs398.html. Because the application is expected to be more complex than applications for regular research projects, it may be up to forty (40) pages in length. Within this page limitation, the application should include separate sections on 1) overall strategy, purpose and plans, 2) mutagenesis (including breeding strategy), 3) phenotyping, 4) database/bioinformatics, and 5) procedures for distribution and sharing of pathogen-free biomaterials and data. The RFA label available in the PHS 398 (rev. 4/98) 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, "Mouse Mutagenesis and Phenotyping: Nervous System and Behavior - MH-99- 007," 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 four 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, send one additional copy to: Dr. Hemin R. Chin Division of Neuroscience & Basic Behavioral Science National Institute of Mental Health 6001 Executive Boulevard, Room 7190, MSC 9643 Bethesda, MD 20892-9643 Rockville, MD 20852 (for express/courier service) Telephone: (301) 443-1706 FAX: (301) 443-9890 Email: [email protected] Applications must be received by October 14, 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. 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. The applicants should also ensure that their revised applications respond to the review criteria by which applications in response to this RFA will be evaluated. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by CSR and for responsiveness by NIH program staff. Incomplete and/or unresponsive applications will be returned to the applicant without review. Those applications that are complete and responsive to this RFA will be evaluated for scientific and technical merit in accordance with the criteria stated below by an appropriate peer review group. There will be no site visits. As part of the initial merit review, all applications will receive a written critique and may undergo a process in which only those applications deemed to have the highest scientific merit will be discussed and assigned a priority score. All applications will receive a second level of review by the appropriate NIH National Advisory Council. 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 their 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. o Significance: What will be the expected impact of mutant mice produced by the facility on our understanding of the genetic bases of nervous system functions and complex behaviors? Will the facility have the capacity to serve as a resource for the wider scientific community? o Approach: Does this study specify methodologies for rapid and efficient genome-wide mutagenesis and high-throughput phenotypic characterization? Is the conceptual framework for efficiently conducting large-scale mutagenesis across the mouse genome and comprehensive high-throughput phenotyping, adequately developed, well- integrated, and appropriate to the aims of the project? Does the proposed strategy enable identification of both dominant and recessive mutations? Does the applicant acknowledge potential problem areas and consider alternative tactics? o 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? o 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)? o Integration with other resources: Are the plans adequate to integrate the mutants and phenotypic data with those collected in other comparable projects? Does the applicant have a plan to share with other mutagenesis and phenotyping facilities mutants that may be of interest to those facilities? Does the application reflect awareness that the proposed facility be prepared to accept mutants produced by other mutagenesis and phenotyping facilities for initial screening and/or focused characterization? Likewise, does the application reflect awareness that some of the mutants produced by the proposed facility may be sent to other mutagenesis and phenotyping facilities? o Exportability and accessibility: What is the likelihood that the mutants and phenotypic information generated in the project will be made widely available in a timely fashion to the scientific community? Are state-of-the-art procedures employed to ensure the distribution of pathogen-free mutant strains, embryos, and/or sperm? What is the likelihood that other patentable research results will be widely available for the scientific community, given the proposed plan to exercise (or to not exercise) intellectual property rights regarding phenotyping assays, mutagenesis protocols, instrumentation, and methodologies? Does the project specify creation of a highly efficient and organized bioinformatics database? Do the investigator"s quality control plans assure that databases provided to the wider scientific community are accurate and highly efficient? o 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 addition to the above criteria, in accordance with NIH policy, all applications will also 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 for humans, animals or the environment, to the extent they may be adversely affected by the project proposed in the application. Applicants will be evaluated in the review process for their response to the Research Objectives described above and for their ability to establish an infrastructure that will permit rapid and efficient achievement of the project aims. This will include evaluation of the proposed project"s ability to serve as a resource to the broader scientific community. In addition, the plan to share research resources and the plan to exercise (or not exercise) intellectual property rights regarding patentable research resources not covered under the DEC will be judged for appropriateness. The initial review group will also examine the safety of the research environment. AWARD CRITERIA The earliest anticipated date of award is August 1, 2000. Subject to the availability of funds, and consonant with the priorities of this RFA, the participating Institutes will provide funds for a project period not to exceed five years. Factors that will be used to make award decisions are as follows: o Quality of the proposed project as determined by rigorous scientific peer review, o Cost effectiveness of the proposed strategy, o Promise of the proposed project to accomplish the goals of this RFA, by which rapid, cost-effective high-throughput mutagenesis and phenotyping will be accomplished, o Promise of the facility to serve as a resource for the broader scientific community, o Adequacy of plans to make widely available to the research community all research resources developed during the project, o Adequacy of plans to exercise (or not exercise) intellectual property rights while permitting wide availability to the research community of patentable research resources (e.g., phenotyping assays, mutagenesis protocols, instrumentation, and methodologies) developed during the project that are not covered under the DEC, o Adequacy of plans for participation by guest investigators, o Availability of funds. SCHEDULE Public Briefing: June 21, 1999 Letter of Intent Receipt Date: August 2, 1999 Application Receipt Date: October 14, 1999 Scientific Review Date: February/March 2000 Advisory Council Date: May/June 2000 Anticipated Award Date: August 1, 2000 INQUIRIES Inquiries concerning this RFA are strongly encouraged, and NIH staff welcomes the opportunity to clarify issues or questions from potential applicants. Direct inquiries regarding programmatic issues to: Dr. Hemin R. Chin Division of Neuroscience & Basic Behavioral Science National Institute of Mental Health 6001 Executive Boulevard, Room 7190, MSC 9643 Bethesda, MD 20892-9643 Telephone: (301) 443-1706 FAX: (301) 443-9890 Email: [email protected] Dr. Jonathan D. Pollock Division of Basic Research National Institute on Drug Abuse 6001 Executive Boulevard, Room 4274, MSC 9555 Bethesda, MD 20892-9555 Telephone: (301) 435-1309 FAX: (301) 594-6043 Email: [email protected] Dr. Robert W. Karp Division of Basic Research National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Suite 402 MSC 7003 Bethesda, MD 20892-7003 Telephone: (301) 443-4223 FAX: (301) 594-0673 Email: [email protected] Dr. Bradley C. Wise Neuroscience and Neuropsychology of Aging Program National Institute on Aging 7201 Wisconsin Avenue, Suite 3C307, MSC 9205 Bethesda, MD 20892-9205 Telephone: (301) 496-9350 FAX: (301) 496-1494 Email: [email protected] Dr. Maria Y. Giovanni Fundamental Retinal Processes National Eye Institute 6120 Executive Boulevard, Suite 350 - MSC 7164 Bethesda, MD 20892-7164 Telephone: (301) 496-0484 FAX: (301) 402-0528 Email: [email protected] Dr. Gabrielle Leblanc Division of Fundamental Neuroscience and Developmental Disorders National Institute of Neurological Disorders and Stroke 6001 Executive Boulevard, Room 2139, MSC 9170 Bethesda, MD 20892-9170 Telephone: (301) 496-5745 FAX: (301) 402-1501 Email: [email protected] Dr. Rochelle Small Division of Human Communication National Institute on Deafness and Other Communication Disorders 6120 Executive Blvd. MSC 7180, Room 400C Bethesda, MD 20892-7180 Telephone: (301) 402-3464 FAX: (301) 402-6251 Email: [email protected] Direct inquiries regarding fiscal matters to: Mr. Bruce L. Ringler Grants Management Branch National Institute of Mental Health 6001 Executive Boulevard, Room 6122, MSC 9605 Bethesda, MD 20892-9605 Telephone: (301) 443-2811 FAX: (301) 443-6885 Email: [email protected] Mr. Gary Fleming Grants Management National Institute on Drug Abuse 6001 Executive Boulevard, Room 3131, MSC 9541 Bethesda, MD 20892-9541 Telephone: (301) 443-6710 FAX: (301) 594-6847 Email: [email protected] Ms. Linda Hilley Office of Planning and Resource Management National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Suite 504 MSC 7003 Bethesda, MD 20892-7003 Telephone: (301) 443-4703 FAX: (301) 443-3891 Email: [email protected] Mr. Joseph Ellis Grants and Contracts Management Office National Institute on Aging 7201 Wisconsin Avenue, Suite 2C231 Bethesda, MD 20892-9205 Telephone: (301) 496-1472 FAX: (301) 402-3672 Email: [email protected] Ms. Carolyn E. Grimes Grants Management Branch National Eye Institute Executive Plaza South MSC 7164, Suite 350 Bethesda, MD 20892-7164 Telephone: 301-496-5884 FAX: 301-496-9997 Email: [email protected] Ms. Tina Carlisle Grants Management Branch National Institute of Neurological Disorders and Stroke 6001 Executive Boulevard, Room 3261, MSC 9190 Bethesda, MD 20892-9190 Telephone: (301) 496-9231 FAX: (301) 402-0219 Email: [email protected] Ms. Sharon Hunt Division of Extramural Activities National Institute on Deafness and Other Communication Disorders 6120 Executive Boulevard MSC 7180, Room 400B Bethesda, MD 20892-7170 Telephone: (301) 402-0909 FAX: (301) 402-1757 Email: [email protected] AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.242 (NIMH), 93.279 (NIDA), 93.273 (NIAAA), 93.866 (NIA), 93.853 (NINDS), 93.173 (NIDCD), and 93.867 (NEI). 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 Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards will be administered under PHS grants policy as stated in the NIH Grants Policy Statement (October 1, 1998). The PHS strongly encourages all grant 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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