MUTANT MOUSE PHENOTYPING: ETHANOL-RELATED BEHAVIOR AND NERVOUS SYSTEM FUNCTION Release Date: December 17, 2001 RFA: RFA-AA-02-007 National Institute on Alcohol Abuse and Alcoholism (http://www.niaaa.nih.gov) Letter of Intent Receipt Date: March 15, 2002 Application Receipt Date: April 15, 2002 THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. MODULAR INSTRUCTIONS MUST BE USED FOR RESEARCH GRANT APPLICATIONS REQUESTING LESS THAN $250,000 PER YEAR IN ALL YEARS. MODULAR BUDGET INSTRUCTIONS ARE PROVIDED IN SECTION C OF THE PHS 398 (REVISION 5/2001) AVAILABLE AT http://grants.nih.gov/grants/funding/phs398/phs398.html. PURPOSE NIAAA has previously provided funding to two Mouse Mutagenesis Centers to create chemically induced single-gene mutants of mice with altered behavioral responses to ethanol. These mutant mice, which will begin to become available to the research community in 2002, will be valuable new tools for elucidating the physiological mechanisms of ethanol's effects on behavior and nervous system function. NIAAA is issuing this RFA in order to promote the extraction of greatest possible amount of information from these mutants, by means of the following types of studies: - Identification of the mutated genes responsible for the altered ethanol- related behavior exhibited by the mutant mice. - Behavioral, anatomical, physiological, and pharmacological studies on these mutants to determine the mechanisms by which the mutations they bear cause alterations in their ethanol-related behavior. - High-throughput mutant screens to identify additional mutant mice with altered ethanol-related behavioral or neurological phenotypes. HEALTHY PEOPLE 2010 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS- led national activity for setting priority areas. This Request for Applications (RFA), Title of RFA, is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, for-profit and non- profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) R01 and R21 award mechanisms. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for an application submitted in response to this RFA may not exceed three years (R21), or five years (R01). This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. The anticipated award date is September 28, 2002. Specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts that have been adopted by the NIH. Complete and detailed instructions and information on Modular Grant applications have been incorporated into the PHS 398 (rev. 5/2001). Additional information on Modular Grants can be found at http://grants.nih.gov/grants/funding/modular/modular.htm. FUNDS AVAILABLE NIAAA intends to commit approximately $1.5 million (total costs) in FY 2003 to fund 6-8 new and/or competitive continuation grants in response to this RFA. An applicant may request a project period of up to three years and a budget for direct costs of up to $100,000 per year for R21 grants, or up to five years with no budget restrictions for R01 grants. However, applicants must request permission in advance from NIAAA to submit an application for which the budget exceeds $500,000 direct costs in any year. Because the nature and scope of the research proposed may vary, it is anticipated that the size of each award will also vary. Although the financial plans of the NIAAA have identified support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. At this time, it is not known if this RFA will be reissued. RESEARCH OBJECTIVES Background The isolation of mutant mice with altered ethanol-related behavior is a powerful method for identifying genes influencing ethanol-related behavior, in a manner unbiased by prior physiological hypotheses. NIAAA has accordingly previously provided funds for this purpose to Mouse Mutagenesis centers at the Jackson Laboratory (http://www.jax.org/nmf/) and the University of Tennessee at Memphis (http://tnmouse.org/index.html). These Centers, along with a third Center at Northwestern University (http://genome.northwestern.edu/), have begun to generate large numbers of chemically induced single-gene mutant mice with alterations in a wide variety of behaviors and nervous system functions. The first two of these centers are screening for mutants with alterations in ethanol consumption, ethanol- induced hypothermia, ataxia, locomotor activation, and anxiolysis. Mutants isolated in these screens will be tested to determine whether they also display alterations in the temporal structure of their drinking behavior (measured with a lickometer), as well as their ethanol-induced sedation, conditioned taste aversion, and operant self-administration. These centers are also screening for mutants with altered sensorimotor gating, anxiety, novelty-seeking, aggression, and responses to other drugs of abuse, all of which traits may be mechanistically related to various types of ethanol- related behavior. All of these mutants will be made available to the general research community for further intensive study. The underlying purpose of creation of mutants with altered behavioral responses to ethanol is the elucidation of the physiological mechanisms mediating such responses. Creation of mutants is thus not an end in itself, but is rather the starting point of such investigation. One informative path for such investigation is the identification of the mutated genes responsible for the behavioral alterations. Some of these genes may encode proteins of previously known function, which have not previously been suspected of mediating ethanol-related behavior. In such a case, identification of the mutated gene may immediately draw attention to the entire biochemical pathway in which the encoded protein functions. In cases where this pathway is not known, the identity of the mutated gene can be the starting point for the elaboration of such a pathway. Such elaboration requires further neuroanatomical, neuropharmacological, and neurophysiological analyses of the mutant mice to determine the sequence of physiological alterations linking the mutated gene with the mutant's altered behavioral responses to ethanol. Comparison of global patterns of gene expression in the nervous systems of either naive or ethanol-exposed mutant and wild-type mice can also help elucidate the physiological changes linking the mutation with the behavioral changes it entrains. This RFA is soliciting proposals employing any current methodology to reveal the causal chain of events linking mutation with altered behavior. Although the mutagenesis centers are screening for mutants with alterations in a range of ethanol-related behaviors (listed above), mutant mice with alterations in more complex neuroadaptive responses to ethanol would also be desirable tools for elucidating the physiological mechanisms of these adaptations. Such adaptations include sensitization, tolerance (physical and motivational), dependence, withdrawal (physical and affective aspects), deprivation- or stress-induced consumption, initiation of consumption, reinforcement, and ethanol discrimination. Mutants with altered nervous system responses to ethanol (such as levels of hormones, neuropeptides, or neurotransmitter metabolites in cerebrospinal fluid) would be of similar value to the research community. NIAAA encourages investigators inclined to develop high-throughput assays of nervous system and behavioral responses to ethanol to respond to this RFA with proposals for mutant screens employing such assays. Collaborations with Established Mutagenesis Centers Applications for studies on existing mutant mice must document either the actual presence of the animals in the investigator's laboratory, or provide a letter from the supplying facility specifying when the mutants will be shipped to the investigator's laboratory. For access to these mutants, investigators should consult the websites of the mutagenesis centers (listed under Background, above). In addition, mutant mice will be available from a distribution facility operated under contract to NIH, solicited under request for proposals RFP NIMH-01-DN-0018, "Mouse Neuroscience Phenotyping and Distributing Center". Once this facility is operational, contact information about it will be posted on the Trans-NIH Mouse Initiative webpage, http://www.nih.gov/science/models/mouse/. Investigators wishing to screen for new mutants should establish a collaboration with an existing Mouse Mutagenesis Center, either one of those mentioned under Background (above), or some other such Center. Potential applicants are encouraged to contact NIAAA Program Staff (see INQUIRIES, below) for more information about existing Mouse Mutagenesis Centers. Investigators may arrange to screen mice on-site at a Mutagenesis Center (under the Center's Visiting Investigator Program), or may have mutant mice shipped from the Center to their own laboratories for screening. Applications must document the collaboration in detail, clearly specifying the respective roles of the investigator and any staff of the Mutagenesis Center. In addition, applicants who receive animals are responsible for all shipping and handling costs, and must provide for the care and welfare of these animals in accordance with all Federal, state and local laws. Applications to set up new mouse mutagenesis facilities will not be considered responsive to this RFA. Areas of Interest The following examples of projects supportable under this RFA are for illustration only, and are not exclusive. - Mapping and identification of the genes mutated in existing mutant mice. - Characterization of complex ethanol-related behavior of existing mutants, e.g., ethanol sensitization, tolerance (physical or motivational), dependence, withdrawal (physical or affective aspects), deprivation- or stress-induced consumption, initiation of consumption, reinforcement, ethanol discrimination. - Identification of neuroanatomical, neurochemical, or neurophysiological mechanisms mediating alterations of ethanol-related behavior in existing mutants (e.g., changes in synaptic connectivity or morphology, receptor density or activity, neurotransmitter synthesis or release, spontaneous or evoked neuronal firing, protein kinase localization and activity, receptor phosphorylation state). - Analysis of altered patterns of gene or protein expression in the nervous system of existing mutants, which could mediate their alterations in ethanol- related behavior. - High-throughput screens for new mutants with altered complex ethanol- related behavior, or altered nervous-system responses to ethanol. SPECIAL REQUIREMENTS Sharing of Materials Generated Under this RFA and Exercise of Intellectual Property Rights Projects funded under this RFA are likely to lead to the creation of new mutant mice and new genetic stocks containing previously existing mutations, as well as other research tools of great value to the broader research community. NIAAA strongly encourages the maximal dissemination of these tools to the broader research community, to ensure that they may be exploited to their full potential. NIAAA accordingly requires applicants who respond to this RFA to propose detailed plans for sharing the research resources generated through the grant. Resources to be shared should include all materials developed in projects funded under the RFA, including but not limited to, mutant animals, preserved embryos and sperm, phenotypic and genetic data, phenotyping assays, and instrumentation. For this purpose, NIAAA views the dissemination of such resources through individual laboratories and websites is not sufficient, since it would force interested investigators to search numerous websites in order to gain access to research tools generated under this RFA. It is preferable that materials generated under this RFA be placed in common, public repositories and databases that are widely accessible by investigators in the scientific community. The investigator's resource sharing plan should include a description of the mechanisms proposed for wide distribution of resources with investigators in the scientific community, and a timetable for such distribution. Mutant mice developed by the mutagenesis centers funded under RFA MH-99-007 (the Jackson Laboratory, University of Tennessee at Memphis, Northwestern University) and RFA HD-99-007 (Baylor College of Medicine) are covered by a Declaration of Exceptional Circumstances (DEC) to the Bayh-Dole Act, 37 C.F.R. 401.3(a)(2), which prohibits patenting thereof. Any mutant stocks developed elsewhere are not covered by this DEC. With regard to such mutant stocks and other patentable research materials, such as phenotyping assays, protocols, instrumentation, and methodologies, NIAAA requires applicants who respond to this RFA to propose a plan addressing whether, and 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 plan should include a description of the applicant's 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. This plan for exercise of intellectual property rights is required in addition to the plan for sharing and disseminating research resources (described above). The reviewers will make an administrative comment on the adequacy of the proposed plans for resource sharing and exercise of intellectual property rights. (This comment will not affect the priority score of the proposal.) NIAAA program staff will consider the adequacy of these plans in determining whether to recommend an application for award. These plans as approved, after negotiation with the applicant as necessary, shall become a condition of the grant award. Where appropriate, grantees may work with the private sector to make resources available to the wider research community at a reasonable cost. Applicants may request funds to defray the costs of sharing resources, with adequate justification. For more detailed guidance on NIH's policies on resource sharing, applicants are referred to "Principles and Guidelines for Recipients of NIH Research Grants and Contracts on Obtaining and Disseminating Biomedical Research Resources," http://www.ott.nih.gov/policy/rt_guide_final.html. Evaluation of any future renewal applications will include assessment of the awardee's adherence to the proposed plan. Applicants are also reminded that the grantee institution is required to disclose each subject invention to NIH within two months after the inventor discloses it in writing to grantee institution personnel responsible for patent matters. NIAAA 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. URLS IN NIH GRANT APPLICATIONS OR APPENDICES All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at: http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this RFA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. LETTER OF INTENT Prospective applicants are asked to submit 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 the RFA in response to which the application may be submitted. 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 allows IC staff to estimate the potential review workload and plan the review. The letter of intent is to be sent to RFA-AA-02-007 Extramural Project Review Branch National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Room 409, MSC 7003 Bethesda, MD 20892-7003 Rockville, MD 20852 (for express/courier service) Telephone: (301) 443-4375 FAX: (301) 443-6077 by the letter of intent receipt date listed. APPLICATION PROCEDURES The PHS 398 research grant application instructions and forms (rev. 5/2001) available at http://grants.nih.gov/grants/funding/phs398/phs398.html must be used in applying for these grants. This version of the PHS 398 is available in an interactive, searchable format. For further assistance contact GrantsInfo, Telephone 301/435-0714, Email: GrantsInfo@nih.gov. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS The modular grant concept establishes specific modules in which direct costs may be requested as well as a maximum level for requested budgets. Only limited budgetary information is required under this approach. The just-in-time concept allows applicants to submit certain information only when there is a possibility for an award. It is anticipated that these changes will reduce the administrative burden for the applicants, reviewers and NIH staff. The research grant application form PHS 398 (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html must be used in applying for these grants, with modular budget instructions provided in Section C of the application instructions. The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. 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. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. 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: Extramural Project Review Branch Attn: AA-02-007 National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Room 409, MSC 7003 Bethesda, MD 20892-7003 Rockville, MD 20852 (for express/courier service) Applications must be received by the application receipt date listed in the heading of this RFA. 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 the CSR and responsiveness by the NIAAA. If the application is not responsive to the RFA, CSR staff may contact the applicant to determine whether to return the application to the applicant or submit it for review in competition with unsolicited applications at the next review cycle. 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 NIAAA 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 review by the NIAAA 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 the written comments reviewers will be asked to discuss the following aspects of the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. (1) Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? (2) Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? (3) Innovation: Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? (4) Investigator: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? (5) Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? (6) For applications proposing to screen for new mutants, are the proposed screens likely to lead to the isolation of mutant mice which will be useful to the research community for investigating the mechanisms of uncontrolled ethanol consumption and ethanol dependence? (7) Will the mutants be bred into genetic stocks which will be convenient for the research community to use? In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the reasonableness of the proposed budget and duration in relation to the proposed research. The reviewers will also be asked to comment administratively on the adequacy of the resource sharing and intellectual property plans, but these comments will not affect the score of the application. Schedule Letter of Intent Receipt Date: March 15, 2002 Application Receipt Date: April 15, 2002 Peer Review Date: June-July 2002 Council Review: August 2002 Earliest Anticipated Start Date: September 28, 2002 AWARD CRITERIA Award criteria that will be used to make award decisions include: - scientific merit (as determined by peer review) - availability of funds - programmatic priorities - For applications proposing to screen for new mutants, how well the proposed screens complement ongoing screens already funded by NIAAA. - Adequacy of the proposed plans for resource sharing and exercise of intellectual property rights. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or answer questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Lisa Neuhold, Ph.D. Neurosciences and Behavioral Research Branch Division of Basic Research National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Suite 402, MSC 7003 Bethesda, MD 20892-7003 Rockville, MD 20850 (for express/courier service) Telephone: (301) 594-6228 FAX: (301) 594-0673 Email: lneuhold@willco.niaaa.nih.gov Antonio Noronha, Ph.D. Chief, Neurosciences and Behavioral Research Branch Division of Basic Research National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Suite 402, MSC 7003 Bethesda, MD 20892-7003 Rockville, MD 20850 (for express/courier service) Telephone: (301) 443-7722 FAX: (301) 594-0673 Email: anoronha@willco.niaaa.nih.gov Direct inquiries regarding fiscal matters to: Ms. Judy Simons Grants Management Branch National Institute on Alcohol Abuse and Alcoholism 6000 Executive Blvd, Suite 504, MCS 7003 Bethesda, MD 20892-7003 Telephone: (301) 443-2434 FAX: (301) 480-3891 Email: jsimons@willco.niaaa.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.273. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant 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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