RFA-AI-00-006: INNOVATIVE GRANTS ON IMMUNE TOLERANCE

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INNOVATIVE GRANTS ON IMMUNE TOLERANCE Release Date: February 9, 2000 RFA: AI-00-006 National Institute of Allergy and Infectious Diseases http://www.niaid.nih.gov National Institute of Diabetes and Digestive and Kidney Diseases http://www.niddk.nih.gov Letter of Intent Receipt Date: August 1, 2000 Application Receipt Date: September 14, 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 of Allergy and Infectious Diseases (NIAID) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), invite applications for exploratory/developmental research project grants to support novel work on the molecular mechanisms and applications of antigen-specific immune tolerance, which is the selective and long-term inactivation of immune responses. The projects should involve a high degree of innovation, and have a clearly articulated potential to improve understanding of immune tolerance. Investigators new to immune tolerance are particularly encouraged to develop projects in this area. Research projects will be supported by the exploratory/developmental research grant mechanism, which provides the resources to carry out preliminary tests of feasibility for new research hypotheses. 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), Innovative Grants on Immune Tolerance , is related to the priority areas of Immunization and Infectious Diseases and Diabetes and Chronic Diseases. Potential applicants may obtain a copy of "Healthy People 2010" 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. MECHANISM OF SUPPORT Specific application instructions have been modified to reflect MODULAR GRANT and JUST-IN-TIME streamlining efforts being examined by the NIH. Complete and detailed instructions on Modular Grant applications can be found at http://grants.nih.gov/grants/funding/modular/modular.htm The mechanism of support will be the Exploratory/Developmental Research Project Grant (R21). The total project period for an application submitted in response to this RFA may not exceed 3 years. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. NIH uses R21 grants to provide short-duration support for preliminary studies of a highly speculative nature, which are expected to yield, within a two- or three-year time frame, sufficient information upon which to base a well-planned and rigorous series of further investigations. 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 July, 2001. FUNDS AVAILABLE The estimated total funds (direct and facilities and administrative [F&A] costs) available for the first year of support will be $1.7 million from NIAID. In FY 2001, the NIAID plans to fund approximately eight to ten awards. NIDDK will provide $1.0 million in FY 2001, to fund approximately 4-5 applications relevant to diseases within the mission of the NIDDK. An applicant may request a project period of up to three years and a budget for direct costs of up to $150,000 per year, excluding F&A costs or consortium arrangements. Although this program is provided for in the financial plans of the NIH, 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 We are growing closer to the day when allergies, autoimmune diseases, and transplant rejection will be treated by selective inactivation of harmful immune responses, without the global impairment of protective immunity. The past two decades of immunological research have produced a wealth of information on the cells and molecules involved in immunoregulation, identifying a variety of approaches to be tested for selective immune inactivation, or tolerance induction. Of particular note is the success achieved in defining certain mechanisms by which antigen-specific immune tolerance can be induced in animal model systems. Some of these mechanisms are now being tested in human autoimmune disease and organ transplantation. There is still a strong need to develop new concepts and practical approaches for tolerance induction, because it is likely that a variety of protocols will be needed to control the broad range of immune-mediated diseases that exist in humans. Immune-mediated diseases afflict millions of individuals and often involve serious recurring or long-term chronic illness. As highlighted by recent success in inducing long-term transplant tolerance in non- human primates, very promising opportunities and important challenges exist to develop effective protocols for the antigen-specific prevention, or even reversal, of detrimental immune responses in human allergy, asthma, autoimmune disease and transplantation. The application of new technologies such as soluble MHC-peptide reagents, the ability to conduct single cell assays, and progress in the genetic manipulation of normal cells, offer opportunities for more definitive analyses of the human immune system and for the construction of experimental animal systems that more directly model human clinical situations. Research Objectives and Scope The goal of this initiative is to support truly innovative projects on immune tolerance and to encourage investigators working in other areas of research to bring novel perspectives and expertise to this field. High risk, high impact projects are sought that have the potential to significantly increase our understanding of the mechanisms that induce long-lived, antigen-specific immune tolerance for application to human disease. Studies relevant to the etiology and/or treatment of Type 1 Diabetes are of particular interest to the NIDDK. Studies on HIV/AIDS are excluded from this program. Exploratory/developmental research grants (R21) will be used to provide funds to develop preliminary studies of a very speculative nature. Within a two- or three-year funding period, it is expected that successful projects will yield sufficient data to support a well-planned and rigorous future grant application to continue the work by competing within the general pool of unsolicited applications. Highly innovative, short-term pilot projects to evaluate new, but as yet speculative, concepts in immune tolerance may include, but are not limited to, research in the following areas: o the mechanistic basis for differences in tolerance induced by systemic versus mucosal routes, o the identification and characterization of promising new T or B cell molecular targets for tolerance induction, o the parameters of tolerance induction to non-peptide self antigens, alloantigens, or allergens, o the molecular events responsible for the loss of tolerance to self antigens, o methods to extend the duration of antigen-specific tolerance, o novel technologies to identify and quantitate tolerant T or B cells, o the development or application of cell and tissue engineering methods to predictably induce tolerance rather than immunity, o the characterization of novel, antigen-specific immunosuppressive cell types, o the identification of mechanisms by which currently known tolerogenic biological or pharmaceutical agents induce and maintain immune tolerance, o the development of simple and reliable assays for the identification of tolerant states in humans, and o the development of vaccine strategies to induce antigen-specific tolerance to disease-related autoantigens or allergens. 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. LETTER OF INTENT Prospective applicants are asked to submit, by August 1, 2000, 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 this RFA. Although a letter of intent is not required, is not binding, does not commit the sender to submit an application, 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 avoid conflict of interest in the review. The letter of intent is to be sent (e-mail, fax or post) to Dr. Nasrin Nabavi at the address listed under INQUIRIES. APPLICATION PROCEDURES Applicants are strongly encouraged to call NIAID or NIDDK program staff with any questions regarding the responsiveness of their proposed project to the goals of this RFA. 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, including a 15- page limit for the research plan, noted below. BUDGET INSTRUCTIONS Modular Grant applications will request direct costs in $25,000 modules. R21 applications may request an annual maximum direct cost of $150,000, and may be for up to two or three years. For modular grant applications, 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 o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments up to a maximum of $150,000) 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. o 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. o 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. o 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. o 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 facilities and administrative) 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. o 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. - List selected peer-reviewed publications, with full citations. o RESEARCH PLAN The research plan (a-d) is limited to 15 pages. Applications that exceed the page limit will be returned without review. An appendix may be included in the application, however, the appendix is not to be used to circumvent the page limit of the research plan. o CHECKLIST - This page should be completed and submitted with the application. If the facilities and administration (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. o 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 are to be submitted on the grant application form PHS 398 (rev. 4/98). These forms are available at most institutional offices of sponsored research, 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, and on the internet at http://grants.nih.gov/grants/funding/phs398/phs398.html For purposes of identification and processing, item 2a on the face page of the application must be marked "YES" and the RFA number "AI-00-006" and the words "INNOVATIVE GRANTS ON IMMUNE TOLERANCE" must be entered on the face page. The RFA label and line 2 of the application should both indicate the RFA number. The RFA label must be affixed to the bottom of the face page. 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. 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. Applications must be received by September 14, 2000. Applications not received as a single package on the receipt date or not conforming to the instructions contained in PHS 398 (rev. 4/98) Application Kit (as modified in, and superseded by, the special instructions below, for the purposes of this RFA), will be judged non-responsive and will be returned to the applicant. If the application submitted in response to this RFA is substantially similar to a grant application already submitted to the NIH for review, but that has not yet been reviewed, the applicant will be asked to withdraw either the pending application or the new one. Simultaneous submission of identical applications will not be allowed, nor will essentially identical applications be reviewed by different review committees. Therefore, an application that is essentially identical to one that has already been reviewed cannot be submitted in response to this RFA. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. Submit a signed, typewritten original of the application, including the checklist, and three signed, exact, 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 mail or courier service) At the time of submission, two additional exact copies of the grant application and all five sets of any appendix material must be sent to Dr. Nasrin Nabavi at the address listed under INQUIRIES. Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. If so, a letter of agreement from either the GCRC Program Director or Principal Investigator should be included with the application. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the NIH Center for Scientific Review and for responsiveness by NIAID staff, those judged to be incomplete or not in the format specified in this RFA will be returned to the applicant without review. Those considered to be non-responsive will be returned without review. 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 NIAID 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 all applications will receive a written critique but only those applications deemed to have the highest scientific merit will be discussed, assigned a priority score, and receive a second level review by the National Advisory Councils of the NIAID and NIDDK. Review Criteria The five criteria to be used in the evaluation of grant applications are listed below. To put those criteria in context, the following information is contained in instructions to the peer reviewers. The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. The reviewers will comment on the following aspects of the application in their written critiques 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 by the reviewers 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 a 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? 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 personnel category will be reviewed for appropriate staffing based on the requested percent effort. The direct costs budget request will be reviewed for consistency with the proposed methods and specific aims. For modular grant applications, any budgetary adjustments recommended by the reviewers will be in $25,000 modules. The duration of support will be reviewed to determine if it is appropriate to ensure successful completion of the requested scope of the project. 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 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: Helen Quill, Ph.D. Division of Allergy, Immunology and Transplantation National Institute of Allergy and Infectious Diseases 6700-B Rockledge Dr., Room 5140 Bethesda, MD 20892-7640 Telephone: (301) 496-7551 FAX: (301) 402-2571 Email: Hquill@niaid.nih.gov Barbara Linder, M.D., Ph.D. Division of Diabetes, Endocrinology and Metabolic Diseases National Institute of Diabetes and Digestive and Kidney Diseases Building 45, Room 5AN18A Bethesda, MD 20892 Telephone: (301) 594-0021 Fax: (301) 480-3503 Email: linderb@extra.niddk.nih.gov Direct review inquiries to: Nasrin Nabavi, Ph.D. Scientific Review Program, Division of Extramural Activities, NIAID 6700-B Rockledge Dr., Room 2212, MSC 7616 Bethesda, MD 20892-7616 Telephone: (301) 435-3567 Fax: (301) 402-2638 Email: nn30t@nih.gov Direct inquiries regarding fiscal matters to: Ms. Pamela Fleming Grants Management Specialist Division of Extramural Activities, NIAID 6700-B Rockledge Dr., Room 2119, MSC 7614 Bethesda, MD 20892-7614 Telephone: (301) 402-6580 FAX: (301) 480-3708 Email: pfleming@niaid.nih.gov Schedule: Letter of Intent Receipt Date: August 1, 2000 Application Receipt Date: September 14, 2000 Peer Review Date: January, 2001 Council Review: June, 2001 Earliest Anticipated Start Date: July, 2001 AUTHORITY AND REGULATIONS This program is described in the Catalogue of Federal Domestic Health Service Act, Sections 93.856, Microbiology and Infectious Diseases Research, No. 93.855 - Immunology, Allergy, and Transplantation Research and 93.847 Diabetes, Endocrinology and Metabolism Research. Awards will be made under the PHS Act Sections 301 & 405 as amended,(42 USC 241 & 284) and administered under NIH grants policies and Federal Regulations 42 CFR Part 52 and 45 CFR Part 74 & 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems review. The Public Health Service 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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