MECHANISMS IN HIV DEMENTIA AND OTHER CNS DISEASES Release Date: February 22, 2000 (inactivated see NOT-NS-03-018.html) PA NUMBER: PAS-00-065 National Institute of Neurological Disorders and Stroke National Institute of Mental Health National Institute on Drug Abuse National Institute on Aging PURPOSE 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. The National Institute of Neurological Disorders and Stroke (NINDS), the National Institute of Mental Health (NIMH), the National Institute on Drug Abuse (NIDA), and the National Institute on Aging (NIA) invite investigator- initiated research grant proposals to study potential common immunological and inflammatory mechanisms involved in the etiology of HIV-1 associated dementia (HAD) and neurodegenerative and/or autoimmune diseases of the nervous system such as Alzheimer's, Parkinson's disease and multiple sclerosis. One intent of this PA is to encourage basic and clinical scientists who have been working in the previously disparate areas of infectious, autoimmune and neurodegenerative disease to develop multidisciplinary collaborations to search for common factors in the causation of these and other related diseases. 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, MECHANISMS IN HIV DEMENTIA AND OTHER CNS DISEASES, is related to the priority area of hypothesis-driven studies of central nervous system disease. Potential applicants may obtain a copy of "Healthy People 2000" at http://odphp.osophs.dhhs.gov/pubs/hp2000/. Full Report: Stock No. 017-001- 00474-0 or Summary Report: Stock No. 017-001-00473-1 can be also obtained through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-512-1800). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign 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. 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 individual research project (R01). The total requested project period for an application submitted in response to this announcement may not exceed five years. Because the nature and scope of the research proposed in response to this PA may vary, it is anticipated that the size of an award will vary also. Collaborative efforts between research sites are acceptable. Sponsoring Institutes may administratively limit the duration and the budget level of an award. Standard receipt dates will be used. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. FUNDS AVAILABLE The estimated total funds (direct and indirect costs) available for the first year of support for all awards made under this PA in FY 2000 will be $1.0 Million from the NINDS, $500,000 from NIMH, $500,000 from NIDA, and $250,000 from NIA. The usual PHS policies governing grant administration and management will apply. Although this program is provided for in the financial plans of the participating institutes, awards pursuant to this PA 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 It is clear that the brain can no longer be considered to be an immunologically privileged organ, although its immunological response repertoire is limited. This limited response capability plus the fact that many of the cells in the brain, i.e. neurons, are post mitotic means that the inflammatory responses mobilized to defend against exogenous antigens, either environmental or infectious, may in fact contribute to cell damage in the brain. Immunologically mediated inflammatory processes are well-recognized to produce cellular damage in HIV infection and autoimmune diseases such as multiple sclerosis. In addition there is growing, but still indirect evidence, that inflammatory processes may be involved in the pathogenesis of age-related neurodegenerative disorders such as Alzheimer's disease. For example there is some evidence that microglial activation and a subsequent release of cytokines may stimulate neurons to produce amyloid precursor protein and possibly beta-amyloid itself. Further evidence for a possible involvement of the immune system in the pathogenesis of Alzheimer's disease is provided by the demonstration that an anti-beta-amyloid antibody was able to inhibit the formation of amyloid plaques produced in a murine model of Alzheimer's disease. There is also some evidence that treatment with anti-inflammatory drugs may halt the progression of Alzheimer's disease. Although it has been demonstrated that neuronal damage associated with injury or infection initiates apoptotic neuronal death, there is little data in human neurons to define the mechanisms which might be involved. Research is needed to determine the events producing neuronal cell death due to inflammation and/or infection that may be common to diverse neurodegenerative or autoimmune diseases as well as those which may be unique to HIV-1 infection. Down regulation of neurotrophin receptors occurs in at least some neurodegenerative diseases and infectious diseases. For example, down regulation of neurotrophin receptors may occur in the presence of HIV-1, tat or other toxic molecules such as TNF-a, interleukins, and nitric oxide. Additional research is required to determine if the association of these molecules with down regulation of neurotrophin receptors is unique to HIV-1 infection or a general occurrence. In view of the growing evidence that a variety of exogenous, i.e. infectious and/or environmental, as well as endogenous factors can produce similar immune responses, i.e. activation of macrophages/microglia with the subsequent release of potentially toxic substances such as chemokines and cytokines, further identification and study of common pathways of immune responses in the central nervous system is warranted. Search for similarities in the inflammatory processes associated with infectious diseases, particularly HIV-1, autoimmune diseases such as multiple sclerosis, and degenerative diseases such as Alzheimer's and Parkinson's disease, may well lead to new discoveries specifically applicable to any one of this group of disorders, as well as possibly providing evidence of common etiological factors in the pathogenesis of this diverse group of diseases. Examples of relevant research include, but are not limited to the following: 1. Study of common pathways for activation of phagocytes/microglia and astroglia in HIV-1-associated dementia (HAD), autoimmune and neurodegenerative disorders. 2. Study of common glial responses to chemokines, cytokines or other inflammatory agents which have been identified as occurring in HAD, MS, or AD. 3. Study of the role of chemokine receptors in the normal function of the brain. 4. Study of the molecular transcriptional control and the mechanisms underlying chemokine-mediated recruitment and trafficking of immune cells from the periphery to the parenchyma of the brain, with emphasis on identifying common as well as unique mechanisms for such recruitment in neurodegenerative and autoimmune diseases or HIV infection. 5. Study of the role of glial cells in providing neural protection both in infection and in immune mediated injury. Does the activation found in at least some cases of HIV-1 infection resemble some of the responses found in autoimmune or neurodegenerative disorders? 6. Identification of any common alterations in blood brain barrier permeability found in HAD, MS, or AD, especially those which may result from macrophage/microglia activation. 7. Study of the interaction of HIV-1 with other infectious agents, particularly those associated with opportunistic infections, resulting in activation of macrophages or microglia. 8. Study of possible common histopathologic or histochemical changes in neurons, microglia or astroglia that may be found in neurodegenerative disorders, MS, or HAD using material from either brain, animal models or tissue culture. 9. Study of the role of noninfectious environmental agents in modulating activation of macrophages/microglia and astroglia during the progression of HAD, MS or AD. 10. Study of excitotoxicity, or increased oxidative stress and their role in producing the apoptosis observed in HAD and AD. Study of the effects of viral and cellular secretory products, released by macrophage/microglia and/ or astrocytes, on neuronal physiology utilizing electrophysiologic, biochemical or imaging techniques. 11. Search for susceptibility genes, especially those which may modulate macrophage or glial cell activation, that may be common to individuals developing HAD, MS, and or AD. 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 are provided that inclusion is inappropriate with respect to the health of the subjects of 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 the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994. Investigators may obtain copies from these sources or from program staff listed in INQUIRIES below who 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. 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 may obtain copies from these sources or from the program staff (listed in INQUIRIES below) who may also provide additional relevant information concerning the policy. 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. For purposes of identification and processing, item 2a on the face page of the application must be marked "YES" and the PA Number (PAS-00-065) and title (MECHANISMS IN HIV DEMENTIA AND OTHER CNS DISEASES) must be entered. If the application submitted in response to this PA 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 PA. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. BUDGET INSTRUCTIONS This program announcement uses Modular Grant Application and Award. In modular grant applications, total direct costs not exceeding $250,000 per year will be requested in $25,000 increments instead of being compiled from detailed and separate budget categories. The implementation of modular application, review and award procedures is described in http://grants.nih.gov/grants/guide/notice-files/not98-178.html . 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 4of 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. 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. 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. 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. Submit a signed, typewritten original of the application, including the checklist, and five signed, exact, single-sided photocopies, and all five sets of appendix material 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) 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 (CSR). Applications that are complete will be evaluated for scientific and technical merit by an appropriate peer review group convened in accordance with NIH peer review procedures. As part of the initial merit review, all applications will receive a written critique, and may undergo a process in which only those applications deemed to have the highest scientific merit will be discussed, assigned a priority score, and receive a second level review by a national advisory council or board. 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? 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; adequacy of plans for including children as appropriate for the scientific goals of the research; the provisions for the protection of human and animal subjects; and the safety of the research environment. 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. INQUIRIES Written and telephone inquiries concerning this PA 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. Program Director Neural Environment Team National Institute of Neurological Disorders and Stroke Neuroscience Center, Room 2115 6001 Executive Boulevard Bethesda, MD 20892-9521 Telephone: (301) 496-1431 FAX: (301) 402-2060 Email: email@example.com Diane M. Rausch, Ph.D. Center for Mental Health Research on AIDS National Institute of Mental Health Neuroscience Center, Room 6209 6001 Executive Boulevard Bethesda, MD 20892-9619 Telephone: (301) 443-7281 FAX: (301) 443-9719 Email: firstname.lastname@example.org Charles Sharp, Ph.D. Division of Neuroscience and Behavioral Research National Institute on Drug Abuse Neuroscience Center, Room 4269 6001 Executive Boulevard Bethesda, MD 20892-9541 Telephone: (301) 443-1887 FAX: (301) 594-6043 Email: email@example.com Steve Snyder, Ph.D. Dementias of Aging Branch Neuroscience and Neuropsychology of Aging Program National Institute on Aging Gateway Building, Suite 3C307 7201 Wisconsin Avenue Bethesda, MD 20892-9205 Telephone: (301) 496-9350 FAX: (301) 496-1494 Email: firstname.lastname@example.org Direct inquiries regarding fiscal matters to: Dianna Jessee Grants Management Branch National Institute of Neurological Disorders and Stroke Neuroscience Center, Room 3261 6001 Executive Boulevard Bethesda, MD 20892-9619 Telephone: (301) 496-9231 FAX: (301) 402-0219 Email: email@example.com Diana S. Trunnell Grants Management Branch National Institute of Mental Health Neuroscience Center, Room 6120 6001 Executive Boulevard Bethesda, MD 20892-9605 Telephone: (301) 443-2805 FAX: (301) 443-2805 Email: Diana Trunnell@nih.gov Gary Fleming, J.D., M.A. Grants Management Branch National Institute on Drug Abuse Neuroscience Center, Room 3131 6001 Executive Boulevard Bethesda, MD 20892-9541 Telephone: (301) 443-6710 FAX: (301) 443-6710 Email: firstname.lastname@example.org Joseph Ellis Grants Management Officer Grants and Contracts Management Office National Institute on Aging Gateway Building, Suite 2N212 7201 Wisconsin Avenue Bethesda, MD 20892-9205 Telephone: (301) 496-1472 FAX: (301) 496-3672 Email: EllisJ@exmur.nia.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.242 for NIMH, 93.853 for NINDS, 93.279 for NIDA, and 93.866 for NIA. 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 Public Health Service Grants Policy Statement (April 1, 1994). The Public Health Service 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 for 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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