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


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.


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 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).


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.


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 

Responsibility for the planning, direction, and execution of the proposed 
project will be solely that of the applicant.


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 



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 

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 

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 

3.  Study of the role of chemokine receptors in the normal function of the 

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.


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.


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 

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.


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 

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.


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 .  

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.

4of 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. 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 : 

- 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.


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 

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 
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.


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.  


Written and telephone inquiries concerning this PA are encouraged.  The 
opportunity to clarify any issues or questions from potential applicants is 

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

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

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

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

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

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

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

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


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, 

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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