Full Text MH-95-003 ROLE OF THE BLOOD BRAIN BARRIER IN HIV NEUROPATHOGENESIS NIH GUIDE, Volume 24, Number 15, April 28, 1995 RFA: MH-95-003 P.T. 34 Keywords: AIDS Neuroscience National Institute of Mental Health National Institute of Neurological Disorders and Stroke Letter of Intent Receipt Date: May 22, 1995 Application Receipt Date: June 27, 1995 PURPOSE The Office on AIDS, National Institute of Mental Health (NIMH), supports investigations directed at developing effective strategies to prevent or reduce behaviors that place individuals at risk for HIV infection and fosters research to enhance the understanding of the profound impact of the Human Immunodeficiency Virus (HIV) infection on the central nervous system (CNS). In addition, the National Institute of Neurological Disorders and Stroke (NINDS) supports research on neurological aspects of HIV infection (neuro-AIDS) in adults and children. The principal objective of this Request for Applications (RFA) is to stimulate research on the role of the blood brain barrier (BBB) in the neuropathogenesis of HIV infection and disease progression. The results of these investigations are expected to constitute preliminary data for proposals to block HIV entry into the CNS, and prevent the detrimental effects of the virus on the CNS. 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, Role of the Blood Brain Barrier in HIV Neuropathogenesis, is related to the priority areas of HIV infection of the nervous system and mental health and disorders. 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) 783-3238). 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. Foreign institutions are not eligible for First Independent Research Support and Transition (FIRST) (R29) awards. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. MECHANISM OF SUPPORT The mechanisms available for support of this RFA are the National Institutes of Health (NIH) research project grant (R01), FIRST (R29) award, small grant award (R03-NIMH only), and the investigator-initiated interactive research project grant. Responsibility for the planning, direction, and execution of the proposed research project will be solely that of the applicant. The anticipated award date is September 1995. 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 also vary. This RFA is a 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. FUNDS AVAILABLE In fiscal year 1995, a total of $1.5 million contributed equally by NIMH and NINDS has been set aside for this RFA for about six to ten awards. Support may be requested for a period of up to five years. Foreign applicants may request no more than three years of support. RESEARCH OBJECTIVES Background The CNS appears to be a prime target of HIV. Investigators have shown that the CNS becomes infected with HIV early during the disease course. Neurobehavioral and neurologic changes occur in the majority of HIV-1 infected individuals. Autopsies have shown evidence of CNS cell damage in 80 to 90 percent of people who die with AIDS. The exact mechanism by which HIV enters the CNS, whether as a free virus and/or via infected cells (e.g., monocyte/macrophages) remains unknown. This RFA is intended to focus attention on investigating the role of the blood-brain barrier (BBB) in HIV neuropathogenesis, with the objective of generating information that will lead to development of therapeutic interventions to prevent the infection and the devastating effects of the virus on the CNS. The blood-brain barrier is an intricate cellular system composed of vascular endothelial cells and perivascular astrocytes that restrict the passage of molecules between the blood stream and the brain parenchyma. The function of this microvascular system is to ensure the proper maintenance of the neuronal microenvironment. This function is accomplished by employing selective transport mechanisms and utilizing tight junctions between neighboring cells to restrict passage of materials. Investigations have detected abnormalities in the human BBB in association with HIV infection. Significantly higher than normal levels of serum proteins (fibrinogen and IgG) were detected in the postmortem brain tissue of HIV-infected individuals as compared to matched seronegative controls. The diffuse leakage into the brain parenchyma, distinct from focal breakdown associated with tissue necrosis, was taken to signify abnormal vascular permeability. Studies have also described similar findings in the post-mortem brain tissue from individuals with AIDS dementia. These observations suggest that abnormal permeability of the BBB is associated with HIV infection. However, the exact role the perturbation of the BBB plays in HIV neuropathogenesis and in disease progression is unclear. For example, one would like to know whether the perturbation of the BBB precedes or succeeds the entry of HIV into the parenchyma. In addition to the brain parenchyma, cerebrospinal fluid (CSF) constitutes the second compartment of the CNS. Investigations have demonstrated that the CSF contains HIV-infected immunocytes throughout the course of the disease. How this and other reported changes in the CSF relate to alterations in the brain parenchyma and vice versa, is poorly understood. It is important that this relationship be defined because the CSF is the only CNS compartment accessible to sampling during life. It can be accessed during the disease progression to facilitate diagnosis, to yield information on the time-course of the CNS disease, and to deliver therapeutic agents. CSF communicates with the blood via the choroid plexus, which shows evidence of HIV infection. Thus, mechanisms underlying communication between the CNS, the CSF, and blood must be better understood to prevent HIV trafficking between these compartments. Areas of Interest The following are examples of research topics pertinent to this RFA to be investigated in humans and/or animal models. This list is not intended to be comprehensive, nor are the examples meant to be exclusive. Researchers responding to this RFA need not limit themselves to these topics; however, a clear linkage of the proposed study to the potential design of therapeutic interventions is desirable. o Define the mechanism(s) by which HIV virions enter, exit, and spread through the CNS. o Identify, characterize, and monitor changes in the BBB associated with HIV infection and disease progression. o Determine whether or not progressive immunodeficiency, caused by HIV, results in changes in the BBB and/or normal trafficking of immunocytes, particularly monocytes. o Determine whether or not HIV infection of circulating monocytes increases the probability of their entry into the CNS. o Identify changes in normal trafficking of immunocytes through the CNS (the brain parenchyma and the CSF) which occur as a result of HIV infection. o Identify and characterize viral-specific and nonspecific mechanisms underlying the perturbation of the BBB occurring during HIV neuropathogenesis. o Characterize potential adverse effects of HIV infection on the development of the BBB. o Develop and characterize in vivo models relevant to this RFA. o Determine changes in the selective passage of substances across the BBB that occur as a result of HIV infection. o Determine whether or not HIV-infected cells traffic from CNS compartments back into circulation. o Characterize functional changes of the choroid plexus associated with HIV infection. o Test neutralization of immunocyte chemoattractants and blocking of cell adhesion molecules (known to facilitate immunocyte trafficking), as means of blocking HIV entry into the CNS. o Determine the impact of current and potential CNS antiretroviral, psychopharmacologic, and other medications on the integrity of the BBB in 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 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 new policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43) and supersedes and strengthens the previous policies (Concerning the Inclusion of Women in Study Populations, and Concerning the Inclusion of Minorities in Study Populations), which have been in effect since 1990. The new policy contains some provisions that are substantially different from the 1990 policies. 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 reprinted in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994. 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, by May 22, 1995, 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 applicatio 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 conflicts of interest in the review. The letter of intent is to be addressed to Dr. Walter L. Goldschmidts or Dr. A.P. Kerza-Kwiatecki at the addresses listed under INQUIRIES. APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 9/91) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research and from the Office of Grants Information, Division of Research Grants, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892, telephone (301) 435-0714. FIRST (R29) award applications must include at least three sealed letters of reference attached to the face page of the original application. FIRST applications submitted without the required number of reference letters will be considered incomplete and will be returned without review. The RFA label available in the PHS 398 (rev. 9/91) 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, "Role of Blood Brain Barrier in HIV Neuropathogenesis" (MH-95-003) must be typed on line 2a of the face page of the application form and the YES box must be marked. 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 could be included with the application. Submit a signed, typewritten original of the application, including the Checklist, and three signed photocopies, in one package to: Division of Research Grants National Institutes of Health 6701 Rockledge Drive, Room 1040 - MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for courier or express service) At the time of submitssion, two additional copies of the application must be sent to Dr. Walter L. Goldschmidts or Dr. A.P. Kerza-Kwiatecki at the addresses listed under INQUIRIES. Applications must be received by June 27, 1995. If an application is received after that date, it will be returned to the applicant without review. The Division of Research Grants (DRG) 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 DRG 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 Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit in accordance with the review criteria stated below, by an appropriate peer review group convened by the NIMH/NINDS. As part of the initial merit review, all applications will receive a written critique and undergo a streamlined (triage) review process in which only those applications deemed to have the highest scientific merit will be discussed, assigned a priority score, and receive a second review by the national advisory council, where applicable. Review Criteria Criteria for scientific/technical merit review of applications are the following: o significance and originality of proposed research from a scientific or technical standpoint; o qualifications and experience of the Principal Investigator and the staff in areas specifically related to the questions under investigation; o adequacy of the conceptual and technical framework for the research, including evidence of familiarity with relevant research literature and proposed techniques; o access to appropriate study population(s), specimens, and equipment; o adequacy of plans to include both genders and minorities and their subgroups as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated; o adequacy of the existing and proposed facilities and resources; o adequacy of the data analysis plan; o appropriateness of the proposed budget, staffing plan, and time frame in relation to the proposed project. The initial review group will also examine the provisions for the protection of human subjects and the safety of the research environment. AWARD CRITERIA The following criteria will be considered in making funding decision: o scientific merit as determined during the peer review process o availability of funds INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Inquiries regarding programmatic issues may be directed to: Walter L. Goldschmidts, Ph.D. Office on AIDS National Institute of Mental Health Parklawn Building, Room 10-75 5600 Fishers Lane Rockville, MD 20857 Telephone: (301) 443-7281 FAX: (301) 443-9719 Email: wgoldsch@aoamh2.ssw.dhhs.gov A.P. Kerza-Kwiatecki, Ph.D. Division of Demyelination, Atrophic, and Dementing Disorders National Institute of Neurological Disorders and Stroke Federal Building, Room 804 7550 Wisconsin Avenue Bethesda, MD 20892 Telephone: (301) 496-1431 FAX: (301) 402-2060 Email: ak45w@nih.gov Ljubisa Vitkovic, Ph.D. Division of Neuroscience and Behavioral Science National Institute of Mental Health Parklawn Building, Room 11C-06 5600 Fishers Lane Rockville, MD 20857 Telephone: (301) 443-5288 FAX: (301) 443-4822 Email: lv5g@nih.gov General information on the NIMH AIDS Programs may be obtained from: Ellen Stover, Ph.D. Director, Office on AIDS National Institute of Mental Health Parklawn Building, Room 10-75 5600 Fishers Lane Rockville, MD 20857 Telephone: (301) 443-7281 FAX: (301) 443-9719 Email: estover@aoamh2.ssw.dhhs.gov Direct inquiries regarding fiscal matters to: Ms. Diana S. Trunnell Grants Management Branch National Institute of Mental Health Parklawn Building, Room 7C-14 5600 Fishers Lane Rockville, MD 20857 Telephone: (301) 443-3065 FAX: (301) 443-6885 Email: dt21a@nih.gov Ms. Dianna Jessee Division of Extramural Activities National Institute of Neurological Disorders and Stroke Federal Building, Room 1004 7550 Wisconsin Avenue Bethesda, MD 20892 Telephone: (301) 496-9231 FAX: (301) 402-0219 Email: dj35j@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance 93.242, Mental Health Research Grants, and 93,853 and 93,854 Neurological Disorders Grants. 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. The PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and to 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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