THE ROLE OF MICROGLIA IN NORMAL AND ABNORMAL IMMUNE RESPONSES OF THE 
NERVOUS SYSTEM
 
Release Date:  December 15, 1999

PA NUMBER:  PA-00-029

National Institute of Neurological Disorders and Stroke 
National Institute of Mental Health
National Center for Research Resources
National Institute on Deafness and other Communicative Disorders
National Institute on Drug Abuse

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.

PURPOSE

The National Institute of Neurological Disorders and Stroke (NINDS), National 
Institute of Mental Health (NIMH), National Center for Research Resources 
(NCRR), National Institute on Deafness and other Communicative Disorders 
(NIDCD), and National Institute on Drug Abuse (NIDA), invite applications to 
promote research into the role of microglia in the initiation and expansion 
of autoimmune processes of the central nervous system (CNS) and the resulting 
injury to CNS components.  Microglia become reservoirs of infectious agents 
including viruses, fungi, treponema and prions.  Under certain conditions, 
they assume the phenotypes and functions of macrophages.  They may become 
activated and then be able to serve in antigen presentation.  The 
contributions of these cells not only to infections of the CNS, but also to 
autoimmunity, are beginning to be appreciated.  The intent of this PA is to 
intensify interest and investigator-initiated research to attract new 
investigators to this field and to mobilize interdisciplinary approaches.

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 The Role of 
Microglia in Normal and Abnormal Immune Responses of the Nervous System, is 
related to autoimmunity response of the CNS which are vital to multiple 
sclerosis and immune-mediated encephalomyelitis.  Potential applicants may 
access "Healthy People 2000" at: http://odphp.osophs.dhhs.gov/pubs/hp2000/ or 
obtain a copy (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 foreign and 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

This PA will use the National Institutes of Health (NIH) research project 
grant (R01) award mechanism. Responsibility for the planning, direction, and 
execution of the proposed project will be solely that of the applicant.

Specific application instructions have been modified to reflect "MODULAR 
GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH.
Complete and detailed instructions and information on Modular Grant 
applications can be found at 
http://grants.nih.gov/grants/funding/modular/modular.htm
 
RESEARCH OBJECTIVES

Microglia are a relatively under-recognized, widely distributed cell 
population within brain parenchyma constituting about 1 to 2% of all cells.  
They have been well known to neuropathologists since they harbor agents 
including viruses such as HIV-1, treponema pallidum, fungi and prions during 
sub-acute or chronic CNS infections.  This, to some extent, emphasizes their 
relationship to macrophages.  Parenchymatous microglia are considered to be 
resident macrophages, and contribute to inflammation within the CNS and to 
development of the glial nodules present in certain viral and fungal CNS 
infections.  Perivascular microglia contribute to the blood-brain barrier.  
Therefore, pathological abnormalities induced by one agent may compromise the 
integrity of the blood-brain barrier and permit entry of another pathological 
agent which, by itself, would not be able to pass the barrier.  Microglia are 
considered to be of bone marrow origin but it is still not known when in 
embryonic life these bone marrow elements enter the CNS and, therefore, the 
environment to which they are exposed including other embryonic cells and 
types of trophic factors.  Their relationship to blood-borne macrophages 
remains unclear including presence and timing of activation, ability to 
phagocytise and phenotypic markers.  It is unknown whether they can traverse 
back across the blood-brain barrier while carrying infected particles, genes 
or trophic factors.

The ability of microglia to harbor HIV-1 has excited new interest in these 
cells.  As the major infected CNS cell, they play a key role in the 
development of AIDS dementia possibly by production of toxic factors 
following infection, or more directly by being unable to provide normal 
metabolic support for neurons.  They appear to serve also as reservoirs of 
active infectious particles so that it is not clear whether or not they 
develop active lysosomal compartments similar to blood-bourne macrophages.  
There is evidence that they can express MHC Class II so that they may be able 
to function as antigen-presenting cells.  If so, they may be equally 
important in initiating and sustaining immune responses to CNS elements such 
as myelin, oligodendroglia and neoplastic astrocytes.  Activation of 
microglia, so that they express Class II and other phenotypic markers, may be 
related to the presence of activated T cells arriving from the periphery.  
Alternatively, activated microglia, especially the perivascular variety, may 
permit entry of and activation of memory T cells. 

Studies to be funded in response to this PA include but are not limited to:

o Defining the relationship between microglia of the various types and 
macrophages and their cells of origin within and without the nervous system.

o Defining phenotypic markers which characterize microglia, distinguish 
between microglial types and states of activation.

o Investigating mechanisms of activation of microglia and their relationships 
to activation of T cells.
  
o Investigating the ability of microglia to serve as antigen-presenting cells 
and to express MHC Class I or II.

o Delineating the contribution of microglia to the development of 
autoimmunity of the CNS via antigen presentation or production of specific 
cytokines.  

o Advancing studies of the contributions of peripheral blood monocytes and 
macrophages to the presence of infected resident microglia.

o Investigating the ability of microglia to elaborate chemokines and 
cytokines and to express receptors for chemokines and cytokines. 

o Investigating contributions of perivascular microglia to the entry of T 
cells and blood macrophages into the CNS across the blood-brain barrier.  
Delineate the surface phenotypes and the chemo/cytokines which facilitate 
this.

o Investigating the role of microglia in diseased brain including multiple 
sclerosis, HIV infections, including the etiology of AIDS dementia. 
 
o Studies of the potential of microglia to serve as therapeutic tools for 
delivery of drugs, enzymes, trophic factors or genes into the CNS.

o Co-sponsorship by the National Institute of Mental Health is limited to 
applications that address the role of microglia in HIV/CNS disease.

Although not formally participating in this program announcement, the 
National Institute on Aging is interested in research on the role of 
microglia in normal and abnormal immune responses of the aging nervous 
system.”

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 sub-populations 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 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 may also obtain copies from these sources or from the program 
staff or contact person listed under INQUIRIES.  Program staff 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. 
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 
address:  http://grants.nih.gov/grants/guide/notice-files/not98-024.html

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) 435-
0714; fax: (301) 480-0525 Email: GrantInfo@NIH.GOV.  The title and number of 
the program announcement must be typed in Section 2 on the face page of the 
application.

Applicants planning to submit an investigator-initiated new (type 1), 
competing continuation (type 2), competing supplement, or any amended/revised 
version of the preceding grant application types requesting $500,000 or more 
in direct costs for any year are advised that he or she must contact the 
Institute or Center (IC) program staff before submitting the application, 
i.e., as plans for the study are being developed.  Furthermore, the 
application must obtain agreement from the IC staff that the IC will accept 
the application for consideration for award.  Finally, the applicant must 
identify, in a cover letter sent with the application, the staff member and 
the Institute or Center who agreed to accept assignment of the application.

This policy requires an applicant to obtain agreement for acceptance of both 
application and any such subsequent amendment.  Refer to the NIH Guide for 
Grants and Contracts, March 20, 1998 at 
http://grants.nih.gov/grants/guide/notice-files/not98-030.html 

The modular grant concept establishes specific modules in which direct costs 
may be requested as well as a maximum level for requested budgets. Only 
limited budgetary information is required under this approach. The just-in-
time concept allows applicants to submit certain information only when there 
is a possibility for an award. It is anticipated that these changes will 
reduce the administrative burden for the applicants, reviewers and Institute 
staff. The research grant application form PHS 398 (rev. 4/98) is to be used 
in applying for these grants, with the modifications noted below.

BUDGET INSTRUCTIONS

Modular Grant applications will request direct costs in $25,000 modules, up 
to a total direct cost request of $250,000 per year. (Applications that 
request more than $250,000 direct costs in any year must follow the 
traditional PHS 398 application instructions.)The total direct costs must be 
requested in accordance with the program guidelines and the modifications 
made to the standard PHS 398 application instructions described below:

PHS 398

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 4 
of 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 - Prepare a Modular Grant Budget Narrative 
page. (See http://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. This is not a Form page.

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. However, the applicant should use the NIH appropriation language 
salary cap and the NIH policy for graduate student compensation in developing 
the budget request.

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. 
Include the Letter of Intent to establish a consortium.

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: 
http://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. All appropriate exclusions must be applied in 
the calculation of the F&A costs for the initial budget period and all future 
budget years.

o 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.

Submit a signed original of the application, including the Checklist, and 
five signed photocopies of the application 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 courier/overnight mail service)

REVIEW CONSIDERATIONS

Applications will be assigned on the basis of established PHS referral 
guidelines.  Applications that are complete will be evaluated for scientific 
and technical merit by an appropriate peer review group convened in 
accordance with the standard NIH peer review procedures.  As part of the 
initial merit review, all applications will 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 applications under review, will 
be discussed, assigned a priority score, and receive a second level review by 
the appropriate national advisory council or board.
 
Review Criteria

(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 
methods?  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 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

Applications will compete for available funds with all other recommended 
applications assigned to the sponsoring Institute.  The following will be 
considered in making funding decisions:  Quality of the proposed project as 
determined by peer review, availability of funds, and program priority.

INQUIRIES

Inquiries 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.
Neural Environment Team
National Institute of Neurological Disorders and Stroke
6001 Executive Boulevard, Room 2115
Bethesda, MD 20892-9521
Telephone: (301) 496-1431
FAX: (301) 402-2060
Email:   ak45w@nih.gov

John D. Strandberg, D.V.M., Ph.D.
Comparative Medicine
National Center for Research Resources
One Rockledge Center, Room 5146
Bethesda, MD 20892-7965
Telephone: (301) 435-0744
FAX: (301) 480-3819
Email:   js430b@nih.gov

Dianne Rausch, Ph.D.
Center for Mental Health Research on AIDS
National Institute of Mental Health
6001 Executive Boulevard, Room 6209, MSC 9619
Bethesda, MD 20892
Telephone: (301) 443-7281
FAX: (301) 443-9719
Email:  dr89b@nih.gov

Thomas M. Johnson, Ph.D.
Program Officer
Division of Human Communication
National Institute on Deafness and other Communication Disorders
Executive Plaza South, 400-C
6120 Executive Boulevard
Bethesda, MD 20892-7180
(overnight mail) Rockville, MD 20850
Telephone: (301) 402-3461
FAX:  (301) 402-6251
Email:  tj65y@nih.gov

Charles William Sharp, Ph.D.
National Institute on Drug Abuse 
Division of Basic Research
6001 Executive Boulevard, Room 4282, MSC 9555
Bethesda, MD 20892-9555
Telephone: (301) 443-1887
FAX: (301) 594-6043
Email: cs107m@nih.gov

Direct inquiries regarding fiscal matters to:

Dianna Jessee
Grants Management Branch
National Institute of Neurological Disorders and Stroke
6001 Executive Boulevard, Room 3261
Bethesda, MD 20892-9190
Telephone:  (301) 496-9231
FAX: (301) 402-0219
Email:   dj35j@nih.gov

Paul Karadbil
Office of Grants Management
National Center for Research Resources
6705 Rockledge Drive, Room 6086
Bethesda, MD 20892-7965
Telephone: (301) 435-0844
FAX: (301) 480-3777
Email:   paulk@ncrr.nih.gov

William F. Caputo
Grants Management Branch
National Institute of Mental Health
6001 Executive Boulevard, Room 6115, MSC 9605
Bethesda, MD 20892
Telephone: (301) 443-0004
FAX: (301) 443-6885
Email: wcaputo@nih.gov

Sherry Dennison
Grants Management Officer 
Division of Extramural Activities
National Institute on Deafness and other Communication Disorders
6120 Executive Boulevard MSC 7180
Bethesda, MD 20892-7180
(overnight mail) Rockville, MD 20850
Telephone: (301) 402-0909
FAX:  (301) 402-1758
Email: sd63u@nih.gov

Gary P. Fleming, J.D., M.A.
Chief, Grants Management Officer
National Institute on Drug Abuse
6001 Executive Boulevard, Room 3131, MSC 9541
Bethesda, MD 20892-9555
Telephone: (301) 443-6710
FAX: (301) 594-6849
Email: gf6s@nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance 
93.853 and 93.854 (NINDS), 93.306 (NCRR), 93.242, 93.281, and 93.282 (NIMH), 
93.174 (NIDCD), and 93.279, 93.278, and 93.277 (NIDA).  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 NIH 
Grants Policy Statement (October 1, 1998).

The 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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