MECHANISMS IN HIV DEMENTIA AND OTHER CNS DISEASES
Release Date: February 22, 2000 (inactivated see NOT-NS-03-018.html)
PA NUMBER: PAS-00-065
National Institute of Neurological Disorders and Stroke
National Institute of Mental Health
National Institute on Drug Abuse
National Institute on Aging
PURPOSE
THIS PA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES
DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED
WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS PA.
The National Institute of Neurological Disorders and Stroke (NINDS), the
National Institute of Mental Health (NIMH), the National Institute on Drug
Abuse (NIDA), and the National Institute on Aging (NIA) invite investigator-
initiated research grant proposals to study potential common immunological
and inflammatory mechanisms involved in the etiology of HIV-1 associated
dementia (HAD) and neurodegenerative and/or autoimmune diseases of the
nervous system such as Alzheimer's, Parkinson's disease and multiple
sclerosis. One intent of this PA is to encourage basic and clinical
scientists who have been working in the previously disparate areas of
infectious, autoimmune and neurodegenerative disease to develop
multidisciplinary collaborations to search for common factors in the
causation of these and other related diseases.
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 PA, MECHANISMS IN HIV
DEMENTIA AND OTHER CNS DISEASES, is related to the priority area of
hypothesis-driven studies of central nervous system disease. Potential
applicants may obtain a copy of "Healthy People 2000" at
http://odphp.osophs.dhhs.gov/pubs/hp2000/. Full Report: Stock No. 017-001-
00474-0 or Summary Report: Stock No. 017-001-00473-1 can be also obtained
through the Superintendent of Documents, Government Printing Office,
Washington, DC 20402-9325 (telephone 202-512-1800).
ELIGIBILITY REQUIREMENTS
Applications may be submitted by domestic and foreign for-profit and non-
profit organizations; public and private institutions, 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
The mechanism of support will be the individual research project (R01). The
total requested project period for an application submitted in response to
this announcement may not exceed five years. Because the nature and scope of
the research proposed in response to this PA may vary, it is anticipated that
the size of an award will vary also. Collaborative efforts between research
sites are acceptable. Sponsoring Institutes may administratively limit the
duration and the budget level of an award. Standard receipt dates will be
used.
Responsibility for the planning, direction, and execution of the proposed
project will be solely that of the applicant.
FUNDS AVAILABLE
The estimated total funds (direct and indirect costs) available for the first
year of support for all awards made under this PA in FY 2000 will be $1.0
Million from the NINDS, $500,000 from NIMH, $500,000 from NIDA, and $250,000
from NIA. The usual PHS policies governing grant administration and
management will apply. Although this program is provided for in the
financial plans of the participating institutes, awards pursuant to this PA
are contingent upon the availability of funds for this purpose and the
receipt of a sufficient number of applications of high scientific merit.
Funding beyond the first and subsequent years of the grant will be contingent
upon satisfactory progress during the preceding years and availability of
funds.
RESEARCH OBJECTIVES
Background
It is clear that the brain can no longer be considered to be an
immunologically privileged organ, although its immunological response
repertoire is limited. This limited response capability plus the fact that
many of the cells in the brain, i.e. neurons, are post mitotic means that the
inflammatory responses mobilized to defend against exogenous antigens, either
environmental or infectious, may in fact contribute to cell damage in the
brain.
Immunologically mediated inflammatory processes are well-recognized to
produce cellular damage in HIV infection and autoimmune diseases such as
multiple sclerosis. In addition there is growing, but still indirect
evidence, that inflammatory processes may be involved in the pathogenesis of
age-related neurodegenerative disorders such as Alzheimer's disease. For
example there is some evidence that microglial activation and a subsequent
release of cytokines may stimulate neurons to produce amyloid precursor
protein and possibly beta-amyloid itself.
Further evidence for a possible involvement of the immune system in the
pathogenesis of Alzheimer's disease is provided by the demonstration that an
anti-beta-amyloid antibody was able to inhibit the formation of amyloid
plaques produced in a murine model of Alzheimer's disease. There is also
some evidence that treatment with anti-inflammatory drugs may halt the
progression of Alzheimer's disease.
Although it has been demonstrated that neuronal damage associated with injury
or infection initiates apoptotic neuronal death, there is little data in
human neurons to define the mechanisms which might be involved. Research is
needed to determine the events producing neuronal cell death due to
inflammation and/or infection that may be common to diverse neurodegenerative
or autoimmune diseases as well as those which may be unique to HIV-1
infection.
Down regulation of neurotrophin receptors occurs in at least some
neurodegenerative diseases and infectious diseases. For example, down
regulation of neurotrophin receptors may occur in the presence of HIV-1, tat
or other toxic molecules such as TNF-a, interleukins, and nitric oxide.
Additional research is required to determine if the association of these
molecules with down regulation of neurotrophin receptors is unique to HIV-1
infection or a general occurrence.
In view of the growing evidence that a variety of exogenous, i.e. infectious
and/or environmental, as well as endogenous factors can produce similar
immune responses, i.e. activation of macrophages/microglia with the
subsequent release of potentially toxic substances such as chemokines and
cytokines, further identification and study of common pathways of immune
responses in the central nervous system is warranted.
Search for similarities in the inflammatory processes associated with
infectious diseases, particularly HIV-1, autoimmune diseases such as multiple
sclerosis, and degenerative diseases such as Alzheimer's and Parkinson's
disease, may well lead to new discoveries specifically applicable to any one
of this group of disorders, as well as possibly providing evidence of common
etiological factors in the pathogenesis of this diverse group of diseases.
Examples of relevant research include, but are not limited to the following:
1. Study of common pathways for activation of phagocytes/microglia and
astroglia in HIV-1-associated dementia (HAD), autoimmune and
neurodegenerative disorders.
2. Study of common glial responses to chemokines, cytokines or other
inflammatory agents which have been identified as occurring in HAD, MS, or
AD.
3. Study of the role of chemokine receptors in the normal function of the
brain.
4. Study of the molecular transcriptional control and the mechanisms
underlying chemokine-mediated recruitment and trafficking of immune cells
from the periphery to the parenchyma of the brain, with emphasis on
identifying common as well as unique mechanisms for such recruitment in
neurodegenerative and autoimmune diseases or HIV infection.
5. Study of the role of glial cells in providing neural protection both in
infection and in immune mediated injury. Does the activation found in at
least some cases of HIV-1 infection resemble some of the responses found in
autoimmune or neurodegenerative disorders?
6. Identification of any common alterations in blood brain barrier
permeability found in HAD, MS, or AD, especially those which may result from
macrophage/microglia activation.
7. Study of the interaction of HIV-1 with other infectious agents,
particularly those associated with opportunistic infections, resulting in
activation of macrophages or microglia.
8. Study of possible common histopathologic or histochemical changes in
neurons, microglia or astroglia that may be found in neurodegenerative
disorders, MS, or HAD using material from either brain, animal models or
tissue culture.
9. Study of the role of noninfectious environmental agents in modulating
activation of macrophages/microglia and astroglia during the progression of
HAD, MS or AD.
10. Study of excitotoxicity, or increased oxidative stress and their role in
producing the apoptosis observed in HAD and AD.
Study of the effects of viral and cellular secretory products, released by
macrophage/microglia and/ or astrocytes, on neuronal physiology utilizing
electrophysiologic, biochemical or imaging techniques.
11. Search for susceptibility genes, especially those which may modulate
macrophage or glial cell activation, that may be common to individuals
developing HAD, MS, and or AD.
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 are provided that inclusion is
inappropriate with respect to the health of the subjects of 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 have been published in the Federal Register of March 28,
1994 (FR 59 14508-14513) and the NIH Guide for Grants and Contracts, Vol. 23,
No. 11, March 18, 1994.
Investigators may obtain copies from these sources or from program staff
listed in INQUIRIES below who may also provide additional relevant
information concerning the policy.
INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS
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.
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
address: https://grants.nih.gov/grants/guide/notice-files/not98-024.html
Investigators may obtain copies from these sources or from the program staff
(listed in INQUIRIES below) who may also provide additional relevant
information concerning the policy.
APPLICATION PROCEDURES
Applications are to be submitted on the grant application form PHS 398 (rev.
4/98) and will be accepted at the standard application deadlines as indicated
in the application kit. Application kits are available at most institutional
offices of sponsored research and may be obtained from the Office 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: GrantInfo@NIH.GOV.
For purposes of identification and processing, item 2a on the face page of
the application must be marked "YES" and the PA Number (PAS-00-065) and title
(MECHANISMS IN HIV DEMENTIA AND OTHER CNS DISEASES) must be entered.
If the application submitted in response to this PA is substantially similar
to a grant application already submitted to the NIH for review, but that has
not yet been reviewed, the applicant will be asked to withdraw either the
pending application or the new one. Simultaneous submission of identical
applications will not be allowed, nor will essentially identical applications
be reviewed by different review committees. Therefore, an application that
is essentially identical to one that has already been reviewed cannot be
submitted in response to this PA. This does not preclude the submission of
substantial revisions of applications already reviewed, but such applications
must include an introduction addressing the previous critique.
BUDGET INSTRUCTIONS
This program announcement uses Modular Grant Application and Award. In
modular grant applications, total direct costs not exceeding $250,000 per
year will be requested in $25,000 increments instead of being compiled from
detailed and separate budget categories. The implementation of modular
application, review and award procedures is described in
https://grants.nih.gov/grants/guide/notice-files/not98-178.html .
o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in
$25,000 increments up to a maximum of $250,000) 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.
o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page
4of the PHS 398. It is not required and will not be accepted with the
application.
o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete 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 https://grants.nih.gov/grants/funding/modular/modular.htm 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. Indicate whether the
collaborating institution is foreign or domestic. 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 :
https://grants.nih.gov/grants/funding/modular/modular.htm
- Complete the educational block at the top of the form page;
- List position(s) and any honors;
- Provide information, including overall goals and responsibilities, on
research projects ongoing or completed during the last three years.
- List selected peer-reviewed publications, with full citations;
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.
Submit a signed, typewritten original of the application, including the
checklist, and five signed, exact, single-sided photocopies, and all five
sets of appendix material 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 mail or courier service)
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 should be included with the application.
REVIEW CONSIDERATIONS
Upon receipt, applications will be reviewed for completeness by the NIH
Center for Scientific Review (CSR). Applications that are complete will be
evaluated for scientific and technical merit by an appropriate peer review
group convened in accordance with NIH peer review procedures. 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 a national advisory council or board.
Review Criteria
The five criteria to be used in the evaluation of grant applications are
listed below. To put those criteria in context, the following information is
contained in instructions to the peer reviewers.
The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health. The
reviewers will comment on the following aspects of the application in their
written critiques 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 by the reviewers 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 a 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
support?
The initial review group will also examine: the appropriateness of proposed
project budget and duration; the adequacy of plans to include both genders
and minorities and their subgroups as appropriate for the scientific goals of
the research and plans for the recruitment and retention of subjects;
adequacy of plans for including children as appropriate for the scientific
goals of the research; the provisions for the protection of human and animal
subjects; and the safety of the research environment.
AWARD CRITERIA
Funding decisions will be made on the basis of scientific and technical merit
as determined by peer review, program balance, and the availability of funds.
INQUIRIES
Written and telephone inquiries concerning this PA are encouraged. The
opportunity to clarify any issues or questions from potential applicants is
welcome.
Direct inquiries regarding programmatic issues to:
A.P. Kerza-Kwiatecki, Ph.D.
Program Director
Neural Environment Team
National Institute of Neurological Disorders and Stroke
Neuroscience Center, Room 2115
6001 Executive Boulevard
Bethesda, MD 20892-9521
Telephone: (301) 496-1431
FAX: (301) 402-2060
Email: ak45w@nih.gov
Diane M. Rausch, Ph.D.
Center for Mental Health Research on AIDS
National Institute of Mental Health
Neuroscience Center, Room 6209
6001 Executive Boulevard
Bethesda, MD 20892-9619
Telephone: (301) 443-7281
FAX: (301) 443-9719
Email: dr89b@nih.gov
Charles Sharp, Ph.D.
Division of Neuroscience and Behavioral Research
National Institute on Drug Abuse
Neuroscience Center, Room 4269
6001 Executive Boulevard
Bethesda, MD 20892-9541
Telephone: (301) 443-1887
FAX: (301) 594-6043
Email: csharp1@nida.nih.gov
Steve Snyder, Ph.D.
Dementias of Aging Branch
Neuroscience and Neuropsychology of Aging Program
National Institute on Aging
Gateway Building, Suite 3C307
7201 Wisconsin Avenue
Bethesda, MD 20892-9205
Telephone: (301) 496-9350
FAX: (301) 496-1494
Email: ss82f@nih.gov
Direct inquiries regarding fiscal matters to:
Dianna Jessee
Grants Management Branch
National Institute of Neurological Disorders and Stroke
Neuroscience Center, Room 3261
6001 Executive Boulevard
Bethesda, MD 20892-9619
Telephone: (301) 496-9231
FAX: (301) 402-0219
Email: dj35j@nih.gov
Diana S. Trunnell
Grants Management Branch
National Institute of Mental Health
Neuroscience Center, Room 6120
6001 Executive Boulevard
Bethesda, MD 20892-9605
Telephone: (301) 443-2805
FAX: (301) 443-2805
Email: Diana Trunnell@nih.gov
Gary Fleming, J.D., M.A.
Grants Management Branch
National Institute on Drug Abuse
Neuroscience Center, Room 3131
6001 Executive Boulevard
Bethesda, MD 20892-9541
Telephone: (301) 443-6710
FAX: (301) 443-6710
Email: gf6s@nih.gov
Joseph Ellis
Grants Management Officer
Grants and Contracts Management Office
National Institute on Aging
Gateway Building, Suite 2N212
7201 Wisconsin Avenue
Bethesda, MD 20892-9205
Telephone: (301) 496-1472
FAX: (301) 496-3672
Email: EllisJ@exmur.nia.nih.gov
AUTHORITY AND REGULATIONS
This program is described in the Catalog of Federal Domestic Assistance No.
93.242 for NIMH, 93.853 for NINDS, 93.279 for NIDA, and 93.866 for NIA.
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 NIH grants policies and Federal Regulations
42 CFR 52 and 45 CFR Part 74 and 92. 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).
The Public Health Service 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 for 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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