MICROARRAY-BASED RESEARCH ON DRUG ABUSE Release Date: December 16, 1999 RFA: DA-00-003 National Institute on Drug Abuse Letter of Intent Receipt Date: February 28, 2000 Application Receipt Date: March 28, 2000 THIS REQUEST FOR APPLICATIONS (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 National Institute on Drug Abuse (NIDA) announces the availability of funds for research project grants for the study of drug abuse and related areas using microarray technology. NIDA supports over 85 percent of the world's research on the health aspects of drug abuse and addiction and serves as the foundation of the Nation's investment in understanding the causes, consequences, and treatment of drug addiction. In an effort to expand our understanding of the basic biology of drug addiction, NIDA is initiating this grant program in order to support innovative studies that exploit the emerging microarray technology. With this announcement, NIDA plans to develop a strong, multidisciplinary basic research program--drawing from neuroscience, genetics, behavioral science, bioengineering, and computational biology--aimed at adapting and applying microarray techniques to the general problem of drug abuse. The creation of collaborative teams that will develop innovative approaches for analyzing microarray data is encouraged. Eventually, it is anticipated that the identification of genes and gene products that may underlie the process of addiction will provide new targets for the development of new medications and therapies for drug abuse. 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, Microarray-Based Research on Drug Abuse, is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2000" at http://odphp.osophs.dhhs.gov/pubs/hp2000. 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. Awards to foreign institutions under R-series awards are generally limited to 5 years. MECHANISM OF SUPPORT The mechanisms available for support of this program announcement include project grant (R01) and exploratory/developmental grant (R21). Applicants are advised to contact NIDA program staff listed under INQUIRIES for additional information and specific application procedures. For research in methods development, the R21 mechanism is particularly appropriate. The exploratory/developmental (R21) grants are non-renewable and limited to $100,000 direct cost amount per year. The R21 mechanism is intended to encourage exploratory research projects with sound methodology and strong rationales in underdeveloped research areas of drug abuse, such as the areas covered in this RFA. Investigators may also choose to include methods development as one component within the R01 mechanism. Specific information on individual research mechanisms can be obtained from the NIDA home page at http://www.nida.nih.gov/Funding.html. 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 3 years. This RFA is a one-time solicitation. FUNDS AVAILABLE NIDA intends to commit approximately $2,000,000 in FY 2000 to fund approximately five-six new grants in response to this RFA. An applicant may request a project period of up to 3 years. 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 NIDA provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of applications of outstanding scientific and technical merit. RESEARCH OBJECTIVES Background Microarrays represent a powerful new technology that has been applied to a variety of research questions. For example, oligonucleotide/cDNA arrays have been used to analyze the overall expression patterns of cells and tissues under various conditions, to identify amplified regions of the genome, and to search for specific changes in gene expression caused by variants or mutant alleles. It has been shown that administration and/or withdrawal of opiates and other drugs of abuse induce the expression of specific genes and their protein products. In some cases, experimental overexpression or knock-out of these genes mimics or blocks the effects of the drugs, suggesting that gene expression plays a crucial role in mediating the response to drugs. Therefore, it is of interest to use microarrays to determine how abused drugs affect the overall gene expression pattern, and ultimately the overall protein expression pattern, in specific target cells. Research has shown that particular regions of the brain, such as the nucleus accumbens, VTA, amygdala and prefrontal cortex, are important sites in the response to addictive drugs. The nature of the relevant changes in gene expression in these and other target brain regions may be relatively small quantitatively. Furthermore, different brain regions may respond in alternate or even opposite ways to the same substance, and within any region, only a particular subset of neurons may play a critical role in the biology of addiction. Consequently, it is of paramount importance to clearly define the regions of the brain to be analyzed so that the signal-to-noise ratio is high. Ultimately, analysis of post-mortem human or mammalian tissue with microarrays may provide a fingerprint of gene and/or protein expression in particular cell types that characterizes the addicted brain. It is anticipated that basic research findings in this area will rapidly feed into NIDA’s applied medications development efforts; the identification of additional genes or gene products that potentially underlie the process of addiction will provide new targets both for traditional drug discovery efforts and for the potential development of gene therapies. In addition, microarrays are a powerful tool that may be relevant to other areas of drug abuse research, such as behavioral genetics. It is often difficult to isolate quantitative trait loci (QTLs) and specific loci implicated in mediating complex behaviors because they map to large areas of the chromosome containing many genes. In some studies, microarrays have been used to compare the expression of all the genes in a target region in control and affected individuals, thus identifying specific candidate genes for further study. In the future, microarray technology may become even more useful and powerful as new data analysis tools and novel applications, such as protein expression microarrays, are developed. Areas of Interest Current areas of research that are considered relevant include but are not limited to: o Characterization of an overall expression pattern of neural tissues or cells in response to addictive drugs. o Profiling the expression of enzymes involved in metabolism of addictive drugs. o Developmental profiling of gene expression in brain regions that mediate addictive behavior. o Identification of unique patterns of gene expression associated with addiction, the response to environmental cues that promote relapse, or other drug abuse behaviors. o Innovative uses of microarrays in studies of the genetics of behavior and/or drug abuse. SPECIAL REQUIREMENTS Data Sharing Plan: Dissemination of Data and Biological Materials The sharing of biological materials, data, and research tools in a timely manner has been an essential element in the rapid progress that has been made in the analysis of complex traits such as substance abuse. PHS policy is that investigators make unique research resources readily available for research purposes to qualified individuals within the scientific community when first results based on these resources have been published (PHS Grants Policy Statement in the July 12, 1996, issue of the NIH Guide to Grants and Contracts). Accordingly, NIDA expects applicants who respond to this RFA to develop and propose detailed plans for sharing the data and materials generated through the grant. It is expected that the information to be distributed will include all novel research tools and clone sets, as well as the data generated from the arrays. It is expected that the Data Sharing Plan will specify the following elements: 1) the creation of comprehensive databases that contain the microarray analysis results collected and produced by the grant, 2) a mechanism or protocol by which the databases can be widely searched and/or distributed to qualified investigators in the scientific community, 3) a mechanism by which biological materials (e.g., DNA samples, arrays) and research tools can be distributed to qualified investigators in the scientific community, and 4) a timetable specifying when the database and/or biological materials and/or research tools will be available for distribution. The Scientific Review Group will be asked to comment on the proposed plan for data sharing and access, and the adequacy of the plan will be considered by NIDA in making funding decisions. The plan must be approved by NIDA (after negotiation with the applicant if necessary) before an award will be made. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," which was published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994, available on the Web at: http://grants.nih.gov/grants/guide/notice-files/not94-100.html. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the Inclusion of Children as Participants in Research Involving Human Subjects that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html Investigators also may obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. NATIONAL ADVISORY COUNCIL ON DRUG ABUSE RECOMMENDED GUIDELINES FOR THE ADMINISTRATION OF DRUGS TO HUMAN SUBJECTS The National Advisory Council on Drug Abuse recognizes the importance of research involving the administration of drugs to human subjects and has developed guidelines relevant to such research. Potential applicants are encouraged to obtain and review these recommendations before submitting an application that will administer compounds to human subjects. The guidelines are available on NIDA's Home Page at http://www.nida.nih.gov under "What's New" or may be obtained by calling (301) 443-2755. LETTER OF INTENT Prospective applicants are asked to submit a letter of intent by February 28, 2000, 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 is 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 NIDA staff to estimate the potential review workload and plan review of the application. The letter of intent is to be sent to: Director, Office of Extramural Program Review National Institute on Drug Abuse 6001 Executive Boulevard, Room 3158, MSC 9547 Bethesda, MD 20892-9547 Telephone: (301) 443-2755 FAX: (301) 443-0538 APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants. Application kits are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone (301) 710-0267, E-mail: [email protected]. 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 $250,000 per year. (Applications that request more than $250,000 direct costs in any year must follow the traditional PHS 398 application instructions.) 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 7b should be completed, indicating Direct Costs (in $25,000 increments up to a maximum of $250,000) and Total Costs [Modular Total Direct plus Facilities and Administrative (F&A) costs] for the initial budget period. Items 8a and 8b should be completed indicating the Direct and Total Costs for the entire proposed period of support. DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4 of the PHS 398. It is not required and will not be accepted with the application. BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the categorical budget table on Form Page 5 of the PHS 398. It is not required and will not be accepted with the application. NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative page (see http://grants.nih.gov/grants/funding/modular/modular.htm for sample pages). At the top of the page, enter the total Direct Costs requested for each year. This is not a Form page. Under Personnel, list key project personnel, including their names, percent of effort, and role in the project. No individual salary information should be provided. However, the applicant should use the NIH appropriation language salary cap and the NIH policy for graduate student compensation in developing the budget request. For Consortium/Contractual costs, provide an estimate of total costs (Direct plus F&A) for each year, each rounded to the nearest $1,000. List the individuals/organizations with whom consortium or contractual arrangements have been made, the percent effort of key personnel, and the role on the project. Indicate whether the collaborating institution is foreign or domestic. The total cost for a consortium/contractual arrangement is included in the overall requested Modular Direct Cost amount. Include the letter of intent to establish a consortium. Provide an additional narrative budget justification for any variation in the number of 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: http://grants.nih.gov/grants/funding/modular/modular.htm - Complete the educational block at the top of the Form page; - List position(s) and any honors; - Provide information, including overall goals and responsibilities, on research projects ongoing or completed during the last three years; and - List selected peer-reviewed publications, with full citations. 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. All appropriate exclusions must be applied 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. 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 title and number of this RFA must be typed in Item 2 on the face page of the application form, and the YES box must be marked. The RFA number must be typed on the label as well. The sample RFA label is available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to allow for this change. Please note this is in the pdf format. 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: Director, Office of Extramural Program Review National Institute on Drug Abuse 6001 Executive Boulevard, Room 3158, MSC 9547 Bethesda, MD 20892-9547 Rockville, MD 20852 (for express/courier service) Applications must be received by March 28, 2000. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Research (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 for responsiveness by NIDA. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by NIDA in accordance with the review criteria stated below. As part of the initial merit review, a process will be used by the initial review group in which applications receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed, assigned a priority score, and receive a second level review by the NIDA 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. (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? (For the R21 mechanism, a strong rationale and conceptual framework are normally sufficient for establishing the feasibility of the project, in lieu of extensive preliminary data.) (3) 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? Does the applicant propose novel approaches to improve the accuracy, efficiency, and usefulness of microarray-based assays? (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? In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o The adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. 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. The review group will also comment on plans for data sharing. Schedule Letter of Intent Receipt Date: February 28, 2000 Application Receipt Date: March 28, 2000 Peer Review Date: Summer 2000 Council Review: September 2000 Earliest Anticipated Start Date: September 29, 2000 AWARD CRITERIA Award criteria that will be used to make award decisions include: o scientific merit (as determined by peer review) o availability of funds o programmatic priorities o adequacy of plans for data sharing INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Rebekah S. Rasooly, Ph.D. Division of Neurosciences & Behavioral Research National Institute on Drug Abuse 6001 Executive Boulevard, Room 4282, MSC 9555 Bethesda, MD 20892 Telephone: (301) 443-6300 FAX: (301) 594-6043 Email: [email protected] Direct inquiries regarding review matters to: Teresa Levitin, Ph.D. Director, Office of Extramural Program Review National Institute on Drug Abuse 6001 Executive Boulevard, Room 3158, MSC 9547 Bethesda, MD 20892-9547 Telephone : (301) 443-2755 FAX: (301) 443-0538 E-mail: [email protected] Direct inquiries regarding fiscal matters to: Gary Fleming, J.D., M.A. 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: [email protected] AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.279. 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. 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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