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) 710-0267; 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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