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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