Release Date: February 26, 1999

RFA:  MH-99-012


National Institute of Mental Health
National Institute of Neurological Disorders and Stroke

Letter of Intent Receipt Date:  May 10, 1999
Application Receipt Date:  June 10, 1999



The National Institute of Mental Health (NIMH) and the National Institute of
Neurological Disorders and Stroke (NINDS) are soliciting applications for
research that will make use of neuroimaging techniques to monitor structural,
functional, and metabolic correlates of human immunodeficiency virus/central
nervous system (HIV/CNS) disease.  Advanced structural and functional
neuroimaging techniques are providing new opportunities to identify clinically
significant abnormalities and relate them to neurological and
neuropsychological dysfunction.  As new and improved therapeutic interventions
are becoming available for controlling HIV disease progression, the importance
of non-invasive monitoring of HIV/CNS disease is necessary for treatment
response monitoring.

This RFA will solicit applications for investigator-initiated research grants
and competitive supplements to use neuroimaging analyses to conduct research
on the neurological and neurobehavioral consequences of HIV in the brain, and
the effects associated with combination antiretroviral therapy.


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 Request for Applications (RFA),
Neuroimaging Analyses as Correlates of HIV/CNS Disease, is related to the
priority area of neurological complications of HIV infection.  Potential
applicants may obtain a copy of "Healthy People 2000" at


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


This RFA will use the National Institutes of Health (NIH) individual research
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.  Competitive continuation/renewal (Type 2) applications
for currently funded R01 grants, as well as competitive supplements to
currently funded R01, P01, or P50 grants will also be considered.

Specific application instructions have been modified to reflect the "MODULAR
GRANT APPLICATION AND AWARD" process which has been adopted by the NIH (see
the NIH Guide, December 15, 1998).

For this RFA, funds must be requested in $25,000 direct cost modules.  A
feature of the modular grant is that no escalation is provided for future
years, and all anticipated expenses for all years of the project must be
included within the number of modules being requested.  Only limited budget
information is required and any budget adjustments made by the Initial Review
Group will be in modules of $25,000.

More detailed information about modular grant applications, including a sample
budget narrative justification pages and a sample biographical sketch, is
available via the Internet at url:

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 30, 1999.


The NIMH and the NINDS intend to commit approximately $2,000,000 in FY 1999 to
fund up to 8 new and/or competitive continuation grants or competitive
supplements in response to this RFA. An applicant may request a project period
of up to 5 years.  Direct costs for competitive supplements will be limited to
$200,000 per year. A minimum of 2 years must be remaining on the parent grant
for competitive supplements to be considered.  Because the nature and scope of
the research proposed may vary, it is anticipated that the size of each award
will also vary. Although the financial plans of the 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.



It is well-established that HIV can penetrate the CNS, frequently very soon
after infection.  One of the consequences of HIV infection is HIV-associated
dementia (HAD) which occurs to varying degrees in up to 50-60 percent of
infected individuals.  HAD consists of a spectrum of progressive cognitive,
motor, and behavioral impairments in the absence of HIV-related opportunistic
infection or malignancy.  The neuropathogenesis of HIV-associated dementia has
remained elusive, despite identification of HIV as the causal agent.  Although
a number of contributing factors have been identified, the series of events
that culminate in motor and cognitive impairments following HIV infection of
the CNS are still not known.  Only with better understanding of
neuropathogenesis will the opportunity to interrupt progression and to design
better treatments for HAD be realized.

One of the limitations in research efforts to identify the pathological
correlates of HAD is the inability to sample CNS tissue during life.  Post-
mortem examination of CNS tissue from infected individuals has provided
detailed information on neuropathological lesions associated with the presence
of HIV within the CNS at end-stage disease.  However, correlations between
viral load in the CNS and the occurrence of HAD prior to death have been
inconclusive.  The discordant findings between pathology and clinical severity
have led to a hypothesis of an indirect mechanism of neuropathogenesis
underlying HAD.

Advanced structural and functional neuroimaging techniques are providing new
opportunities to identify clinically significant abnormalities and relate them
to neurological and neuropsychological dysfunction.  This goal of this RFA is
to stimulate research using state of the art image analyses, including MRS,
MRI, fMRI, PET, and SPECT, to correlate structural, functional and metabolic
changes with neurological and neurobehavioral consequences of HIV in the
brain, and the effects associated with combination antiretroviral therapy.

Examples of research supported under this initiative include, but are not
limited to, the following:

o  research to measure metabolic parameters that may be important in HIV-
induced brain injury;

o  correlative studies of metabolic changes with other parameters that are
reflective of HIV-induced brain injury, such as astrocytosis or changes in
synaptophysin levels;

o  studies to identify regional metabolic changes reflective of brain injury
or dysfunction;

o  studies to monitor changes in patients with HIV dementia in response to
Highly Active Antiretoviral Therapy;

o  studies to identify early morphologic or metabolic alterations which may be
associated with the onset of cognitive impairment;

o  confirmation studies of neuroimaging findings with neuropathology
identified at autopsy;

o  studies to assess comorbidity effects on the brain in the context of HIV
infection and treatment, such as use of illicit drugs or alcohol abuse;

o  studies to monitor blood-brain barrier integrity in HIV infections;

o  studies to monitor CNS disease progression while HIV infection is in
remission; and

o  studies to identify surrogate markers for viral load within the CNS.


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 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 was published in the Federal Register of March 28, 1994 (FR
59 14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No.
11, March 18, 1994, available on the web at:


It is the policy of NIH that children (i.e., individuals under the age of 21)
must be included in all human subjects research, conducted or supported by the
NIH, unless there are scientific and ethical reasons not to include them. 
This policy applies to all initial (Type 1) applications submitted for receipt
dates after October 1, 1998.

All investigators proposing research involving human subjects should read the
"NIH Policy and Guidelines on the Inclusion of Children as Participants in
Research Involving Human Subjects" that was published in the NIH Guide for
Grants and Contracts, March 6, 1998, and is available at the following URL

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.


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.


Applicants are strongly encouraged to contact the program contacts listed
under INQUIRIES with any questions regarding the responsiveness of their
proposed project to the goals of this RFA.

The research grant application form PHS 398 (rev. 4/98) is to be used in
applying for these grants.  Application kits 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:  Applications are also available on the World
Wide Web at:


o  FACE PAGE:  Items 7a and 7b should be completed, indicating Direct Costs
(in $25,000 increments) and Total Costs [Modular Total Direct plus Facilities
and Administrative (F&A) costs] for the initial budget period.  Items 8a and
8b should be completed indicating the Direct and Total Costs for the entire
proposed period of support.

of the PHS 398.  It is not required and will not be accepted with the

categorical budget table on Form Page 5 of the PHS 398.  It is not required
and will not be accepted with the application.

o  NARRATIVE BUDGET JUSTIFICATION - Use a Modular Grant Budget Narrative page.
(See for sample pages.) 
At the top of the page, enter the total direct costs requested for each year.

o  Under Personnel, list key project personnel, including their names, percent 
of effort, and roles on the project. No individual salary information should
be provided.

For Consortium/Contractual costs, provide an estimate of total costs (direct
plus facilities and administrative) for each year, each rounded to the nearest
$1,000. List the individuals/organizations with whom consortium or contractual
arrangements have been made, the percent effort of key personnel, and the role
on the project.  The total cost for a consortium/contractual arrangement is
included in the overall requested modular direct cost amount.

Provide an additional narrative budget justification for any variation in the
number of modules requested.

o  BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by
reviewers in the assessment of each individual's qualifications for a specific
role in the proposed project, as well as to evaluate the overall
qualifications of the research team.  A biographical sketch is required for
all key personnel, following the instructions below.  No more than three pages
may be used for each person.  A sample biographical sketch may be viewed at:

- Complete the educational block at the top of the form page;
- List current position(s) and then previous positions;
- List selected peer-reviewed publications, with full citations;
- Provide information, including overall goals and responsibilities, on
research projects ongoing or completed during the last three years.

o  OTHER SUPPORT - Form Page 7.  This form must be completed for applications
in response to this RFA to allow awards to be negotiated and made on or before
September 30, 1999.

o  CHECKLIST - This page should be completed and submitted with the
application.  If the F&A rate agreement has been established, indicate the
type of agreement and the date. It is important to identify all exclusions
that were used in the calculation of the F&A costs for the initial budget
period and all future budget years.

The applicant should provide the name and phone number of the individual to
contact concerning fiscal and administrative issues if additional information
is necessary following the initial review.

Applications not conforming to these guidelines will be considered
unresponsive to this RFA and will be returned without further review.

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
99-012 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:

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
Bethesda, MD  20892-9619

Applications must be received by June 10, 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.


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/NINDS 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 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 NIMH and NINDS
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

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.


Letter of Intent Receipt Date:    May 10, 1999
Application Receipt Date:         June 10, 1999
Peer Review Date:                 June/July 1999
Council Review:                   September 1999
Earliest Anticipated Start Date:  September 30, 1999


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 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
Bethesda, MD  20892-9619
Telephone:  (301) 443-7281

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
Telephone:  (301) 496-1431
FAX:  (301) 402-2060

Direct inquiries regarding fiscal matters to:

Diana S. Trunnell
Grants Management Branch
National Institute of Mental Health
6001 Executive Boulevard, Room 6115 MSC 9605
Bethesda, MD  20892-9605
Telephone: (301) 443-2805
FAX:  (301) 443-6885

Dianna Jessee
Grants Management Branch
National Institute of Neurological Disorders and Stroke
6001 Executive Boulevard, Room 3261 MSC 9190
Bethesda, MD  20892
Telephone:  (301) 496-9231
FAX:  (301) 402-0219

Although this RFA is being issued by NIMH and NINDS, the other components of
NIH listed below also have an interest in and support research on the topics
covered.  Applicants may wish to contact each of these NIH components listed
below to find out about other funding opportunities.  Institutes and Centers
at NIH use different grant mechanisms to support their portfolios of research;
the Institutes listed here may not use all of the mechanisms specified for
this RFA.

Tanya J. Lehky, M.D.
Division of Acquired Immunodeficiency Syndrome
National Institute of Allergy and Infectious Diseases
Telephone:  (301) 496-0700
Email:  tl84e@

Henry Francis, M.D.
Center on AIDS and Other Medical Consequences on Drug Abuse
National Institute on Drug Abuse
Telephone:  (301) 443-1801


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 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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