CENTRAL NERVOUS SYSTEM AS THE HIV SANCTUARY Release Date: September 4, 1998 RFA: NS-99-002 P.T. National Institute of Neurological Disorders and Stroke National Institute of Drug Abuse National Institute of Mental Health Letter of Intent Receipt Date: November 1, 1998 Application Receipt Date: December 11, 1998 PURPOSE The National Institute of Neurological Disorders and Stroke (NINDS), the National Institute of Drug Abuse (NIDA), and the National Institute of Mental Health (NIMH) invite investigator-initiated research grant applications that address the potential role of the central nervous system (CNS) as a reservoir for HIV. HIV can penetrate the CNS, and a subset of HIV-infected individuals develop motor and/or cognitive impairments to varying degrees. The mechanisms responsible for this CNS dysfunction are not well known. Direct injury by the virus or viral components and the abnormal secretion of cytokines likely damage nervous system cells. It is assumed that halting HIV replication and/or elimination of virus would prevent CNS damage. This Request for Applications (RFA) solicits research applications to study mechanisms of HIV trafficking through the blood brain barrier (BBB), CNS viral localization, control and eradication, and the CNS as a potential virus reservoir. Applications addressing the anti-HIV CNS drug discovery, drug delivery and pharmacology are especially encouraged. 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, Central Nervous System As The HIV Sanctuary, is related to the priority area of neurological complications of HIV infection. 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 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 grant R01. The total requested project period for an application submitted in response to this RFA may not exceed five years. Because the nature and scope of the research proposed in response to this RFA may vary, it is anticipated that the size of an award will vary also. Collaborative efforts between research centers and sites are acceptable. Budget escalation's in future years should be limited to 3% of recurring costs. Some sponsoring Institutes may administratively limit the duration and the budget level of an award. The anticipated award date is June 1, 1999. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. This RFA is one-time solicitation. Future competing continuation applications will compete with all investigator initiated applications and will be reviewed according to the customary peer review procedures. FUNDS AVAILABLE The estimated total funds (direct and indirect costs) available for the first year of support for all awards made under this RFA in FY 1999 will be $1.8M. The usual PHS policies governing grants administration and management will apply. Although this program is provided for in the financial plans of the participating institutes, 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 HIV can penetrate the nervous system resulting in a wide range and severity of pathological and clinical manifestations. Gaps in neuro-AIDS knowledge and in research efforts represent an opportunity to NINDS and other Institutes and Centers (IC) of the NIH family to contribute to progress in newly identified areas. The "NIH Plan to Implement Recommendations of the NIH AIDS Research Program Evaluation Task Force" has been developed in response to the 1996 "Report of the NIH AIDS Research Program Evaluation Task Force", and to provide new research initiatives for NIH HIV/AIDS research programs. Concurrently, and as the result of these recommendations, a number of workshops and panels have been convened to re-examine research programs and priorities of ICs. The outgrowth of these activities have led to stronger cooperative ventures among the Institutes with interest in neuro-AIDS, particularly in such high priority areas as the role of the BBB in CNS HIV infection, neuropathogenesis, and anti-HIV strategies. This RFA has been developed in order for the NINDS to implement recommendations relevant to HIV infection of the nervous system, especially the question whether the CNS functions as the HIV sanctuary, and to provide other NIH Institutes a joint vehicle in our shared anti-AIDS mission. Research Objectives and Scope HIV infection frequently result in dementia and other neurological disorders. During the last decade, numerous studies have indicated that while microglial cells are the primary target for HIV infection, other cells including astrocytes and capillary endothelial cells of the BBB may also be infected with low viral levels. Therefore, much attention has been paid to the role of microglial cells with great emphasis on altered levels of cytokines, biochemical pathways, and more recently, chemokines in the neuropathogenesis of AIDS. The presence of HIV in microglial and capillary endothelial cells suggests that one mode of entry of HIV into the CNS may be mediated by trafficking of the infected macrophages across the BBB. Brain pathology in HIV-infected individuals does not correlate with the viral load in the brain. This suggests that an indirect mechanism independent from viral presence or replication may contribute to CNS pathology. Several recent observations suggest that interaction between virus, endothelial cells, and astrocytes can cause cell damage via regulatory proteins in the absence of viral replication by deregulating the cascade of events that control normal cell function. Thus, future attempts to understand the molecular pathogenesis of HIV-induced CNS dysfunction may include the study of communication between endothelial cells and astrocytes in the presence of viral regulatory proteins, drugs of abuse, and factors released by infected microglial cells. These studies may focus on deregulatory events involving indirect pathways, with the anticipation of developing more effective anti- viral strategies. Recent reports indicate that highly active anti-retroviral (HAART) therapy is effective in reducing HIV mRNA in the cerebrospinal fluid (CSF) to levels that appear to be similar to the reduction observed in the general circulation. This is surprising because macrophages and microglial cells, which are believed to be the main reservoirs of replicating HIV in the brain, can be persistently infected and produce virus without cytolysis, and consequently are expected to exhibit slower turnover during therapy compared to lymphocytes. It has also been shown that in vitro opioids can modulate the growth of HIV in these cells. The objective of this RFA is to determine if the CNS serves as a source of reinfection, especially following the systemic anti-HIV treatment. Supporting studies could be proposed for elucidation of mechanisms of HIV trafficking through blood brain barrier, development of anti-HIV CNS drugs, drug delivery and pharmacology, and control of the CNS viral dissemination and/or HIV eradication or neutralization. Examples of relevant research include, but are not limited to, the following: o Development of methodology to modulate BBB to control viral dissemination and viral load, and to enhance drug delivery; o Analysis of the mechanisms underlying the neurological and neurobehavioral consequences of HIV infection of the CNS and peripheral nervous system (PNS); o Quantitation of HIV burden in astrocytes, neurons, and cells of the immune system of patients with different levels of neurological involvement, and following anti-viral therapy; o Identification of viral genes or gene products that affect neurovirulence and/or neuroinvasiveness of HIV; o Assessment of the effect of viral load, viral strain, viral products, and HIV location on neuropathogenicity; o Elucidation of the role of the immune system, intracellular signaling pathways, receptors, and cytokines in viral tropism, and pathogenicity, and HIV associated dementia; o Investigation of signal transduction which may induce recruitment and proliferation of inflammatory cells and further cytokine/chemokine dysfunction; o Refinement and assessment of structural imaging of the brain using computerized tomography (CT), magnetic resonance (MR), MR spectroscopy and functional MR, single photon emission computerized tomography (SPECT), and positron emission tomography (PET) in diagnosis and treatment of neurological disease; o Identification of surrogate markers for use in rapid and early diagnostic tests of HIV infection, and for the measure of neuropathogeneic damage and treatment success; o Studies of the CNS viral load versus peripheral blood as a marker/measure of neurological impairment; o Development of new therapeutics and clinical trials for the nervous system diseases/disorders, and measurement of new drugs' effectiveness in treatment of CNS and PNS HIV disease; o Development of animals, in vitro systems, and computer models of HIV disease, and potential treatments; o Elucidation of the influence of drugs of abuse and associated conditions/illnesses, e.g., head trauma, nutritional problems, hepatitis, tuberculosis, comorbid mental illness, on the blood brain barrier and the cytopathologic processes involved in HIV infection, persistence and replication within the nervous system, including appropriate animal models. o Determination of the effects of prenatal exposure to drugs of abuse in HIV infected children (and appropriate animal models) on the developmental trajectory of the CNS as an HIV reservoir; o Investigation of possible common links for neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and HIV-dementia, where microglial activation is a common pathway for neural destruction; o Determination of the relationship of HIV to opportunistic disease, development and evaluation of new strategies for prevention, assessment, and treatment of opportunistic and parasitic infections, and HIV-associated malignancies. The areas outlined above are not intended to be all-inclusive. SPECIAL REQUIREMENTS In addition to yearly progress reports, the Principal Investigators of grants funded under this RFA will provide brief summary reports of the outcomes of the research at the conclusion of the funding period and one year later. The reports will summarize the major scientific knowledge gained and identify other substantive outcomes such as publications, patents, and new grants, contracts, or research studies based on this research. 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. 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 is available at the following URL address: https://grants.nih.gov/grants/guide/notice-files/not98-024.html LETTER OF INTENT Prospective applicants are asked to submit, by November 1, 1998, 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 review 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. Kerza-Kwiatecki at the address listed under INQUIRIES. APPLICATION PROCEDURES Applicants are strongly encouraged to contact program staff listed under INQUIRES with any questions regarding the responsiveness of their proposed project to the goals of this RFA. Applications are to be submitted on the research grant application form PHS 398 (rev. 5/95). Application kits are available at most institutional offices of sponsored research and may be obtained 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. For purposes of identification and processing, item 2 on the face page of the application must be marked "YES" and the RFA number "NS-99-002" and the title of this RFA "CENTRAL NERVOUS SYSTEM AS THE HIV SANCTUARY" must be entered. 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. 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 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/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) and for responsiveness by sponsoring Institutes 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 a Scientific Review Group (SRG) established by the NINDS, and 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 the national advisory council or board, when applicable. 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. The earliest anticipated date of award is June 1, 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: A. P. Kerza-Kwiatecki, Ph.D. Division of Convulsive, Infectious, and Immune Disorders National Institute of Neurological Disorders and Stroke 7550 Wisconsin Avenue, Room 504 Bethesda, MD 20892 Telephone: (301) 496-1431 FAX: (301) 402-2060 Email: ak45w@nih.gov Sander G. Genser, M.D., M.P.H. Center for AIDS and Other Medical Consequences of Drug Abuse National Institute on Drug Abuse Parklawn Building, Room 10A-08 Rockville, MD 20857 Telephone: (301) 443-1801 FAX: (301) 594-6566 Email: sg73f@nih.gov Charles W. Sharp, Ph.D Division of Basic Research National Institute on Drug Abuse Parklawn Building, Room 10A-31 Rockville, MD 20857 Telephone: (301) 443-1887 FAX: (301) 594-6043 Email: cs107m@nih.gov Diane M. Rausch, Ph.D. Office of AIDS Research National Institute of Mental Health Parklawn Building, Room 18-101 Rockville, MD 20857 Telephone: (301) 443-6100 FAX: (301) 443-9719 Email: dr89b@nih.gov Direct inquiries regarding fiscal matters to: Dianna Jessee Grants Management Branch National Institute of Neurological Disorders and Stroke 7550 Wisconsin Avenue, Room 1004 Bethesda, MD 20892 Telephone: (301) 496-9231 FAX: (301) 402-0219 Email: dj35j@nih.gov Jack R. Manischewitz, Ph.D. Grants Management Branch National Institute on Drug Abuse Parklawn Building, Room 8A-54 Rockville, MD 20857 Telephone: (301) 443-6710 FAX: (301) 594-6847 Email: jm198m@nih.gov Diana S. Trunnell Grants Management Branch National Institute of Mental Health Parklawn Building, Room 7C-08 Rockville, MD 20857 Telephone: (301) 443-2805 FAX: (301) 443-6885 Email: Diana_Trunnell@nih.gov Schedule Letter of Intent Receipt Date: November 1, 1998 Application Receipt Date: December 11, 1998 Earliest Award Date: June 1, 1999 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance Nos. 93.855, 93.279, 93.242, and 93.853. 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 PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. 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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