HIV/CNS TISSUE NETWORK Release Date: March 12, 1998 RFA: MH-98-009 P.T. National Institute of Allergy and Infectious Diseases National Institute on Drug Abuse National Institute of Mental Health National Institute of Neurological Disorders and Stroke Letter of Intent Receipt Date: May 5, 1998 Application Receipt Date: June 5, 1998 PURPOSE This Request for Applications (RFA) solicits grant applications to develop and implement a procedure for collection of Central Nervous System (CNS) tissues from HIV infected patients through a standardized autopsy protocol. Applications responding to this RFA must describe a process for recruitment and selection of HIV-infected individuals into a protocol that will include regular assessments of neurological status, assessment of drug use history with verification by objective measures when possible, regular blood and CSF collection for virological and serological studies, and implementation of the necessary events culminating in the collection of CNS tissue at autopsy. Of particular interest to NIDA is documentation of drug use history and verification by objective measures when possible. A standardized autopsy protocol, developed during several workgroups with participation of contributing Institute Program staff and extramural researchers, has been recommended, and applicants should use this protocol in their research design. 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, HIV/CNS Tissue Network, is related to the priority area of the 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, 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 Grants awarded through this RFA will use the National Institutes of Health resource-related research project grant (R24). This mechanism is used to support projects that enhance capabilities to contribute to extramural research. 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. The anticipated award date is September 30, 1998. 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 large research centers and satellite sites are encouraged. 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 1998, a maximum of $2 million will be available for support of four to eight applications responding to this RFA, contributed by the sponsoring Institutes. RESEARCH OBJECTIVES Background It is well established that HIV can enter the CNS, frequently within weeks of infection. Neurons are likely not infected, rather productive infection of the brain occurs primarily via blood-derived macrophages and resident microglia. The mechanisms by which HIV causes neurobehavioral impairments, either direct or indirect, must be determined if therapeutic interventions can be realized. To accomplish this, there is a critical need for high quality CNS tissue from HIV infected individuals. CNS tissue is not accessible to biopsy during life, and the use of post-mortem CNS tissue is necessary for the sophisticated morphometrical and molecular biological approaches required to identify the underlying mechanisms responsible for HIV-induced motor/cognitive dysfunction. In addition, as new and improved drugs are developed to control disease progression in infected individuals, the potential impact of the CNS as a protected viral reservoir take on increasing importance for disease management. Although post-mortem CNS tissue is currently collected at a number of research sites, there is insufficient effort directed toward standardizing the collection and processing of this tissue for use by multiple investigators. In addition, in order to increase the value of this tissue for research, a clinical history, including neuropsychological status prior to death, is essential. This is costly and requires cooperation of investigators across many disciplines. One of the consequences of this has been a paucity of optimal tissue and many constraints on investigators desiring such tissue without either collaborative or physical proximity to the collection site. Objective The objective of this RFA is to establish a network of investigators who use a standardized protocol for acquisition of CNS tissue from HIV-infected individuals for use in research on the neuropathology associated with the CNS impairments that result from HIV infection. Funding through this RFA will provide resources for investigators that describe a process for CNS tissue collection using a standardized collection protocol (established by a Steering Committee, described below) from HIV-infected individuals who have appropriate clinical history available, including neuropsychological status as outlined below. It is expected that applicants funded through this RFA will be willing and able to distribute tissue to independent investigators upon request when deemed appropriate, based on guidelines to be established by the Steering Committee. The applicant should describe a process by which requests for tissue will be reviewed and decisions made by an internal committee of researchers appointed for this purpose. A mechanism for detailed cataloguing of collected tissue should also be described. A detailed report itemizing all requests for tissue and the decision made regarding each request must be included in the annual report each year. Some examples that would be appropriate for response to this RFA include but are not limited to: 1) large regional research facilities that recruit from multiple cohorts from various sites and can provide resources for both tissue acquisition and storage; 2) single Institutional research facilities with sufficient cohorts available for recruitment, resources for tissue collection, and limited storage facilities; and 3) clinical sites capable of recruitment and tissue acquisition but with minimal storage facilities. Collaborative arrangements between groups of investigators with complimentary resources are encouraged. Expansion of existing facilities with tissue banks in place as well as facilities planning de novo development may request resources for acquisition of HIV/CNS tissue. Applications will also be accepted from research laboratories that can provide for acquisition and storage of tissue from SIV-infected non-human primate animal models for HIV/CNS disease. It is expected that the accompanying budget would reflect the size and complexity of the research endeavor proposed. Applicants for this RFA must describe in detail a process for: 1. recruiting and selecting appropriate participants, with careful attention to all of the legal and ethical issues that would be encountered in identifying such a cohort and a description of the protocol for obtaining all the necessary consents; 2. obtaining a clinical history, including a history of disease-related therapeutic interventions as well as current and past substance abuse or addiction; 3. obtaining clinical assessments on participants conducted regularly and including serum, plasma, urine, hair, and CSF sampling; 4. obtaining neuropsychological assessments within 6 months prior to the autopsy; 5. conducting the autopsy within 24 hours of death, with collection and histological processing of tissue (describe); 6. cataloguing and storing tissue, or properly preparing tissue for shipment to another storage site; 7. evaluating and making decisions concerning requests from and distributing tissue to other researchers. An underlying requirement is the ability of the Principal Investigator to put together an appropriate team capable of carrying out the proposed process. Accordingly, the application should provide detailed documentation of this ability. Applications for collection and storage of animal tissue must include a description of the relevance of the model for HIV/CNS disease; appropriate clinical data on the animals from which the tissue is derived, including assessment of neurological status of the animal prior to death; and a detailed description of the necropsy protocol to include CNS tissue acquisition similar to that outlined for collection of human CNS material. SPECIAL REQUIREMENTS The awardees will establish a Network Steering Committee (detailed below) to provide oversight for tissue collection and storage, and for processing of tissue requests. Applicants should describe a protocol for tissue collection using the following guidelines, which were developed by extramural researchers during several workgroups convened for this purpose. After award, a final common protocol based on these guidelines will be agreed upon by the Network Steering Committee. Clinical History Preferred: At time of death, the description of the clinical history should include: age; sex; ethnicity; HIV risk category; clinical parameters and therapeutic interventions for previous 6 months; virological status to include CD4 count and virus load; proximal cause of death; neurocognitive assessment within previous 6 months; neurological status at time of death; information on CNS opportunistic infections; and post-mortem interval. A detailed history of current and previous illicit drug use should be obtained. There are a number of instruments available for this process. Two of these instruments are designed for administration by a trained lay interviewer, the Alcohol Use Disorder and Associated Disabilities Interview Schedule-Alcohol and Drugs-revised (AUDADIS- ADR)and the Composite International Diagnostic Interview-Substance Abuse Module (CIDI-SAM). Two other instruments are designed for administration by a trained clinical interviewer, the Psychiatric Interview for Substance and Mental Disorder (PRISM) and the Schedule for Clinical Assessment in Neuropsychiatry (SCAN). Applicants are encouraged to discuss specific issues related to assessment of drug use with the NIDA contact listed under inquiries. Minimal: At time of death, the description of the clinical history should include: clinical parameters and therapeutic interventions for previous 6 months; agonal time, with capability of obtaining virological status (CD4 count and virus load) post-mortem; proximal cause of death; neurological status at time of death; information on CNS opportunistic infections; and post-mortem interval. Any information on previous drug use or substance abuse that is available should be documented. Autopsy should be performed within 24 hours of death. Preferred tissue collection and processing: Fixation procedure should include 10% formalin fixation with processing within 3 days of collection; cryopreserved tissue should be collected within 24 hours of death and quick frozen in isopentaine or liquid N2; CSF should be collected, spun and aliquoted (minimum 50Fl), pellets and supernatants stored in liquid N2 or in storage facility at -80 degrees C. Minimal fixation procedure: Tissue may be stored up to 2 weeks in 10% formalin, with a detailed description of how the tissue was processed; frozen tissue should include detailed information on the process, e.g., OCT, liquid NO2, ultra freezer; CSF should be removed and frozen. Brain dissection: The brain should be removed within 24 hours post-mortem and weighed. Cerebrospinal fluid may be aspirated through the infundibulum at this time. The external aspects of the brain should be examined and briefly described, including meninges, circle of Willis, gyri/sulci, herniation, and cranial nerves. The brain stem and cerebellum should be separated from the cerebral hemispheres with an oblique cut through cerebral peduncles and the cerebral hemispheres divided sagittally into left and right with a cut along the longitudinal fissure. The entire undissected left brain hemisphere should be placed in 10% formalin to await further serial dissection (for morphometry, volumetric analysis, or for full hemispheric microscopic sections). The right hemisphere should be sliced into serial 8-10 mm thick coronal (transverse) slabs. Starting from the frontal tip, alternate slabs should be fixed and frozen. Odd numbered slabs should be placed flat in buffered formalin to fix for at least 2 days. Even numbered brain slabs should be slipped into plastic bags and quick frozen. The optimal freezing temperature is that of liquid nitrogen, however, dry ice or a minus 80 ultra freezer is adequate. The brain stem with cerebellum should be sliced into 4-5 mm thick transverse slab and again, alternate slabs should be fixed and frozen. Routine neuropathologic evaluation of the brain specimens should be performed on routine 2 x 2 cm sections taken from the formalin fixed (odd numbered) slabs of the right hemisphere and of the formalin fixed slabs of the brain stem and cerebellum. 1-2 cm block of tissue dissected from the alternate fixed and frozen sections of the right hemisphere should include: frontal cortex, parietal cortex, head of caudate nucleus, corpus callosum, cingulate gyrus, insular cortex, putamen, globus pallidus, thalamus, hypothalamus, hippocampus, cerebellar cortex and dentate nucleus, midbrain including substantia nigra, pons, medulla, mid-temporal cortex, and inferior parietal cortex. In addition, collection of the following tissues is desired: spinal cord, with cryopreservation of portions of cervical, high and low thoracic, and lumbar regions, and remaining tissue into formalin; preferred peripheral nerve collection to include fibular head, motor and sensory roots, plexus, and DRG; minimal peripheral nerve should include a 5 cm. section of sural nerve, part snap frozen, and rest to be fixed in glutaraldehyde; section of spleen, part in fixative and part cryopreserved; bone marrow sample; thymus; samples of lymph nodes; liver samples. Blood sampling should include 20 cc, aliquated and frozen, with a minimum of 5 cc. In addition, a hair sample and urine sample should be obtained and processed for drug screening. Controls: Collection of tissue from a limited number of HIV-negative individuals for control tissue should be included in the design. HIV negative is defined by a seronegative assay within 1 month of death, or negative serum sample at autopsy, and can include all degenerative diseases, cancer, or transplant patients. Recent clinical history that is available should be obtained, including substance abuse. A detailed description on the record keeping process should include how many samples were taken and their processing history. Successful applicants will be required to provide the funding Institute with an annual report detailing the tissue collected, stored and distributed throughout the year of funding. Continued funding for successive years will depend on successfully achieving the goals outlined in the application. Terms and Conditions of Awards: A Network Steering Committee will be established comprised of the Principle Investigators of each funded site and 3-5 extramural researchers chosen by the funding Institutes. It is expected that the Steering Committee will function as an oversight committee for tissue collection and processing of requests. This committee will meet at the onset of the funding period, finalize a common protocol for tissue to be used by all of the awardees and then semi-annually to review the protocol for tissue collection and make modifications as necessary. This Network Steering Committee will also establish criteria for processing and filling requests for tissue. The Program representatives from each of the funding Institutes will regularly attend these meetings. The Steering Committee will also be charged with the task of identifying an appropriate mechanism to develop a common data base to catalogue available tissue and procedures for making it accessible to the extramural community. 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). 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 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 5, 1998, 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: Dianne 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 APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 5/95) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research or from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910; telephone (301) 435-0714; fax (301) 480-0525; Email: ASKNIH@OD.NIH.GOV. The RFA label available in the PHS 398 (rev. 5/95) 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, HIV/CNS Tissue Network, MH-98-009, must be typed in section 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 M. Rausch, Ph.D. Office of AIDS Research National Institute of Mental Health Parklawn Building, Room 18-101 Bethesda, MD 20857 Applications must be received by June 5, 1998. 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 NIH Center for Scientific Review (CSR) and for responsiveness by sponsoring Institute 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 the NIMH in accordance with the review criteria stated below. 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 appropriate national advisory council or board, when applicable. Review Criteria o originality of proposed protocols; o appropriateness, adequacy, and qualifications of proposed team members that will carry out the protocol; o appropriateness and adequacy of the sites and facilities that will contribute to achieving the goals; o appropriateness and adequacy of the methodology proposed to carry out the research design; o appropriateness of the methods to be used to assess neurological and neurocognitive status and ability to implement these assessments; o appropriateness of the instruments to be used to assess current and past substance abuse; o qualifications and research experience of the Principal Investigator and staff, and commitment of each investigator to the proposed process; o availability of the resources necessary to carry out the research design; o appropriateness of the proposed budget and duration in relation to the proposed research; o adequacy of process by which collected tissue will be catalogued and stored; o adequacy of the process by which requests for tissue will be reviewed, processed, and made available to outside requests; 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 is key to the success of this initiative and will be evaluated accordingly. The initial review group will also examine the provisions for the protection of human and animal subjects, the safety of the research environment, and conformance with the NIH Guidelines for the Inclusion of Women and Minorities as Subjects in Clinical Research. AWARD CRITERIA Award decisions will be made based on scientific merit as determined by peer review, responsiveness of the applicant to the guidelines outlined in the RFA, and availability of funds. 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 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 Tanya Lehky, M.D. Division of AIDS National Institute of Allergy and Infectious Diseases 6003 Executive Boulevard, Room 2C15, MSC 7610 Bethesda, MD 20892-7610 Telephone: (301) 435-3768 FAX: (301) 402-3171 Email: tl84e@nih.gov Lynda Erinoff, Ph.D. Office on AIDS National Institute on Drug Abuse Parklawn Building, Room 9A-30 Rockville, MD 20857 Telephone: (301) 443-6058 FAX: (301) 443-4100 Email: le30q@nih.gov 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 Direct inquiries regarding fiscal matters to: 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 Ann Devine Division of Extramural Affairs National Institute of Allergy and Infectious Diseases 6003 Executive Boulevard, Room 4C-23 Bethesda, MD 20892-7610 Telephone: (301) 402-5601 FAX: (301) 480-3780 Email: ad22x@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 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 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.855 and 93.856 for NIAID, 93.279 for NIDA, 93.242 for NIMH, and 93.853 for 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 grants policy as stated in the Public Health Service Grants Policy Statement (April 1, 1994). PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the nonuse 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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