PA-00-029: THE ROLE OF MICROGLIA IN NORMAL AND ABNORMAL IMMUNE RESPONSES OF THE NERVOUS SYSTEM

Department of Health
and Human Services (HHS)

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THE ROLE OF MICROGLIA IN NORMAL AND ABNORMAL IMMUNE RESPONSES OF THE NERVOUS SYSTEM Release Date: December 15, 1999 PA NUMBER: PA-00-029 National Institute of Neurological Disorders and Stroke National Institute of Mental Health National Center for Research Resources National Institute on Deafness and other Communicative Disorders National Institute on Drug Abuse THIS PA 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 PA. PURPOSE The National Institute of Neurological Disorders and Stroke (NINDS), National Institute of Mental Health (NIMH), National Center for Research Resources (NCRR), National Institute on Deafness and other Communicative Disorders (NIDCD), and National Institute on Drug Abuse (NIDA), invite applications to promote research into the role of microglia in the initiation and expansion of autoimmune processes of the central nervous system (CNS) and the resulting injury to CNS components. Microglia become reservoirs of infectious agents including viruses, fungi, treponema and prions. Under certain conditions, they assume the phenotypes and functions of macrophages. They may become activated and then be able to serve in antigen presentation. The contributions of these cells not only to infections of the CNS, but also to autoimmunity, are beginning to be appreciated. The intent of this PA is to intensify interest and investigator-initiated research to attract new investigators to this field and to mobilize interdisciplinary approaches. 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 PA The Role of Microglia in Normal and Abnormal Immune Responses of the Nervous System, is related to autoimmunity response of the CNS which are vital to multiple sclerosis and immune-mediated encephalomyelitis. Potential applicants may access "Healthy People 2000" at: http://odphp.osophs.dhhs.gov/pubs/hp2000/ or obtain a copy (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 foreign and domestic, for-profit and non- profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT This PA will use the National Institutes of Health (NIH) research project grant (R01) award mechanism. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. 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 and information on Modular Grant applications can be found at http://grants.nih.gov/grants/funding/modular/modular.htm RESEARCH OBJECTIVES Microglia are a relatively under-recognized, widely distributed cell population within brain parenchyma constituting about 1 to 2% of all cells. They have been well known to neuropathologists since they harbor agents including viruses such as HIV-1, treponema pallidum, fungi and prions during sub-acute or chronic CNS infections. This, to some extent, emphasizes their relationship to macrophages. Parenchymatous microglia are considered to be resident macrophages, and contribute to inflammation within the CNS and to development of the glial nodules present in certain viral and fungal CNS infections. Perivascular microglia contribute to the blood-brain barrier. Therefore, pathological abnormalities induced by one agent may compromise the integrity of the blood-brain barrier and permit entry of another pathological agent which, by itself, would not be able to pass the barrier. Microglia are considered to be of bone marrow origin but it is still not known when in embryonic life these bone marrow elements enter the CNS and, therefore, the environment to which they are exposed including other embryonic cells and types of trophic factors. Their relationship to blood-borne macrophages remains unclear including presence and timing of activation, ability to phagocytise and phenotypic markers. It is unknown whether they can traverse back across the blood-brain barrier while carrying infected particles, genes or trophic factors. The ability of microglia to harbor HIV-1 has excited new interest in these cells. As the major infected CNS cell, they play a key role in the development of AIDS dementia possibly by production of toxic factors following infection, or more directly by being unable to provide normal metabolic support for neurons. They appear to serve also as reservoirs of active infectious particles so that it is not clear whether or not they develop active lysosomal compartments similar to blood-bourne macrophages. There is evidence that they can express MHC Class II so that they may be able to function as antigen-presenting cells. If so, they may be equally important in initiating and sustaining immune responses to CNS elements such as myelin, oligodendroglia and neoplastic astrocytes. Activation of microglia, so that they express Class II and other phenotypic markers, may be related to the presence of activated T cells arriving from the periphery. Alternatively, activated microglia, especially the perivascular variety, may permit entry of and activation of memory T cells. Studies to be funded in response to this PA include but are not limited to: o Defining the relationship between microglia of the various types and macrophages and their cells of origin within and without the nervous system. o Defining phenotypic markers which characterize microglia, distinguish between microglial types and states of activation. o Investigating mechanisms of activation of microglia and their relationships to activation of T cells. o Investigating the ability of microglia to serve as antigen-presenting cells and to express MHC Class I or II. o Delineating the contribution of microglia to the development of autoimmunity of the CNS via antigen presentation or production of specific cytokines. o Advancing studies of the contributions of peripheral blood monocytes and macrophages to the presence of infected resident microglia. o Investigating the ability of microglia to elaborate chemokines and cytokines and to express receptors for chemokines and cytokines. o Investigating contributions of perivascular microglia to the entry of T cells and blood macrophages into the CNS across the blood-brain barrier. Delineate the surface phenotypes and the chemo/cytokines which facilitate this. o Investigating the role of microglia in diseased brain including multiple sclerosis, HIV infections, including the etiology of AIDS dementia. o Studies of the potential of microglia to serve as therapeutic tools for delivery of drugs, enzymes, trophic factors or genes into the CNS. o Co-sponsorship by the National Institute of Mental Health is limited to applications that address the role of microglia in HIV/CNS disease. Although not formally participating in this program announcement, the National Institute on Aging is interested in research on the role of microglia in normal and abnormal immune responses of the aging nervous system. 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 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 have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513), and in the NIH GUIDE FOR GRANTS AND CONTRACTS, Volume 23, Number 11, March 18, 1994. Investigators may also obtain copies from these sources or from the program staff or contact person listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. 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 APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 4/98) and will be accepted at the standard application deadlines as indicated in the application kit. Application kits are available at most institutional offices of sponsored research and may be obtained from the Office of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone (301) 710-0267, fax: (301) 480-0525 Email: GrantInfo@NIH.GOV. The title and number of the program announcement must be typed in Section 2 on the face page of the application. Applicants planning to submit an investigator-initiated new (type 1), competing continuation (type 2), competing supplement, or any amended/revised version of the preceding grant application types requesting $500,000 or more in direct costs for any year are advised that he or she must contact the Institute or Center (IC) program staff before submitting the application, i.e., as plans for the study are being developed. Furthermore, the application must obtain agreement from the IC staff that the IC will accept the application for consideration for award. Finally, the applicant must identify, in a cover letter sent with the application, the staff member and the Institute or Center who agreed to accept assignment of the application. This policy requires an applicant to obtain agreement for acceptance of both application and any such subsequent amendment. Refer to the NIH Guide for Grants and Contracts, March 20, 1998 at http://grants.nih.gov/grants/guide/notice-files/not98-030.html 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 o 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. 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 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. 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. Submit a signed original of the application, including the Checklist, and five signed photocopies of the application 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 courier/overnight mail service) REVIEW CONSIDERATIONS Applications will be assigned on the basis of established PHS referral guidelines. Applications that are complete will be evaluated for scientific and technical merit by an appropriate peer review group convened in accordance with the standard NIH peer review procedures. 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 applications under review, will be discussed, assigned a priority score, and receive a second level review by the appropriate national advisory council or board. Review Criteria (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 methods? 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 provisions for the protection of human and animal subjects, the safety of the research environment, and conformance with the NIH Guidelines for the Inclusion of Women and Minorities as Subjects in Clinical Research. AWARD CRITERIA Applications will compete for available funds with all other recommended applications assigned to the sponsoring Institute. The following will be considered in making funding decisions: Quality of the proposed project as determined by peer review, availability of funds, and program priority. INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: A. P. Kerza-Kwiatecki, Ph.D. Neural Environment Team National Institute of Neurological Disorders and Stroke 6001 Executive Boulevard, Room 2115 Bethesda, MD 20892-9521 Telephone: (301) 496-1431 FAX: (301) 402-2060 Email: ak45w@nih.gov John D. Strandberg, D.V.M., Ph.D. Comparative Medicine National Center for Research Resources One Rockledge Center, Room 5146 Bethesda, MD 20892-7965 Telephone: (301) 435-0744 FAX: (301) 480-3819 Email: js430b@nih.gov Dianne Rausch, Ph.D. Center for Mental Health Research on AIDS National Institute of Mental Health 6001 Executive Boulevard, Room 6209, MSC 9619 Bethesda, MD 20892 Telephone: (301) 443-7281 FAX: (301) 443-9719 Email: dr89b@nih.gov Thomas M. Johnson, Ph.D. Program Officer Division of Human Communication National Institute on Deafness and other Communication Disorders Executive Plaza South, 400-C 6120 Executive Boulevard Bethesda, MD 20892-7180 (overnight mail) Rockville, MD 20850 Telephone: (301) 402-3461 FAX: (301) 402-6251 Email: tj65y@nih.gov Charles William Sharp, Ph.D. National Institute on Drug Abuse Division of Basic Research 6001 Executive Boulevard, Room 4282, MSC 9555 Bethesda, MD 20892-9555 Telephone: (301) 443-1887 FAX: (301) 594-6043 Email: cs107m@nih.gov Direct inquiries regarding fiscal matters to: Dianna Jessee Grants Management Branch National Institute of Neurological Disorders and Stroke 6001 Executive Boulevard, Room 3261 Bethesda, MD 20892-9190 Telephone: (301) 496-9231 FAX: (301) 402-0219 Email: dj35j@nih.gov Paul Karadbil Office of Grants Management National Center for Research Resources 6705 Rockledge Drive, Room 6086 Bethesda, MD 20892-7965 Telephone: (301) 435-0844 FAX: (301) 480-3777 Email: paulk@ncrr.nih.gov William F. Caputo Grants Management Branch National Institute of Mental Health 6001 Executive Boulevard, Room 6115, MSC 9605 Bethesda, MD 20892 Telephone: (301) 443-0004 FAX: (301) 443-6885 Email: wcaputo@nih.gov Sherry Dennison Grants Management Officer Division of Extramural Activities National Institute on Deafness and other Communication Disorders 6120 Executive Boulevard MSC 7180 Bethesda, MD 20892-7180 (overnight mail) Rockville, MD 20850 Telephone: (301) 402-0909 FAX: (301) 402-1758 Email: sd63u@nih.gov Gary P. Fleming, J.D., M.A. Chief, Grants Management Officer National Institute on Drug Abuse 6001 Executive Boulevard, Room 3131, MSC 9541 Bethesda, MD 20892-9555 Telephone: (301) 443-6710 FAX: (301) 594-6849 Email: gf6s@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance 93.853 and 93.854 (NINDS), 93.306 (NCRR), 93.242, 93.281, and 93.282 (NIMH), 93.174 (NIDCD), and 93.279, 93.278, and 93.277 (NIDA). Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards will be administered under PHS grants policy as stated in the NIH Grants Policy Statement (October 1, 1998). The PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the nonuse 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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