MICROARRAY-BASED RESEARCH ON ALCOHOL’s EFFECTS ON BEHAVIOR, NERVOUS SYSTEM FUNCTION, AND ORGAN PATHOPHYSIOLOGY Release Date: April 6, 2000 RFA: AA-00-004 National Institute on Alcohol Abuse and Alcoholism (http://www.niaaa.nih.gov) Letter of Intent Receipt Date: June 19, 2000 Application Receipt Date: July 18, 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 National Institute on Alcohol Abuse and Alcoholism (NIAAA) announces the availability of funds for research project grants for the study of ethanol’s effects on behavior, nervous system function, and organ pathophysiology using emerging microarray technology. NIAAA also encourages the formation of multidisciplinary teams of investigators-- drawing from neuroscience, genetics, molecular biology, biochemistry, behavioral science, bioengineering, and computational biology--for this purpose. NIAAA anticipates that such studies will aid in the identification of genes and gene products mediating neurobiological and behavioral changes and tissue damage induced by acute and chronic exposure to ethanol, thereby providing new targets for the development of medications for prevention and treatment of alcoholism and the biomedical consequences of alcohol abuse. 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), Microarray-Based Research on Alcohol’s Effects on Behavior, Nervous System Function, and Organ Pathophysiology, 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) research project grant (R01) and the NIAAA exploratory/developmental grant (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 3 years. Applications for competitive supplements to funded NIAAA grants will also be considered responsive to this RFA. Competitive supplement applications are limited in duration to the funding period of the parent grant. 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 earliest anticipated award date is December, 2000 under expedited Council review procedures. Applicants may also submit applications for Investigator-Initiated Interactive Research Project Grants (IRPG). Interactive Research Project Grants require the coordinated submission of related research project grants (R01) from investigators who wish to collaborate on research, but do not require extensive shared physical resources. These applications must share a common theme and describe the objectives and scientific importance of the interchange of, for example, ideas, data, and materials among the collaborating investigators. A minimum of two independent investigators with related research objectives may submit concurrent, collaborative, cross- referenced individual R01 applications. Applicants may be from one or several institutions. Further information on these and other grant mechanisms may be obtained from the program staff listed in the INQUIRIES section of this RFA or from the NIAAA Web site http://www.niaaa.nih.gov/ under Research Programs/Program Announcements. FUNDS AVAILABLE The NIAAA intends to commit approximately $2 million in FY 2001 to fund six to eight new and/or competitive continuation grants in response to this RFA. An applicant may request a project period of up to 3 years with direct costs not to exceed $300,000 per year. Waivers for exceptional circumstances to exceed this limit should contact Program Staff as indicated under Inquiries below. Under the R21 mechanism, direct costs are limited to $100,000 per year. (See Program Announcement PA-99-131, NIAAA Exploratory/Developmental Grant Program, http://grants.nih.gov/grants/guide/pa-files/PA-99-131.html, for a complete description of the R21 mechanism.) Because the nature and scope of the research proposed might vary, it is anticipated that the size of awards will also vary. Although the financial plans of the NIAAA 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 meritorious applications. At this time, it is not known if this RFA will be reissued. 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 ethanol induces the expression of specific genes and their protein products. The precise changes in gene expression depend on the dose and duration of ethanol exposure, and the tissue preparation under study. It seems likely that some of these changes in gene expression play a crucial role in mediating physiological and behavioral responses to ethanol. Therefore, it is of interest to use microarrays to determine how ethanol affects 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, ventral tegmental area, amygdala and prefrontal cortex are important sites in the response to ethanol. The critical 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 ethanol, and within any region, only a particular subset of neurons may play a critical role in responses to ethanol. It is therefore of paramount importance to define the regions of the brain to be analyzed as precisely as possible, so that the signal-to-noise ratio is high. Ultimately, analysis of post-mortem human or mammalian tissue with microarrays may provide a comprehensive profile of gene and/or protein expression in particular cell types, which collectively characterizes the physiological states of neurons associated with behavioral phenomena such as tolerance, dependence, and withdrawal. This approach can also highlight differences in gene expression between individuals (or strains of animal) with high vs. low responses to ethanol (e.g., sedation, ataxia, withdrawal, locomotor activation). Ethanol is a potent teratogen that causes a spectrum of brain damage, including fetal alcohol syndrome. Depending on dose of ethanol and timing of exposure, specific brain regions and cell populations are differentially affected. Analysis of tissues with microarrays could provide insights about the relationship between functional alterations during development and subsequent neurological and behavioral deficits. Responses in plasticity to specific prenatal and postnatal manipulations can also be evaluated. The initiation and progression of ethanol-induced organ pathogenesis is a complex process that involves the induction of genes and their protein products at multiple sites. Elucidating the specific molecular targets of ethanol’s actions in specific organs will facilitate the development of appropriate drug interventions. As with brain, it will be important to delineate specific cell populations for evaluation with microarrays. The technology and analytic methodology for micorarray-based studies are now at a relatively early stage of development. NIAAA encourages studies using current technology, as well as those which incorporate development and improvement of microarray-based methods. Areas of Interest Current areas of research that are considered relevant include but are not limited to: o Characterization of overall gene expression pattern of neural tissues or cells in response to acute or chronic exposure to ethanol. o Identification of unique patterns of gene expression due to prenatal and/or neonatal exposure to ethanol. o Identification of unique patterns of gene expression describing organ system pathology due to ethanol exposure, e.g., cardiomyopathy, pancreatitis, alcoholic liver disease. o Identification of unique patterns of gene expression associated with specific behavioral responses to ethanol. o Comparison of gene expression patterns in strains of animals differing in specific responses to ethanol (e.g., consumption, sedation, and withdrawal). SPECIAL REQUIREMENTS SHARING OF MATERIALS GENERATED UNDER THIS RFA Projects funded under this RFA are likely to lead to the creation of new gene arrays, gene expression data, analytic methods for gene expression patterns, and other research tools which will be of great value to the broader research community, beyond the laboratories which will create them. 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 that will be generated through the grant. It is expected that the investigator’s resource sharing plan will include a description of the mechanisms proposed for wide distribution of resources with investigators in the scientific community, and a timetable for distribution of resources. The reviewers will make an administrative comment on the adequacy of the proposed plan for resource sharing. (This comment will not affect the priority score of the proposal.) NIAAA program staff will consider the adequacy of the plan in determining whether to recommend an application for award. The sharing plan 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. 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. 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 a 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. 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 Institute staff to estimate the potential review workload and avoid conflict of interest in the review. The letter of intent is to be sent to RFA-AA-00-004, Extramural Project Review Branch, National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Suite 409, MSC 7003 Bethesda, MD 20892-7003 by the letter of intent receipt date listed in the heading of this RFA. 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: GrantsInfo@nih.gov. Applications are also available at: http://grants.nih.gov/grants/forms.htm. 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 All applications will use the Modular Grant format and request direct costs in $25,000 modules. 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 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 roles on 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 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 sample RFA label 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 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: RFA :AA-00-004 Extramural Project Review Branch National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Suite 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. Incomplete applications will be returned to the applicant without further consideration. 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? (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: June 19, 2000 Application Receipt Date: July 18, 2000 Peer Review Date: October 2000 Earliest Anticipated Start Date: December, 2000 under expedited Council review procedures. 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 on neuroscience and behavior to: Robert W. Karp, Ph.D. Division of Basic Research National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Suite 402, MSC 7003 Bethesda, MD 20892-7003 Telephone: (301) 443-2239 FAX: (301) 594-0673 Email: rkarp@willco.niaaa.nih.gov Direct inquiries regarding programmatic issues on prenatal ethanol exposure and ethanol-induced organ pathology to: Laurie Foudin, Ph.D. Division of Basic Research National Institute on Alcohol Abuse and Alcoholism 6000 Executive Boulevard, Suite 402, MSC 7003 Bethesda, MD 20892-7003 Telephone: (301) 443-0912 FAX: (301) 594-0673 Email: lfoudin@willco.niaaa.nih.gov Direct inquiries regarding fiscal matters to: Judy Simons Grants Management Branch 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) 443-2434 FAX: (301) 443-3891 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 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. 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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