This Program Announcement expires on June 1, 2004, unless reissued. HIV-1 INFECTION OF THE CENTRAL NERVOUS SYSTEM Release Date: March 20, 2001 PA NUMBER: PA-01-072 (see replacement PA-04-154) National Institute of Mental Health (http://www.nimh.nih.gov/) National Institute of Neurological Disorders and Stroke (http://www.ninds.nih.gov/) National Institute on Drug Abuse (http://www.nida.nih.gov/) THIS PA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. THIS PA INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING AN APPLICATION IN RESPONSE TO THIS PA. THIS PA REPLACES PA-97-017. PURPOSE The National Institute of Mental Health (NIMH), the National Institute of Neurological Disorders and Stroke (NINDS), and the National Institute on Drug Abuse (NIDA) invite research grant applications through this program announcement (PA) to support research focused on determining the pathogenic mechanisms involved in Human Immunodeficiency Virus (HIV)-1 associated neurobehavioral and neurological dysfunction. The objective of this cooperative effort is to foster investigations that will provide the foundation for the rapid development of therapeutic interventions to prevent and treat the effects of HIV-1 on the central nervous system (CNS). Applications ranging from basic research to clinical diagnosis and treatment are of interest. Multidisciplinary research teams and collaborative alliances are encouraged but not required. HEALTHY PEOPLE 2010 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This Program Announcement (PA),HIV-1 Infection of the Central Nervous System, is related to the priority area of research on HIV infections. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. MECHANISM OF SUPPORT This PA will use the National Institutes of Health (NIH) research project grant (R01) and exploratory/developmental grant (R21) award mechanisms. Applicants are encouraged to contact program staff listed under INQUIRIES for additional information. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for an R01 application submitted in response to this PA may not exceed five years. The total project period for R21 application may not exceed three years. For all R21 applications and those competing R01 applications requesting up to $250,000 direct costs per year, specific application instructions have been modified to reflect MODULAR GRANT and JUST-IN-TIME streamlining efforts being undertaken at NIH. 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: http://grants.nih.gov/grants/funding/modular/modular.htm. Applications that request more than $250,000 in any year must use the standard PHS 398 (rev. 4/98) application instructions. Exploratory/development (R21) grants are limited to an average of $125,000 in direct costs per year for up to 3 years. While variations from year to year are permissible, in no case may any year be more than $200,000 in direct costs, and total direct costs for the entire project period may not exceed $375,000. If less than 3 years are requested, the maximum amount of the total direct costs may not exceed $125,000 per year. Exploratory/ developmental grants are not renewable. Information and application instructions for the R21 mechanism, generally applicable to NIMH, NIDA, and NINDS are available in the NIH Guide for Grants and contracts at: http://grants.nih.gov/grants/guide/pa-files/PA-99-134.html. Applicants for R21 grants are encouraged to consult with NIMH, NIDA, or NINDS program staff (see INQUIRIES). RESEARCH OBJECTIVES Background Research on the neuropathogenesis of HIV-1 infection in the last fifteen years has significantly improved our understanding of mechanisms of neurologic and neuropsychiatric complications associated with Acquired Immune Deficiency Syndrome (AIDS). Improved therapies have also significantly reduced the incidence of HIV Associated Dementia (HAD). However, there are many fundamental gaps in our knowledge about mechanisms of HIV-1 entry into the brain, establishment of viral reservoirs and reseeding of systemic compartments. These issues are particularly relevant since potent anti-retroviral therapy does not penetrate the blood-brain barrier and may not be effective in eradication of CNS reservoirs. Drug resistant viral reservoirs in the CNS may not only be important in reseeding of systemic compartments but also contribute to worsening of neurologic disease in long-term AIDS survivors. It is therefore imperative to develop an improved understanding of pathophysiology of HIV infection of the brain using novel approaches and technologies. Furthermore research on the development of novel drugs that penetrate the blood-brain barrier are needed to better manage neurologic and neuropsychiatric complications as well as eradicate CNS viral reservoirs. In an effort to intensify the depth, focus and coordination of key neuro-AIDS issues, the NIMH, NINDS and NIDA are jointly issuing this Program Announcement. Applicants are encouraged to contact Program Staff of the appropriate institute regarding specific areas of interest. Studies of HIV-1 infection of the brain have been slowed by the lack of well characterized infected human CNS tissues. Such tissue samples [brain, cerebral spinal fluid (CSF), blood] from HIV patients are currently available from the National NeuroAIDS Tissue Consortium (http://www.hivbrainbanks.org), which can be used as a resource for research studies. The following are examples of research areas that are pertinent to this Program Announcement. I. Research on the mechanisms of establishment of CNS viral reservoirs. Some of the areas of study and questions may include: a. Analysis of timing of establishment of CNS reservoirs (Can the establishment of these reservoirs with early drug intervention such as potent anti-retroviral therapy be prevented? Is the establishment of CNS reservoirs different from reservoirs in systemic compartments?) b. An in-depth study of the cell populations that serve as reservoirs in CNS c. Whether there are low levels of viral replication in the CNS reservoirs and whether that contributes to the emergence and evolution of drug resistant strains d. Whether viral strains evolve and establish heterogeneity in different regions and cell populations in the brain, and whether they are different from blood- derived viruses II. Research on mechanisms of reseeding of the peripheral compartment from the CNS - some of the questions and approaches may include: a. Whether HIV-1 reenters the peripheral circulation, and if so, is it in association with reverse migrating cells or as free virus b. Sequencing studies using neurovirulent strains to determine whether brain- specific sequences can be detected in peripheral compartments after cessation of potent anti-retroviral therapy, tracking molecular signatures of virus reseeding from the CNS to the periphery III. Research on the role of CNS viral load in contributing to neurologic and neuropsychiatric dysfunction (Is the amelioration of CNS dysfunction following potent anti-retroviral therapy associated with changes in CNS viral load? Is the reduction in peripheral viral load a good predictor of improvement of CNS symptoms and can this serve as a sufficient marker to monitor brain specific symptoms?) IV. Assessment of HIV-induced CNS degeneration and dysfunction using novel imaging techniques [positron emission tomography (PET), magnetic resonance spectroscopy (MRS), magnetic resonance imaging (MRI), functional magnetic resonance imaging (fMRI), functional magnetic resonance spectroscopy (fMRS): a. Studies of association of unique imaging signatures with specific HIV-induced neuropsychiatric or cognitive dysfunction b. Analysis of blood-brain barrier (BBB) abnormalities following HIV-1 infection c. Studies of subtle HIV-1 induced changes in brain metabolism by imaging techniques d. Use of various imaging technologies to track improvements in HIV induced CNS dysfunction following potent anti-retroviral therapy V. Research to develop HIV-1 therapeutic agents capable of penetrating the BBB (alternate approaches may include manipulation of efflux transporters, such as P-glycoproteins, to improve access of anti-HIV agents across the BBB) VI. Research on the co-modulation of neural processes and related biologicals systems by HIV-1 and other neurotoxins (e.g., methamphetamine, opiates or cocaine) and/or therapeutic agents (e.g., azidothymidine (AZT), methadone) VII. Research to determine the role of opportunistic infections in neurobehavioral and neurological complications of HIV infection 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 are provided indicating 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 UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," published in the NIH Guide for Grants and Contracts on August 2, 2000 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html), a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm. The revisions relate to NIH defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable, and b) all investigators to report accrual, and to conduct and report analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects" that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html Investigators also may obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. URLS IN NIH GRANT APPLICATIONS OR APPENDICES All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. APPLICATION PROCEDURES Applicants are strongly encouraged to contact the program contacts listed under INQUIRIES with any questions regarding their proposed project and the goals of this PA. Applications are to be submitted on the grant application form PHS 398 (rev. 4/98) and will be accepted at the standard application deadlines for AIDS applications as indicated in the application kit (January 1, May 1 and September 1). 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) 710-0267, Email: GrantsInfo@nih.gov. Applications are also available on the World Wide Web at: http://grants.nih.gov/grants/forms.htm. SPECIFIC APPLICATION INSTRUCTIONS FOR MODULAR GRANTS 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. Additional information about modular grant applications is available at: http://grants.nih.gov/grants/funding/modular/modular.htm. 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 all 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 all 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 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. 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 program staff before submitting the application, i.e., as plans for the study are being developed. Furthermore, the application must obtain agreement from the Institute staff that the Institute 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 Institute who agreed to accept assignment of the application. This policy requires an applicant to obtain agreement for acceptance of both any such 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 Any application subject to this policy that does not contain the required information in a cover letter sent with the application will be returned to the applicant without review. The title and number of the program announcement 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 5 signed 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) REVIEW CONSIDERATIONS Applications will be assigned on the basis of established PHS referral guidelines. Applications will be evaluated for scientific and technical merit by an appropriate scientific 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 The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments reviewers will be asked to discuss the following aspects of the application 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 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 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 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? In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o The adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. o The reasonableness of the proposed budget and duration in relation to the proposed research o The adequacy of the proposed protection for humans, animals or the environment, to the extent they may be adversely affected by the project proposed in the application. AWARD CRITERIA Applications will compete for available funds with all other recommended applications assigned to the 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: Jeymohan Joseph, Ph.D. Center for Mental Health Research on AIDS National Institute of Mental Health 6001 Executive Boulevard, Room 6202, MSC 9619 Bethesda, MD 20892-9619 Telephone: (301) 443-3012 FAX: (301) 443-9719 E-Mail: jjeymoha@mail.nih.gov A.P. Kerza-Kwiatecki, Ph.D. Neural Environment National Institute of Neurological Disorders and Stroke 6001 Executive Boulevard, Room 2115, MSC 9521 Bethesda, MD 20892-9521 Telephone:(301)496-1431 FAX: (301) 402-2060 E-Mail: ak45w@nih.gov Charles Sharp, Ph.D. Division of Neuroscience and Behavioral Research National Institute on Drug Abuse 6001 Executive Boulevard, Room 4282, MSC 9555 Bethesda, MD 20892 Telephone:(301)443-1887 Fax: (301) 594-6043 E-Mail: cs107m@nih.gov Direct inquiries regarding fiscal matters to: Diana S. Trunnell Grants Management Branch National Institute of Mental Health 6001 Executive Boulevard, Room 6115, MSC 9605 Bethesda, MD 20892-9605 Telephone: (301) 443-2805 FAX: (301) 443-6885 E-Mail: Diana_Trunnell@nih.gov Dianna Jessee Grants Management Branch National Institute of Neurological Disorders and Stroke 6001 Executive Boulevard , Room 3290, MSC 9537 Bethesda, MD 20892-9537 Telephone: (301) 496-7416 FAX: (301) 402-0219 E-Mail: dj35j@nih.gov Gary P. Fleming, J.D., M.A. Grants Management Branch National Institute on Drug Abuse 6001 Executive Boulevard, Room 3131, MSC 9541 Bethesda, MD 20892 Telephone:(301) 443-6710 FAX: (301) 594-6849 E-Mail: gf6s@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.242 (NIMH), No. 93.853 (NINDS), and No. 93.279 (NIDA). Awards are made under authorization of the Public Health Service Act as amended (42 Usc 241 and 284) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS 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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