GENE EXPRESSION PROFILING IN THE NERVOUS SYSTEM Release Date: November 22, 1999 RFA: MH-00-002 National Institute of Mental Health National Institute of Neurological Disorders and Stroke National Eye Institute National Institute of Child Health and Human Development National Institute on Aging National Institute on Deafness and Other Communication Disorders National Institute on Drug Abuse Letter of Intent Receipt Date: February 28, 2000 Application Receipt Date: March 29, 2000 THIS RFA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA. PURPOSE The purpose of this Request for Applications (RFA) is to solicit feasibility studies for profiling gene expression patterns in the mammalian nervous system. Exploratory research projects supported under this RFA will utilize neural tissue-specific cDNA reagents and state-of-the-art microarray technologies, in order to quantify in a highly parallel way expression profiles of genes in mammalian neural tissue. The creation of collaborative teams is encouraged, in which scientists with expertise in neuroscience research, genomics, and bioinformatics work to apply innovative approaches for analyzing microarray data. Such feasibility studies will permit functional analyses of mouse and human neural tissue that aim to understand genes influencing the nervous system in their full biological context. The widespread availability of innovative methods for gene expression profiling will stimulate many avenues of research on nervous system functioning and complex behavioral disorders. 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, Gene Expression Profiling in the Nervous System, is related to one or more priority areas. Applicants may obtain a copy of "Healthy People 2000" at ELIGIBILITY REQUIREMENTS Applications may be submitted by foreign and 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 This RFA will use the National Institutes of Health (NIH) Exploratory/ Developmental Grants (R21) mechanism. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. Because the purpose of R21 Exploratory/Developmental Grants is to support exploratory studies, establish feasibility of new approaches, and to help acquire preliminary data for use in preparing traditional R01 support, R21 grant applications received in response to this RFA are limited to two years with a maximum of $150,000 direct costs requested per year, and are not renewable. The anticipated award date is September 30, 2000. For all competing R21 awards, specific application instructions have been modified to reflect MODULAR GRANT and JUST-IN-TIME streamlining efforts being undertaken at NIH. More detailed information about modular grant applications, including a sample budget narrative justification pages and a sample biographical sketch, is available via the Internet at FUNDS AVAILABLE This RFA is a one-time solicitation. It is anticipated that about $3,750,000 in total costs (including all direct and facilities and administrative costs) will be available for this initiative in Fiscal Year 2000, during which it is anticipated that 15 awards will be made. The total project period for an application submitted in response to this RFA may not exceed two 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 for the second year of the grant will be contingent upon satisfactory progress during the first year and availability of funds. For the purpose of accomplishing the goals of this RFA, subcontracts may be included in the budget to support investigators at sites other than the awardee institution. All direct and facilities and administrative subcontract costs in a given year will be counted toward the maximum of $150,000 direct costs requested by the awardee institution for that year. RESEARCH OBJECTIVES Precise spatio-temporal expression of genes during development is critical for determining and maintaining the structure and function of the mammalian nervous system. The determination of the profile of genes expressed in various brain cell types during development and aging, as well as alterations in gene expression patterns during pathophysiological states or in response to external influences, will provide valuable information that will contribute to a greater understanding of nervous system functioning. This information may provide an experimental framework for new approaches and strategies that will lead to the improved diagnosis, treatment, and the eventual prevention of brain disorders. In order to determine such expression patterns and decipher the molecular anatomy of the mammalian nervous system, NIH launched the Brain Molecular Anatomy Project (BMAP) as an interdisciplinary project to establish state-of- the-art technologies and informatics systems. This multi-institute effort consists of several distinct components. The gene discovery component of BMAP is aimed at cataloguing the full repertoire of genes expressed in the nervous system, under both normal and abnormal conditions. The first funded BMAP gene discovery project supports construction of normalized, serially subtracted cDNA libraries from 10 brain regions of adult mouse brain, spinal cord, and retina (strain C57BL6J). To date, a total of 32,031 mouse brain 3 EST sequences have been submitted to the dbEST database maintained by the National Center for Biotechnology Information (NCBI). By the end of the two-year project period, approximately 100,000 5 and 3 mouse brain EST sequences will be generated and used to identify a non-redundant collection of >20,000 mouse brain UniGene cDNA sets. The sequences of these mouse brain ESTs will be accessible through the NCBI-maintained dbEST database (, and all of the BMAP cDNA clones - including those representing members of unique mouse brain UniGene sets - will be made available to the scientific community through a distributor to be designated. In addition to the BMAP mouse brain UniGene sets, other genomic resources have been generated in recent years. For example, cDNA clones comprising UniGene sets for human and other mammals have been isolated, collected, and are available from many commercial distributors. The availability of these genomic resources, along with DNA microarray technologies, presents a unique and unprecedented scientific opportunity for the neuroscience community to advance gene discovery and gene expression analysis. DNA microarray technologies offer the ability to monitor simultaneously the expression patterns of large numbers of genes that are relevant to nearly every aspect of neuroscience research. Nevertheless, there are many scientific issues and technical obstacles that need to be resolved before cDNA microarray technology can be used widely by individual neuroscientists for global analysis of gene expression patterns in the nervous system. This RFA is intended to support research that will develop and apply experimental approaches and technologies to quantify, in a highly parallel way, expression profiles of genes in mammalian neural tissue. These projects may utilize existing gene profiling resources, e.g., UniGene sets, array facilities, and analytic tools, currently available to the neuroscience community. Applicants are encouraged to provide a plan to disseminate to the scientific community protocols, procedures, analytical tools, and other materials that may be developed in the course of the project. Research topics of interest include, but are not limited to, the following: o Pilot projects to test the feasibility of determining global gene expression patterns of the nervous system, and to monitor changes in these patterns during development and under normal and experimental/pathological conditions. o Projects to develop arrays containing restricted sets of cDNA clones and monitor alterations of gene expression in specific brain regions or cell types in the nervous system that occur in response to experimental manipulations such as administration of abused substances. o Projects to develop efficient experimental protocols for using cDNA arrays for studies of gene expression patterns in mammalian neural tissue. Methods for preparation of microarray hybridization probes from a small amount of pathological specimen, embryonic tissue, micro-dissected tissue or single cell are of particular interest. o Projects to expand or enhance the capability of currently available image analysis and bioinformatics tools to measure and record data from microarrays. The development and application of novel data tracking and management systems are of particular interest. o Projects to develop higher-order analysis bioinformatics tools and software algorithms to process microarray data for statistical analysis, cluster analysis, and mathematical modeling to characterize gene-gene interactions and functional pathways in the nervous system. LETTER OF INTENT Prospective applicants are asked to submit, by February 28, 2000, 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. Send the letter of intent 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: 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: The application is also available at SPECIFIC APPLICATION INSTRUCTIONS FOR MODULAR GRANTS The modular grant concept establishes specific modules in which direct costs may be requested as well as a maximum level for requested budgets. Only limited budgetary information is required under this approach. The just-in-time concept allows applicants to submit certain information only when there is a possibility for an award. It is anticipated that these changes will reduce the administrative burden for the applicants, reviewers and Institute staff. The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants, with the modifications noted below. BUDGET INSTRUCTIONS Modular Grant applications will request direct costs in $25,000 modules, up to a total direct cost request of $150,000 per year. The total direct costs must be requested in accordance with the program guidelines and the modifications made to the standard PHS 398 application instructions described below: PHS 398 FACE PAGE: Items 7a and 8a should be completed to indicate Modular Direct Costs requested and Items 7b and 8b should reflect Total Costs (Modular Direct plus F&A costs). Item 7 should reflect costs for the Initial Budget Period and item 8 should reflect costs for the Total Project Period. DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD: Do not complete Form Page 4 of the PHS 398 (rev 4/98). It is not required nor will it be accepted at the time of application. BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT: Do not complete the categorical budget tables on page 5 of the PHS 398 (rev. 4/98) Form. Only the requested total direct costs line for each year should be completed based on the number of $25,000 modules being requested. Applicants may not request a change in the amount of each module. A maximum of six modules (up to $150,000) may be requested for an R21 application. Applicants may request up to two years of support for this RFA. Direct cost budgets will remain constant throughout the life of the project (i.e., the same number of modules requested for all Project periods). Any necessary escalation should be considered when determining the number of modules to be requested. However, in the event that the number of modules requested must change in any future year due to the nature of the research proposed, appropriate justification must be provided. Total Direct Costs for the Entire Proposed Project Period should be shown in the box provided. BUDGET JUSTIFICATION: o Budget justifications should be provided under "Justifications" on Form Page 5 of the PHS 398. o List the names, role on the project and proposed percent effort for all project personnel (salaried or unsalaried)and provide a narrative justification for each person based on his/her role on the project. o Identify all consultants by name and organizational affiliation and describe the services to be performed. o Provide a general narrative justification for individual categories (equipment, supplies, etc.) required to complete the work proposed. More detailed justifications should be provided for high cost items. Any large one-time purchases, such as large equipment requests, must be accommodated within these limits. CONSORTIUM/CONTRACTUAL COSTS: If collaborations or subcontracts are involved that require transfer of funds from the grantee to other institutions, it is necessary to establish formal subcontract agreements with each collaborating institution. A letter of intent from each collaborating institution should be submitted with the application. Only the percentage of the consortium/contractual total costs (direct and facilities and administrative costs) relative to the total direct costs of the overall project needs to be stated at this time. The following example should be used to indicate the percentage cost of the consortium, "The consortium agreement represents 27 percent of overall direct costs requested in the first year." A budget justification for the consortium should be provided as described in the "Budget Justification" section above (no Form Page 5 required for the consortium). Please indicate whether the consortium will be in place for the entire project period and identify any future year changes in the percentage relative to the parent grant. If there is a possibility of an award, the applicant will be requested to identify actual direct and facilities and administrative costs for all years of the consortium. Please note that total subcontract costs need not be calculated in $25,000 modules. However, when subcontract funds are added to the parent grant budget, the total direct cost amount must be included in the number of $25,000 modules requested. BIOGRAPHICAL SKETCH: The Biographical Sketch provides information used by reviewers in the assessment of each individual"s qualifications for a specific role in the proposed project, as well as to evaluate the overall qualifications of the research team. A biographical sketch is required for all key personnel, following the instructions below. No more than three pages may be used for each person. A sample biographical sketch may be viewed at: - Complete the educational block at the top of the form page, - List position(s) and any honors, - List selected peer-reviewed publications, with full citations, - Provide information, including overall goals and responsibilities, on research projects ongoing or completed during the last three years. OTHER SUPPORT: Do not complete the "Other Support" pages (Form Page 7). Selected other support information relevant to the proposed research may be included in the Biographical Sketch as indicated above. Complete Other Support information will be requested by NIH staff if there is a possibility for an award. CHECKLIST: This page should be completed and submitted with the application. If the F&A rate agreement has been established, indicate the type of agreement and the date. It is important to identify all exclusions that were used in the calculation of the F&A costs for the initial budget period and all future budget years. The applicant should provide the name and phone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. Applications not conforming to these guidelines will be considered unresponsive to this RFA and will be returned without further review. Any application subject to this policy that does not contain the required information in a cover letter sent with the application will be returned to the applicant without review. 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 and must display the RFA number MH-00-001. A sample modified mailing label is available at Please note this is in pdf format. 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 number and title, MH-00-002: Gene Expression Profiling in the Nervous System, 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 signed single-sided 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) Submit one additional copy of the application, for receipt by the application receipt date of March 29, 2000, 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) Applications must be received by March 29, 2000. 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 Applications will be reviewed for scientific and technical merit by an appropriate peer review group convened by NIMH in accordance with the review criteria stated below. 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, generally the top one half of applications under review, will be discussed, assigned a priority score, and receive a second level review by the appropriate national advisory council or board. Review Criteria The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments reviewers will be asked to discuss the following aspects of the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. o Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge by advanced? What will be the effect of these studies on the concepts or methods that drive this field? o Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant develop multidisciplinary collaborations and acknowledge potential problem areas? Are alternative tactics considered? 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? 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? The initial review group will also examine: the appropriateness of proposed project budget and duration, the adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research and plans for the recruitment and retention of subjects, the provisions for the protection of human and animal subjects, and the safety of the research environment. AWARD CRITERIA The anticipated date of award is September 30, 2000. The following will be considered in making funding decisions: o Quality of the proposed project as determined by rigorous scientific peer review. o Promise of the proposed project to accomplish the goals of this RFA, by which global gene expression profiling of mammalian neural tissue will be accomplished. o Program priorities and program balance. o Availability of funds. SCHEDULE Letter of Intent Receipt Date: February 28, 2000 Application Receipt Date: March 29, 2000 Scientific Review Date: June 2000 Advisory Council Date: September 2000 Anticipated Award Date: September 30, 2000 INQUIRIES Written and telephone inquiries concerning this RFA are strongly encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Dr. Hemin R. Chin Division of Neuroscience and 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: Dr. Robert Baughman National Institute of Neurological Disorders and Stroke 6001 Executive Boulevard, Room 2137, MSC 9527 Bethesda, MD 20892-9527 Telephone: (301) 496-1779 FAX: (301) 402-1501 Email: Dr. Maria Y. Giovanni Fundamental Retinal Processes National Eye Institute Executive Plaza South, Suite 350 6120 Executive Blvd. - MSC 7164 Bethesda, MD 20892-7164 Telephone: (301) 496-0484 FAX: (301) 402-0528 Email: Dr. Deborah Henken Center for Research for Mothers and Children National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 4B01, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 496-5541 FAX: (301) 480-0303 Email: Dr. Bradley C. Wise Neuroscience and Neuropsychology of Aging Program National Institute on Aging Gateway Building, Suite 3C307 7201 Wisconsin Ave MSC9205 Bethesda, MD 20892-9205 Telephone: (301) 496-9350 Fax: (301) 496-1494 Email: 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: Dr. Rebekah Rasooly 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: Direct inquiries regarding fiscal matters to: Ms. Diana S. Trunnell Grants Management Branch National Institute of Mental Health 6001 Executive Boulevard, Room 6115, MSC 9605 Bethesda, MD 20892-9605 Telephone: (301) 443-2805 FAX: (301) 443-6885 Email: Ms. Dawn Richardson Grants Management Branch National Institute of Neurological Disorders and Stroke 6001 Executive Blvd., Room 3270, MSC 9190 Bethesda, MD 20892-9190 Telephone: (301) 496-7484 FAX: (301) 402-0219 Email: Mr. William W. Darby 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 E-mail: Mr. E. Douglas Shawver Grants Management Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 8A17, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 496-1303 FAX: (301) 402-0915 Email: Mr. Joseph Ellis Grants Management Branch National Institute on Aging 7201 Wisconsin Ave, Suite 2N212, MSC9205 Bethesda, MD 20892-9205 Telephone: (301) 496-1472 Fax: (301) 402-3672 Email: Ms. Sharon Hunt Division of Extramural Research National Institute on Deafness and Other Communication Disorders 6120 Executive Boulevard, Room 400B - MSC 7180 Bethesda, MD 20892-7170 Telephone: (301) 402-0909 FAX: (301) 402-1757 Email: Mr. Gary Fleming Grants Management Branch 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: AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance Nos. 93.242 (NIMH), 93.853(NINDS), 93.867 (NEI), 93.865 (NICHD), 93.866 (NIA), 93.173 (NIDCD), and 93.279 (NIDA). 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 NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74 or 92. 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 policy as stated in the NIH Grants Policy Statement (October 1, 1998). The PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

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