GLIAL CELL INFLAMMATORY MECHANISMS OF HIV-1 INDUCED CELL INJURY IN THE NERVOUS 
SYSTEM

RELEASE DATE:  March 20, 2003 

PA NUMBER:  PAS-03-084   

EXPIRATION DATE:  1 November 2005, unless reissued

National Institute of Neurological Disorders and Stroke (NINDS)
 (http://www.ninds.nih.gov)
National Institute of Mental Health (NIMH)
 (http://www.nimh.nih.gov)

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S):  93.853 (NINDS), 93.242 (NIMH)

THIS PA CONTAINS THE FOLLOWING INFORMATION

o Purpose of the PA
o Research Objectives
o Mechanisms of Support
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Where to Send Inquiries
o Submitting an Application
o Peer Review Process
o Review Criteria
o Award Criteria
o Required Federal Citations

PURPOSE OF THIS PA  

The National Institute of Neurological Disorders and Stroke (NINDS) and the 
National Institute of Mental Health (NIMH) invite applications to promote 
research into the role of neuroinflammation in the initiation and expansion 
of cellular injury and death in the context of HIV-1 infection of the central 
nervous system (CNS).  Recent evidence indicates that microglial and 
astrocytic activation results in the release of excitotoxins, arachidonic 
acid metabolites, reactive oxygen species, cytokines and chemokines that lead 
to neurodegeneration and cognitive impairment in HIV-1 infected individuals. 
The intent of this PAS is to intensify interest and investigator-initiated 
research, to attract new investigators to this field, and to mobilize 
interdisciplinary approaches.

RESEARCH OBJECTIVES

Neurological dysfunction is a devastating complication of HIV-1 infection, 
affecting an estimated 25% of individuals chronically infected with the 
virus.  Symptoms of dysfunction include cognitive deficits, motor impairment, 
and behavioral problems.  The pathophysiological mechanisms underlying the 
changes in neurological function are as yet, unresolved, but may include 
neuroinflammatory responses to HIV-1 infection. The low number of HIV-1 
infected cells in the brain does not explain the extent of the neuropathology 
observed in HIV-1 encephalopathy. Emerging evidence indicates HIV-1 proteins 
exhibit toxicity to nerve cells only when non-neuronal cells, such as 
macrophages, microglia, or astrocytes are present.  This suggests that 
indirect mechanisms are important mediators of HIV-1 induced neuronal injury 
or death. 

At least two glial cell types appear to participate in CNS inflammation.  
Microglia, considered to be resident macrophages of the CNS, are a widely 
distributed cell population within brain parenchyma constituting about 1 to 
2% of all cells.  Upon activation, microglia release proinflammatory 
molecules such as cytokines and chemokines, as well as mediators of cell 
injury such as free radicals. Astrocytes in the brain (which constitute about 
50% of all cells) can act as antigen presenting cells, can be induced to 
express a variety of pro-inflammatory and immune-regulatory molecules, and 
can interact with immune cells infiltrating the CNS.  

Astrocytes maintain homeostasis of the neural environment by regulating 
extracellular pH, modulating ion and neurotransmitter levels in the 
microenvironment, and regulating the movement of molecules from the vascular 
compartment into the parenchyma of the CNS by forming an integral component 
of the blood-brain barrier.  In addition, astrocytes and neurons are 
metabolically coupled. Localized inflammatory processes in the brain may 
modulate astrocyte function, resulting in changes in the local environment 
that leave neurons and other cells vulnerable to injury.  

Future discoveries into mechanisms that regulate neuroinflammation in HIV-1 
infected CNS could lead to the development of new treatment strategies for 
NeuroAIDS.

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

o Investigating the role of microglia and astrocytes in the etiology of AIDS 
dementia.

o Advancing studies on cell-cell interactions in the neuroinflammatory 
cascade.

o Investigating the roles of excitotoxicity, the production of nitric oxide, 
and the production of reactive oxygen species as mechanisms of 
neuropathogenesis in HIV-1 infection of the CNS.  

o Defining phenotypic markers which characterize activated microglia and 
astrocytes in the context of HIV-1 infection of the nervous system.

o Delineating the contribution of microglia and astrocytes to the development 
of inflammation of the HIV-1 infected CNS via antigen presentation or 
production of specific cytokines and chemokines.  

o Investigating contributions of perivascular microglia and astrocytes to the 
entry of blood macrophages into the CNS across the blood-brain barrier.  

o Investigating the role of HIV-1 proteins in the activation of microglia and 
astrocytes, or their role in mediating damage to neurons.

o Development of animal models of HIV-1 induced neuroinflammation.

o Development of assays that use human neurons as targets of HIV-1 induced 
neuroinflammation.

o Delineation of apoptotic pathways involved in the death of CNS cells in the 
context of HIV-1 infection. 
 
o Investigating how neuroinflammation affects astrocytic maintenance of the 
neural environment.

o Investigating mechanisms by which HIV-1 induced inflammatory agents 
released from activated astroglial and microglial cells can precipitate 
psychiatric illnesses such as major depression. 

o Identifying biological mediators of psychiatric illnesses that influence 
HIV-1 disease progression.

o Investigate mechanisms by which peripherally induced inflammatory agents 
such as cytokines and chemokines influence astroglial and microglial cells 
and examine the contribution of these responses to the pathogenesis evident 
in the central nervous system response to HIV-1 infection.

MECHANISM(S) OF SUPPORT 

This PAS will use the NIH R01 and R21 award mechanisms.  As an applicant, you 
will be solely responsible for planning, directing, and executing the 
proposed project. The proposed project period during which the research will 
be conducted should adequately reflect the time required to accomplish the 
stated goals and should be no more than 5 years for R01 grants. The R21 
grants are one-time awards to support innovative, high impact research 
projects that would either 1) assess the feasibility of a novel avenue of 
investigation, 2) involve high risk experiments that could lead to a 
breakthrough in a particular field, or 3) demonstrate the feasibility of new 
technologies that could have major impact in a specific area. For this PA, 
participating NIH institutes will use the NINDS guidelines for the R21 
mechanism, which can be found at 
http://www.ninds.nih.gov/funding/r21guidelines.htm.  R21 proposals are 
limited to two years with a maximum of $275,000 direct costs for the two year 
period.  For example, you may request $100,000 in the first year and $175,000 
in the second year.  The request should be tailored to the needs of your 
project.  Normally, no more than $200,000 may be requested in any single 
year. This program is appropriate both for new investigators seeking to 
establish independent research careers and for established investigators 
wishing to explore new areas of neuroscience or develop novel technologies. 

This PAS uses just-in-time concepts.  It also uses the modular as well as the 
non-modular budgeting formats (see 
https://grants.nih.gov/grants/funding/modular/modular.htm).  Specifically, if 
you are submitting an application with direct costs in each year of $250,000 
or less, use the modular format.  Otherwise follow the instructions for non-
modular research grant applications.  This program does not require cost 
sharing as defined in the current NIH Grants Policy Statement at 
https://grants.nih.gov/archive/grants/policy/nihgps_2001/part_i_1.htm.  

FUNDS AVAILABLE

NINDS has set aside $1,500,000 total costs in addition to funds available for 
applications sent in response to this PAS that score within the NINDS payline 
(see NINDS Funding Strategy 
http://www.ninds.nih.gov/funding/ninds_funding_strategy.htm), depending on 
the overall scientific merit of the applications and the availability of 
funds throughout the duration of this solicitation (3 years). 

NIMH plans to pay up to $500,000 in total costs in FY 2004 for applications 
sent in response to this PAS, depending on the overall scientific merit of 
the applications and the availability of funds.

ELIGIBLE INSTITUTIONS 

You may submit (an) application(s) if your institution has any of the 
following characteristics:

o For-profit or non-profit organizations 
o Public or private institutions, such as universities, colleges, hospitals, 
and laboratories 
o Units of State and local governments
o Eligible agencies of the Federal government  
o Domestic or foreign
o Faith-based or community-based organizations 

INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS

Any individual with the skills, knowledge, and resources necessary to carry 
out the proposed research is invited to work with their institution to 
develop an application for support.  Individuals from underrepresented racial 
and ethnic groups as well as individuals with disabilities are always 
encouraged to apply for NIH programs.  

WHERE TO SEND INQUIRIES

We encourage your inquiries concerning this PA and welcome the opportunity 
answer questions from potential applicants.  Inquiries may fall into three 
areas:  scientific/research, peer review, and financial or grants management 
issues:

o Direct your questions about scientific/research issues to:

Michael Nunn, Ph.D.
Neural Environment Cluster
National Institute of Neurological Disorders and Stroke
6001 Executive Blvd., Room 2118
Bethesda, MD  20892
Telephone: (301) 496-1431
FAX: (301) 480-2424
Email: mn52e@nih.gov

Or 

Kathy L. Kopnisky, Ph.D.
Center for Mental Health Research on AIDS
National Institute of Mental Health
6001 Executive Blvd., Room 6199
Bethesda, MD  20892
Phone: (301) 443-7726
Fax: (301) 443-9719
Email: kkopnisk@mail.nih.gov

o Direct your questions about financial or grants management matters to:

Michael Loewe
Grants Management Branch
National Institute of Neurological Disorders and Stroke
6001 Executive Blvd., Room 3254
Bethesda, MD  20892
Telephone: (301) 496-9231
FAX: (301) 402-0219
Email: ml70m@nih.gov

Or

Brian Albertini
Grants Management Branch
National Institute of Mental Health
6001 Executive Blvd., Room 6123
Bethesda, MD  20892
Phone: (301) 443-0004
Email: albertib2@mail.nih.gov

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001).  The PHS 398 is available at 
https://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive 
format.  For further assistance contact GrantsInfo, Telephone (301) 710-0267, 
Email: GrantsInfo@nih.gov.

APPLICATION RECEIPT DATES: Applications submitted in response to this program 
announcement will be accepted at the standard application deadlines for AIDS-
related grant applications, which are available at 
https://grants.nih.gov/grants/dates.htm.  Application deadlines are also 
indicated in the PHS 398 application kit.

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications requesting 
up to $250,000 per year in direct costs must be submitted in a modular grant 
format.  The modular grant format simplifies the preparation of the budget in 
these applications by limiting the level of budgetary detail.  Applicants 
request direct costs in $25,000 modules.  Section C of the research grant 
application instructions for the PHS 398 (rev. 5/2001) at 
https://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step 
guidance for preparing modular grants.  Additional information on modular 
grants is available at 
https://grants.nih.gov/grants/funding/modular/modular.htm.

SPECIFIC INSTRUCTIONS FOR APPLICATIONS REQUESTING $500,000 OR MORE PER YEAR: 
Applications requesting $500,000 or more in direct costs for any year must 
include a cover letter identifying the NIH staff member within one of NIH 
institutes or centers who has agreed to accept assignment of the application.   

Applicants requesting more than $500,000 must carry out the following steps:

1) Contact the IC program staff at least 6 weeks before submitting the 
application, i.e., as you are developing plans for the study; 

2) Obtain agreement from the IC staff that the IC will accept your 
application for consideration for award; and,
  
3) Identify, in a cover letter sent with the application, the staff member 
and IC who agreed to accept assignment of the application.  

This policy applies to all investigator-initiated new (type 1), competing 
continuation (type 2), competing supplement, or any amended or revised 
version of these grant application types. Additional information on this 
policy is available in the NIH Guide for Grants and Contracts, October 19, 
2001 at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html. 

SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of 
the application, including the checklist, and five signed photocopies 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/courier service)

APPLICATION PROCESSING: Applications must be received by or mailed on or 
before the receipt dates described at 
https://grants.nih.gov/grants/funding/submissionschedule.htm. The CSR will not 
accept any application in response to this PA 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 a substantial revision of an application already reviewed, but 
such application must include an Introduction addressing the previous 
critique.

Although there is no immediate acknowledgement of the receipt of an 
application, applicants are generally notified of the review and funding 
assignment within 8 weeks.

PEER REVIEW PROCESS

Applications submitted for this PA will be assigned on the basis of 
established PHS referral guidelines.  An appropriate scientific review group 
convened in accordance with the standard NIH peer review procedures 
(http://www.csr.nih.gov/refrev.htm) will evaluate applications for scientific 
and technical merit.  

As part of the initial merit review, all applications will:

o Receive a written critique.
o Undergo a selection process in which only those applications deemed to have 
the highest scientific merit, generally the top half of applications under 
review, will be discussed and assigned a priority score.
o Receive a second level review by the appropriate national advisory council 
or board.

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 your application in order to judge the likelihood that the 
proposed research will have a substantial impact on the pursuit of these 
goals: 

o Significance 
o Approach 
o Innovation
o Investigator
o Environment
  
The scientific review group will address and consider each of these criteria 
in assigning your application's overall score, weighting them as appropriate 
for each application.  Your 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, you 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 your study address an important problem? If the aims 
of your application are achieved, how do they advance scientific knowledge?  
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?  Do you acknowledge potential problem areas and consider alternative 
tactics?

(3) INNOVATION:  Does your project employ novel concepts, approaches or 
methods? Are the aims original and innovative?  Does your project challenge 
existing paradigms or develop new methodologies or technologies?

(4) INVESTIGATOR: Are you appropriately trained and well suited to carry out 
this work?  Is the work proposed appropriate to your experience level as the 
principal investigator and to that of other researchers (if any)?

(5) ENVIRONMENT:  Does the scientific environment in which your 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?

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following 
items will be considered in the determination of scientific merit and the 
priority score:

PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human 
subjects and protections from research risk relating to their participation 
in the proposed research will be assessed. (See criteria included in the 
section on Federal Citations, below).
 
INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of 
plans to include subjects from both genders, all racial and ethnic groups 
(and subgroups), and children as appropriate for the scientific goals of the 
research will be assessed.  Plans for the recruitment and retention of 
subjects will also be evaluated. (See Inclusion Criteria in the sections on 
Federal Citations, below).

CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to 
be used in the project, the five items described under Section f of the PHS 
398 research grant application instructions (rev. 5/2001) will be assessed.  

ADDITIONAL CONSIDERATIONS 

DATA SHARING:  The adequacy of the proposed plan to share data.

BUDGET:  The reasonableness of the proposed budget and the requested period 
of support in relation to the proposed research.

AWARD CRITERIA

Applications submitted in response to a PA will compete for available funds 
with all other recommended applications.  The following will be considered in 
making funding decisions:  

o Scientific merit of the proposed project as determined by peer review
o Availability of funds 
o Relevance to program priorities

REQUIRED FEDERAL CITATIONS 

HUMAN SUBJECTS PROTECTION:  Federal regulations (45CFR46) require that 
applications and proposals involving human subjects must be evaluated with 
reference to the risks to the subjects, the adequacy of protection against 
these risks, the potential benefits of the research to the subjects and 
others, and the importance of the knowledge gained or to be gained.

MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD:  Research components 
involving Phase I and II clinical trials must include provisions for 
assessment of patient eligibility and status, rigorous data management, 
quality assurance, and auditing procedures.  In addition, it is NIH policy 
that all clinical trials require data and safety monitoring, with the method 
and degree of monitoring being commensurate with the risks (NIH Policy for 
Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 
1998: https://grants.nih.gov/grants/guide/notice-files/not98-084.html).  

INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: 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 clinical research projects unless a 
clear and compelling justification is provided indicating 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 clinical research should read the AMENDMENT "NIH 
Guidelines for Inclusion of Women and Minorities as Subjects in Clinical 
Research - Amended, October, 2001," published in the NIH Guide for Grants and 
Contracts on October 9, 2001 (https://grants.nih.gov/grants/guide/notice-
files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are 
available at https://grants.nih.gov/grants/funding/women_min/guidelines
_amended_10_2001.htm.  The amended policy incorporates: the use of an NIH 
definition of clinical research; updated racial and ethnic categories in 
compliance with the new OMB standards; clarification of language governing 
NIH-defined Phase III clinical trials consistent with the new PHS Form 398; 
and updated roles and responsibilities of NIH staff and the extramural 
community.  The policy continues to require for all NIH-defined Phase III 
clinical trials that: a) all applications or proposals and/or protocols must 
provide a description of plans to conduct analyses, as appropriate, to address 
differences by sex/gender and/or racial/ethnic groups, including subgroups if 
applicable; and b) investigators must report annual accrual and progress in 
conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group 
differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS:  
The NIH maintains a policy 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 is available at 
https://grants.nih.gov/grants/funding/children/children.htm. 

REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH 
policy requires education on the protection of human subject participants for 
all investigators submitting NIH proposals for research involving human 
subjects.  You will find this policy announcement in the NIH Guide for Grants 
and Contracts Announcement, dated June 5, 2000, at 
https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

HUMAN EMBRYONIC STEM CELLS (hESC):  Criteria for federal funding of research 
on hESCs can be found at https://grants.nih.gov/grants/stem_cells.htm and at  
https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html.  Only 
research using hESC lines that are registered in the NIH Human Embryonic Stem 
Cell Registry will be eligible for Federal funding (see http://escr.nih.gov).   
It is the responsibility of the applicant to provide the official NIH 
identifier(s)for the hESC line(s)to be used in the proposed research.  
Applications that do not provide this information will be returned without 
review. 

PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The 
Office of Management and Budget (OMB) Circular A-110 has been revised to 
provide public access to research data through the Freedom of Information Act 
(FOIA) under some circumstances.  Data that are (1) first produced in a 
project that is supported in whole or in part with Federal funds and (2) 
cited publicly and officially by a Federal agency in support of an action 
that has the force and effect of law (i.e., a regulation) may be accessed 
through FOIA.  It is important for applicants to of this amendment.  NIH has 
provided guidance at 
https://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.

Applicants may wish to place data collected under this PA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time.  If so, the application should 
include a description of the archiving plan in the study design and include 
information about this in the budget justification section of the 
application. In addition, applicants should think about how to structure 
informed consent statements and other human subjects procedures given the 
potential for wider use of data collected under this award.

URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals 
for NIH funding must be self-contained within specified page limitations. 
Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) 
should not be used to provide information necessary to the review because 
reviewers are under no obligation to view the Internet sites.   Furthermore, 
we caution reviewers that their anonymity may be compromised when they 
directly access an Internet site.understand the basic scope 

HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to 
achieving the health promotion and disease prevention objectives of "Healthy 
People 2010," a PHS-led national activity for setting priority areas. This PA 
is related to one or more of the priority areas. Potential applicants may 
obtain a copy of "Healthy People 2010" at 
http://www.health.gov/healthypeople.

AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the 
intergovernmental review requirements of Executive Order 12372 or Health 
Systems Agency review.  Awards are made under the authorization of Sections 
301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) 
and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92.  All 
awards are subject to the terms and conditions, cost principles, and other 
considerations described in the NIH Grants Policy Statement.  The NIH Grants 
Policy Statement can be found at 
https://grants.nih.gov/grants/policy/policy.htm.

The PHS strongly encourages all grant recipients to provide a smoke-free 
workplace and discourage the 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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