NEUROIMAGING ANALYSES AS CORRELATES OF HIV/CNS DISEASE Release Date: February 26, 1999 RFA: MH-99-012 P.T. National Institute of Mental Health National Institute of Neurological Disorders and Stroke Letter of Intent Receipt Date: May 10, 1999 Application Receipt Date: June 10, 1999 THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. THIS RFA INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING AN APPLICATION IN RESPONSE TO THIS RFA. PURPOSE The National Institute of Mental Health (NIMH) and the National Institute of Neurological Disorders and Stroke (NINDS) are soliciting applications for research that will make use of neuroimaging techniques to monitor structural, functional, and metabolic correlates of human immunodeficiency virus/central nervous system (HIV/CNS) disease. Advanced structural and functional neuroimaging techniques are providing new opportunities to identify clinically significant abnormalities and relate them to neurological and neuropsychological dysfunction. As new and improved therapeutic interventions are becoming available for controlling HIV disease progression, the importance of non-invasive monitoring of HIV/CNS disease is necessary for treatment response monitoring. This RFA will solicit applications for investigator-initiated research grants and competitive supplements to use neuroimaging analyses to conduct research on the neurological and neurobehavioral consequences of HIV in the brain, and the effects associated with combination antiretroviral therapy. 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 Request for Applications (RFA), Neuroimaging Analyses as Correlates of HIV/CNS Disease, is related to the priority area of neurological complications of HIV infection. Potential applicants may obtain a copy of "Healthy People 2000" at http://www.crisny.org/health/us/health7.html 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 RFA will use the National Institutes of Health (NIH) individual research grant (R01) award mechanism. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for an application submitted in response to this RFA may not exceed 5 years. Competitive continuation/renewal (Type 2) applications for currently funded R01 grants, as well as competitive supplements to currently funded R01, P01, or P50 grants will also be considered. Specific application instructions have been modified to reflect the "MODULAR GRANT APPLICATION AND AWARD" process which has been adopted by the NIH (see the NIH Guide, December 15, 1998). For this RFA, funds must be requested in $25,000 direct cost modules. A feature of the modular grant is that no escalation is provided for future years, and all anticipated expenses for all years of the project must be included within the number of modules being requested. Only limited budget information is required and any budget adjustments made by the Initial Review Group will be in modules of $25,000. More detailed information about modular grant applications, including a sample budget narrative justification pages and a sample biographical sketch, is available via the Internet at url: https://grants.nih.gov/grants/funding/modular/modular.htm This RFA is one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. The anticipated award date is September 30, 1999. FUNDS AVAILABLE The NIMH and the NINDS intend to commit approximately $2,000,000 in FY 1999 to fund up to 8 new and/or competitive continuation grants or competitive supplements in response to this RFA. An applicant may request a project period of up to 5 years. Direct costs for competitive supplements will be limited to $200,000 per year. A minimum of 2 years must be remaining on the parent grant for competitive supplements to be considered. Because the nature and scope of the research proposed may vary, it is anticipated that the size of each award will also vary. Although the financial plans of the Institutes provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of applications of outstanding scientific and technical merit. RESEARCH OBJECTIVES Background It is well-established that HIV can penetrate the CNS, frequently very soon after infection. One of the consequences of HIV infection is HIV-associated dementia (HAD) which occurs to varying degrees in up to 50-60 percent of infected individuals. HAD consists of a spectrum of progressive cognitive, motor, and behavioral impairments in the absence of HIV-related opportunistic infection or malignancy. The neuropathogenesis of HIV-associated dementia has remained elusive, despite identification of HIV as the causal agent. Although a number of contributing factors have been identified, the series of events that culminate in motor and cognitive impairments following HIV infection of the CNS are still not known. Only with better understanding of neuropathogenesis will the opportunity to interrupt progression and to design better treatments for HAD be realized. One of the limitations in research efforts to identify the pathological correlates of HAD is the inability to sample CNS tissue during life. Post- mortem examination of CNS tissue from infected individuals has provided detailed information on neuropathological lesions associated with the presence of HIV within the CNS at end-stage disease. However, correlations between viral load in the CNS and the occurrence of HAD prior to death have been inconclusive. The discordant findings between pathology and clinical severity have led to a hypothesis of an indirect mechanism of neuropathogenesis underlying HAD. Advanced structural and functional neuroimaging techniques are providing new opportunities to identify clinically significant abnormalities and relate them to neurological and neuropsychological dysfunction. This goal of this RFA is to stimulate research using state of the art image analyses, including MRS, MRI, fMRI, PET, and SPECT, to correlate structural, functional and metabolic changes with neurological and neurobehavioral consequences of HIV in the brain, and the effects associated with combination antiretroviral therapy. Examples of research supported under this initiative include, but are not limited to, the following: o research to measure metabolic parameters that may be important in HIV- induced brain injury; o correlative studies of metabolic changes with other parameters that are reflective of HIV-induced brain injury, such as astrocytosis or changes in synaptophysin levels; o studies to identify regional metabolic changes reflective of brain injury or dysfunction; o studies to monitor changes in patients with HIV dementia in response to Highly Active Antiretoviral Therapy; o studies to identify early morphologic or metabolic alterations which may be associated with the onset of cognitive impairment; o confirmation studies of neuroimaging findings with neuropathology identified at autopsy; o studies to assess comorbidity effects on the brain in the context of HIV infection and treatment, such as use of illicit drugs or alcohol abuse; o studies to monitor blood-brain barrier integrity in HIV infections; o studies to monitor CNS disease progression while HIV infection is in remission; and o studies to identify surrogate markers for viral load within the CNS. 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 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 was published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994, available on the web at: https://grants.nih.gov/grants/guide/notice-files/not94-100.html 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 Investigators also may obtain copies of the policy from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of the RFA in response to which the application may be submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows Institute staff to estimate the potential review workload and avoid conflict of interest in the review. The letter of intent is to be sent to Dr. Dianne Rausch at the address listed under INQUIRIES, by the letter of intent receipt date listed in the heading of this RFA. APPLICATION PROCEDURES Applicants are strongly encouraged to contact the program contacts listed under INQUIRIES with any questions regarding the responsiveness of their proposed project to the goals of this RFA. The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants. Application kits are available at most institutional offices of sponsored research and from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone (301) 710-0267, Email: GrantsInfo@nih.gov. Applications are also available on the World Wide Web at: https://grants.nih.gov/grants/forms.htm. BUDGET INSTRUCTIONS o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments) and Total Costs [Modular Total Direct plus Facilities and Administrative (F&A) costs] for the initial budget period. Items 8a and 8b should be completed indicating the Direct and Total Costs for the entire proposed period of support. o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4 of the PHS 398. It is not required and will not be accepted with the application. o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the categorical budget table on Form Page 5 of the PHS 398. It is not required and will not be accepted with the application. o NARRATIVE BUDGET JUSTIFICATION - Use a Modular Grant Budget Narrative page. (See https://grants.nih.gov/grants/funding/modular/modular.htm for sample pages.) At the top of the page, enter the total direct costs requested for each year. o Under Personnel, list key project personnel, including their names, percent of effort, and roles on the project. No individual salary information should be provided. For Consortium/Contractual costs, provide an estimate of total costs (direct plus facilities and administrative) for each year, each rounded to the nearest $1,000. List the individuals/organizations with whom consortium or contractual arrangements have been made, the percent effort of key personnel, and the role on the project. The total cost for a consortium/contractual arrangement is included in the overall requested modular direct cost amount. Provide an additional narrative budget justification for any variation in the number of modules requested. o BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by reviewers in the assessment of each individual's qualifications for a specific role in the proposed project, as well as to evaluate the overall qualifications of the research team. A biographical sketch is required for all key personnel, following the instructions below. No more than three pages may be used for each person. A sample biographical sketch may be viewed at: https://grants.nih.gov/grants/funding/modular/modular.htm - Complete the educational block at the top of the form page; - List current position(s) and then previous positions; - List selected peer-reviewed publications, with full citations; - Provide information, including overall goals and responsibilities, on research projects ongoing or completed during the last three years. o OTHER SUPPORT - Form Page 7. This form must be completed for applications in response to this RFA to allow awards to be negotiated and made on or before September 30, 1999. o CHECKLIST - This page should be completed and submitted with the application. If the F&A rate agreement has been established, indicate the type of agreement and the date. It is important to identify all exclusions that were used in the calculation of the F&A costs for the initial budget period and all future budget years. The applicant should provide the name and phone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. Applications not conforming to these guidelines will be considered unresponsive to this RFA and will be returned without further review. The RFA label available in the PHS 398 (rev. 4/98) application form must be affixed to the bottom of the face page of the application. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number, NEUROIMAGING ANALYSES AS CORRELATES OF HIV/CNS DISEASE, MH- 99-012 must be typed on line 2 of the face page of the application form and the YES box must be marked. Submit a signed, typewritten original of the application, including the Checklist, and three signed photocopies, in one package to: CENTER FOR SCIENTIFIC REVIEW NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application must be sent to: Dianne Rausch, Ph.D. Office of AIDS Research National Institute of Mental Health 6001 Executive Boulevard, Room 6209 MSC 9619 Bethesda, MD 20892-9619 Applications must be received by June 10, 1999. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NIMH staff. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by NIMH/NINDS in accordance with the review criteria stated below. As part of the initial merit review, a process will be used by the initial review group in which applications receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed, assigned a priority score, and receive a second level review by the NIMH and NINDS Advisory Councils. 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 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, minorities and their subgroups, and children as appropriate for the scientific goals of the research and plans for the recruitment and retention of subjects; the provisions for the protection of human and animal subjects; and the safety of the research environment. Schedule Letter of Intent Receipt Date: May 10, 1999 Application Receipt Date: June 10, 1999 Peer Review Date: June/July 1999 Council Review: September 1999 Earliest Anticipated Start Date: September 30, 1999 AWARD CRITERIA Award criteria that will be used to make award decisions include: o scientific merit (as determined by peer review) o availability of funds o programmatic priorities INQUIRIES 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: Dianne Rausch, Ph.D. Office of AIDS Research National Institute of Mental Health 6001 Executive Boulevard, Room 6209 MSC 9619 Bethesda, MD 20892-9619 Telephone: (301) 443-7281 Email: dr89b@nih.gov A. P. Kerza-Kwiatecki, Ph.D. Division of Convulsive, Infectious, and Immune Disorders National Institute of Neurological Disorders and Stroke 6001 Executive Boulevard, Room 2117 MSC 9160 Bethesda, MD 20892 Telephone: (301) 496-1431 FAX: (301) 402-2060 Email: ak45w@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 Email: Diana_Trunnell@nih.gov Dianna Jessee Grants Management Branch National Institute of Neurological Disorders and Stroke 6001 Executive Boulevard, Room 3261 MSC 9190 Bethesda, MD 20892 Telephone: (301) 496-9231 FAX: (301) 402-0219 Email: dj35j@nih.gov Although this RFA is being issued by NIMH and NINDS, the other components of NIH listed below also have an interest in and support research on the topics covered. Applicants may wish to contact each of these NIH components listed below to find out about other funding opportunities. Institutes and Centers at NIH use different grant mechanisms to support their portfolios of research; the Institutes listed here may not use all of the mechanisms specified for this RFA. Tanya J. Lehky, M.D. Division of Acquired Immunodeficiency Syndrome National Institute of Allergy and Infectious Diseases Telephone: (301) 496-0700 Email: tl84e@ nih.gov Henry Francis, M.D. Center on AIDS and Other Medical Consequences on Drug Abuse National Institute on Drug Abuse Telephone: (301) 443-1801 Email: hf23n@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.242 (NIMH) and 93.854 (NINDS). 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 policy as stated in the NIH Grants Policy Statement (October 1, 1998). The PHS 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 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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