IMMUNOLOGICAL PHENOTYPING OF MOUSE MUTANTS Release Date: February 11, 1999 RFA: AI-99-005 P.T. National Institute of Allergy and Infectious Diseases National Center for Research Resources National Eye Institute National Heart, Lung, and Blood Institute National Institute of Diabetes and Digestive and Kidney Diseases National Institute of Environmental Health Sciences Office of Research on Women's Health Letter of Intent Receipt Date: March 15, 1999 Application Receipt Date: May 6, 1999 THIS RFA USES THE MODULAR GRANT APPLICATION AND AWARD PROCESS. THIS RFA INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE FOLLOWED WHEN PREPARING AN APPLICATION IN RESPONSE TO THIS RFA. PURPOSE The National Institute of Allergy and Infectious Diseases (NIAID), the National Center for Research Resources (NCRR), the National Eye Institute (NEI), the National Heart, Lung and Blood Institute (NHLBI), the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute of Environmental Health Sciences (NIEHS), and the Office of Research on Women's Health (ORWH) invite applications to develop new technologies to rapidly screen normal and mutagenized mice in order to detect and characterize abnormal immune responses, with an emphasis on immune dysfunction associated with autoimmune disease. This Request for Applications (RFA) addresses many of the recommendations of the NIH Committee on "Priority Setting for Mouse Genomics and Genetics Resources". Applications for highly innovative exploratory/ developmental projects are being sought. 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, Immunological Phenotyping of Mouse Mutants, is related to the priority area of diabetes and chronic disabling conditions. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001- 00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-512-1800). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic for-profit and non-profit organizations; public and private institutions, such as universities, colleges, hospitals, laboratories, units of State and local governments; and eligible agencies of the Federal government. Foreign institutions are not eligible to apply for this RFA. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT The mechanism of support will be the exploratory/developmental (R21) research grant. This mechanism provides short-duration support for preliminary studies of a highly speculative nature which are expected to yield, with this time frame, sufficient information to form for basis for a rigorous series of further investigations. Applicants may request up to two years of support and up to $150,000 per year in direct costs. With compelling justification, exceptions to these cost limitations can be made if specific costly reagents, animals, specimens or laboratory modifications are needed to perform these studies. Program staff may be able to advise prospective applicants concerning relevant resources available from NIAID-supported resources. Contact Dr. Vicki Seyfert at the address listed under INQUIRIES for further information on such NIAID- supported resources. Awards made under this RFA are not renewable; however, applicants may elect to seek continuing support for this research through the unsolicited research projects (R01) grant mechanism. Specific application instructions have been modified to reflect the "MODULAR GRANT APPLICATION AND AWARD" process which has been adopted by the NIH (see the NIH Guide, December 15, 1998). For this RFA, funds must be requested in $25,000 direct cost modules. A feature of the modular grant is that no escalation is provided for future years, and all anticipated expenses for all years of the project must be included within the number of modules being requested. Only limited budget information is required and any budget adjustments made by the Initial Review Group will be in modules of $25,000. 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 url: http://grants.nih.gov/grants/funding/modular/modular.htm FUNDS AVAILABLE The estimated total funds (direct and indirect costs) available for the first year of support for all awards made under this RFA will be $2,000,000. In Fiscal Year 1999, the participating Institutes and Centers (ICs) plan to fund 8 to 10 awards. The usual PHS policies governing grants administration and management will apply. Although this program is provided for in the financial plans of the participating ICs, awards pursuant to this RFA are contingent upon the availability of funds for this purpose and the receipt of a sufficient number of applications of high scientific merit. Funding beyond the first and subsequent years of the grant will be contingent upon satisfactory progress during the preceding years and availability of funds. RESEARCH OBJECTIVES Background Transgenic and gene-targeted mutant mice represent extremely valuable tools for biomedical research. Scientists have recently developed strategies for conducting large-scale mutagenesis in mice, providing even more powerful tools, previously restricted to simpler experimental systems such as Drosophila and C. elegans. The large scale application of random chemical mutagenesis and other more targeted genetic techniques is expected to substantially tax the ability of researchers to phenotype large numbers of mutant mice. In some instances, e.g., when mutations cause developmental abnormalities that are easily identified on visual inspection, the problems involved in phenotypic screening are relatively straightforward. In contrast, mutations that affect immune cell populations and/or immune function are most often not readily identifiable upon gross examination. Moreover, current assays for evaluating immune responses are generally labor intensive and time consuming, often requiring the purification of individual cell populations and the demonstration of antigen-specific or lectin-stimulated immune responses over a period of days. In many instances, thorough characterization of immune function would require volumes of blood, serum, or tissue that could be obtained only by sacrificing genetically unique mice. Many immune-mediated disorders, including autoimmune diseases, evolve over time and may not be evident, even with a thorough microscopic and functional evaluation performed at a single point in time. Novel, high throughput technologies are needed to assess immune development, immune function, loss of immune self-tolerance, and autoimmune injury in mice. In other instances, existing technologies might be adapted to provide higher throughput, rapid and more accurate analysis, or scaled down using newer principles of micro and nanofabrication. In all cases, new technologies for phenotyping mouse mutants should be rapid, accurate, relatively cost efficient and should minimize the necessity to sacrifice valuable mutant mice. Research Objectives and Scope The objective of this RFA is to support the development of new technologies to rapidly phenotype large numbers of mutant mice and assess the characteristics of immune dysfunction in these animals with an emphasis on the susceptibility to, and the initiation and progression of, autoimmune disease. Such technologies may include, but are not limited, to the following: o High throughput assays for analyzing immune cell types and function from small volumes of blood, including development of microfabricated devices for purifying and characterizing cells and development of antigen or tethered antigen "chips" for identification of antigen specific B or T cells; o Modification of existing technologies for characterizing antigen-specific T cells using soluble MHC/tetramers, ELISPOT assays or laser-mediated cell dissection from tissue samples; o High throughput assays for analyzing cytokine or chemokine levels in small volumes of blood, serum, or tissue samples; o High throughput assays for assessing changes in gene expression in single cells or small numbers of cells including development of microfabricated devices to separate and isolate DNA, and to amplify and analyze DNA using cDNA microarrays; o High throughput methods to extract individual cells from tissue samples; o High throughput assays to assess changes in protein expression from small volumes of blood including development of antibody "chips" for evaluating expression of specific proteins; o High throughput methods to extract individual cells from tissue samples; o Development of methods to accelerate autoimmune processes in susceptible strains of mice, e.g., development of mouse strains which have genetic backgrounds that enhance self-reactivity and autoimmunity, or development of mouse strains that are more susceptible to immune deviation following exposure to chemical or other environmental agents and; o Identification of markers for self-reactivity that can be adapted for use in a high throughput assay. Applicants are required to provide information on: how proposed new technologies or refinements to those in development represent improvements over current methods; the aspects of immune function and autoimmunity to be tested; and the levels of throughput that can be achieved (number of mice processed per day/week). Proposals to develop feasible early predictors of subsequent autoimmune disease are especially encouraged since such screens would greatly facilitate progress in the identification of informative mutants. 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 sub-populations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear, compelling rationale, and justification are 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", published in the Federal Register of March 28, 1994 (FR 59 14508- 14513) and the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994 which is available via the WWW. at: http://grants.nih.gov/grants/guide/notice-files/not94-100.html NIH POLICY AND GUIDELINES ON THE 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 which is available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html Investigators may obtain copies from these sources or from the program contacts at the address listed under INQUIRIES who may also provide additional relevant information concerning the policy. LETTER OF INTENT Prospective applicants are asked to submit, by March 15, 1999, a letter of intent that includes a descriptive title of the overall proposed research; the name, address and telephone number of the Principal Investigator; and the number and title of this RFA. Although the 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 subsequent applications, the information that it contains allows NIAID staff to estimate the potential review workload and to avoid conflict of interest in the review. The letter of intent is to be sent to Dr. Madelon Halula at the address listed under INQUIRIES. APPLICATION PROCEDURES Applicants are strongly encouraged to call the program contacts listed in INQUIRIES below with any questions regarding the responsiveness of their proposed project to the goals of this RFA. 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 from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone (301) 435-0714, email: GrantsInfo@nih.gov. Applications are also available on the World Wide Web at: http://grants.nih.gov/grants/forms.htm. BUDGET INSTRUCTIONS o 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. 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 - Use 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. 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. 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. The total cost for a consortium/contractual arrangement is included in the overall requested modular direct cost amount. 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 current position(s) and then previous positions; - 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. o OTHER SUPPORT - Form Page 7. This form must be completed for applications in response to this RFA to allow awards to be negotiated and made on or before September 30, 1999. o 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. The RFA label available in the application form PHS 398 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. 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. 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/courier service) At the time of submission, two additional exact copies of the application and all five sets of any appendix material must be sent to Dr. Madelon Halula at the address listed under INQUIRIES. These copies must be sent at the same time as the original and three copies are sent to the Center for Scientific Review (CSR), failure to do so will prevent the application from being peer reviewed in time for award in fiscal year 1999. Applications must be received by May 6, 1999. If an application is received after that date, it will be returned to the applicant without review. The 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 and adherence to the Special Instructions above by CSR and for responsiveness by NIAID staff. 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 the 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 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 National Advisory Allergy and Infectious Diseases 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. 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? The initial review group will also examine: the appropriateness of proposed project budget and duration; the adequacy of plans to include both genders and minorities and their subgroups 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. Schedule Letter of Intent Receipt Date: March 15, 1999 Application Receipt Date: May 6, 1999 Scientific Review Date: July 1999 Advisory Council Date: September 1999 Earliest Award Date: September 30, 1999 AWARD CRITERIA Funding decisions will be made on the basis of scientific and technical merit as determined by peer review, program balance, and the availability of funds. The earliest anticipated date of award is September 30, 1999. INQUIRIES Written and telephone 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: Dr. Vicki Seyfert Division of Allergy Immunology and Transplantation National Institute of Allergy and Infectious Diseases 6003 Executive Boulevard, Room 4A21 Bethesda, MD 20892-7610 Telephone: (301) 496-7551 FAX: (301) 402-2571 Email: vs62y@nih.gov John D. Strandberg, D.V.M., Ph.D. Comparative Medicine National Center for Research Resources 6705 Rockledge Drive, MSC 7965 Bethesda, MD 20892-7965 Telephone: (301) 435-0744 or 435-0884 FAX: (301) 480-3819 Email: johns@ncrr.nih.gov Dr. Ellen S. Liberman Lens and Cataract and Glaucoma Programs National Eye Institute 6120 Executive Boulevard, Suite 350, MSC 7164 Bethesda MD 20892-7164 Telephone: (301) 496-0484 FAX: (301) 402-0528 Email: ellenliberman@nei.nih.gov Barbara Linder, M.D., Ph.D. Division of Diabetes, Endocrinology and Metabolic Diseases National Institute of Diabetes and Digestive and Kidney Diseases 45 Center Drive, Room 5AN18A Bethesda, MD 20892 Telephone: (301) 594-0021 FAX: (301) 480-3503 Email: linderb@extra.niddk.nih.gov John Fakunding, Ph.D. Division of Heart and Vascular Diseases National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 9200, MSC 7940 Bethesda, MD 20892 Telephone: (301) 435-0544 FAX: (301) 480-1454 Email: jf46f@nih.gov Jerrold J. Heindel, Ph.D. Division of Extramural Research and Training National Institute of Environmental Health Sciences P.O. Box 12233 Research Triangle Park, NC 27709 Telephone: (919) 541-0781 FAX: (919) 541-5460 Email: Heindelj@niehs.nih.gov Direct inquiries regarding review issues and special instructions for application preparation; address the letter of intent to; and mail two copies of the application and all five sets of appendices to: Madelon Halula, Ph.D. Division of Extramural Activities National Institute of Allergy and Infectious Diseases Solar Building, Room 4C16 6003 Executive Boulevard Bethesda, MD 20892 Telephone: (301) 402-2636 FAX: (301) 402-2638 Email: mh30x@nih.gov Direct inquiries regarding fiscal matters to: Pamela G. Fleming Division of Extramural Activities National Institute of Allergy and Infectious Diseases 6003 Executive Boulevard, Room 4C25 Bethesda, MD 20892-7610 Rockville, MD 20852 (for express/courier service Telephone: (301) 402-6580 FAX: (301) 480-3780 Email: pf49e@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance Nos. 93.856 and 93.855. Awards are made under authorization of the Public Health Service Act, Sec. 301 (c), Public Law 78-410, as amended. Awards will be administered under PHS grants policies and Federal Regulations 42 CFR Part 52 and 45 CFR Part 74. 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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