NON-HUMAN PRIMATE MODELS FOR HIV/CNS DISEASE Release Date: January 29, 1999 RFA: MH-99-009 P.T. National Institute of Mental Health National Institute of Neurological Disorders and Stroke Letter of Intent Receipt Date: April 13, 1999 Application Receipt Date: May 13, 1999 PURPOSE The National Institute of Mental Health (NIMH) and the National Institute of Neurological Disorders and Stroke (NINDS) solicit research using non-human primates infected with simian immunodeficiency virus (SIV) as a model for HIV infection of humans to study the effects of lentiviral infection of the CNS and the resulting neuropsychologic and neurologic pathology. The mechanisms by which HIV causes neurobehavioral impairments, either direct or indirect, must be determined if therapeutic interventions can be realized. The use of the SIV model of AIDS provides a critical opportunity to study the mechanisms underlying HIV neuropathogenesis. This request for applications (RFA) will solicit research grants directed toward expanding the use of SIV-infected non-human primates to address the effects of this virus on the CNS to increase understanding of the resulting pathology and identify therapeutic targets for prevention and/or treatment of the functional and neurological consequences. 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, Non-Human Primate Models for HIV/CNS Disease, is related to the priority area of neurological effects 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) research project 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. 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, 1999. FUNDS AVAILABLE There will be approximately $2.5 million in FY 1999 to fund new and/or competitive continuation grants in response to this RFA. Although the financial plans of the sponsoring 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 The neuropathogenesis of human immunodeficiency virus (HIV)-associated dementia has remained elusive, despite identification of HIV as the causal agent. A number of contributing factors have been identified, however the series of events that culminate in motor and cognitive impairments following HIV infection of the central nervous system (CNS) are still not known. HIV does not readily infect neurons, rather the primary infected cells of the CNS are brain macrophages and microglia. The pathophysiology of these cells that occurs with HIV disease is likely to be similar, at least in part, to that which occurs in several neurodegenerative diseases, such as multiple sclerosis, Alzheimer's and Parkinson's diseases, and perhaps many other. Thus, studies of neurodegenerative pathways are important and valuable to the elucidation of the etiology of many nervous system disorders. The importance of the SIV model of AIDS to aid in deciphering and understanding the mechanisms underlying human AIDS neuropathogenesis is supported by several critical facts. HIV and SIV are genetically and structurally similar, and both viruses utilize the CD4 receptor to gain entry into the cell. The clinical manifestations of the disease caused by HIV in humans is comparable in many ways to the disease caused by SIV in non-human primates. The incidence of neuropsychologic and neurologic disease that occurs in HIV-infected humans also occurs in SIV-infected monkeys, and the neuropathologic findings in both populations are nearly indistinguishable. Better understanding of HIV-associated neuropathogenesis will provide the opportunity to interrupt progression and to design better treatments for HIV- associated dementia. This becomes increasingly important as patients live longer yet still harbor HIV-infected cells in the CNS. The use of the SIV model will allow the identification of neuropathological markers important for HIV-associated dementia. Studies funded in response to this RFA include but are not limited to: o studies to test for motor/cognitive impairments in SIV-infected monkeys and identify neuropathological and biochemical correlates; o studies to identify and characterize neurovirulent virus for use in these studies; o studies to correlate neurologic findings with immunologic markers of disease progression or response to therapies; o studies on the genotype and phenotype of SIV isolates that cause CNS pathology and overt manifestations of CNS disease in infected monkeys; o the cellular targets of SIV infection within the CNS; o the relationship between nervous system disease in SIV-infected monkeys and peripheral immunologic parameters of disease development; o the genetic elements related to SIV/AIDS that determine surface glycoprotein expression, regulatory gene expression (i.e., nef, tat), and the differences between distinct cellular tropic phenotypes and pathologic potential; o identification and characterization of the selection of neurotropic strains in vivo; o expansion of vaccine and pathogenesis studies to include questions related to SIV-induced nervous system disease; o studies to identify altered expression of neuropeptides or neurotransmitters that may contribute to the associated dysfunction. 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 The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants. These forms 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. 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, 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 Rockville, MD 20892-9619 Applications must be received by May 13, 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 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 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 the applications under review, will be discussed, assigned a priority score, and receive a second level review by the National Advisory of Mental Health and National Advisory Neurological Disorders and Stroke 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. Because of the limited availability of non-human primates, collaborative efforts and the extension of current virological and immunological studies using non-human primates to address the neurological complications of SIV/HIV infection are strongly encouraged. Schedule Letter of Intent Receipt Date: April 13, 1999 Application Receipt Date: May 13, 1999 Peer Review Date: June 1999 Council Review: Aug/Sep 1999 Earliest Anticipated Start Date: Sept 1, 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 Rockville, MD 20892-9619 Telephone: (301) 443-7281 FAX: (301) 443-9719 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 20892-9160 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 Rockville, MD 20852-9605 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 20892-9190 Telephone: (301) 496-9231 FAX: (301) 402-0219 Email: dj35j@nih.gov The National Institute of Drug Abuse is interested in applications on studies involving substances of abuse focusing on the above or related research areas. Questions concerning studies of interest to the National Institute of Drug Abuse should be addressed to: Charles Sharp, Ph.D. National Institute of Drug Abuse 6001 Executive Boulevard, Room 4284 MSC 9555 Bethesda, MD 20892-9555 Telephone: (301) 443-1887 FAX: (301) 594-6043 Email: cs107m@nih.gov Nonhuman primate research opportunities may be available through the National Center for Research Resources-supported Regional Primate Research Centers Program (see NIH Guide Notice, January 17, 1997, "Procedures for Accessing Regional Primate research Centers). Questions may be directed to: Jerry Robinson, Ph.D. National Center for Research Resources 6705 Rockledge Drive, Room 6172 Bethesda, MD 20892 Telephone: (301) 435-0744 FAX: (301) 480-3819 Email: jerryr@ncrr.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 5600 Fishers Lane 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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