This Program Announcement expires on April 30, 2004, unless reissued.

THE BIOLOGY OF NON-HUMAN STEM CELLS IN THE ENVIRONMENT OF THE NERVOUS SYSTEM

Release Date:  April 9, 2001

PA NUMBER:  PA-01-078

National Institute of Neurological Disorders and Stroke
 (http://www.ninds.nih.gov)
National Institute of Mental Health
 (http://www.nimh.nih.gov)
National Institute on Deafness and Other Communication Disorders
 (http://www.nidcd.nih.gov/)
National Institute on Aging
 (http://www.nih.gov/nia/)
National Institute of Child Health and Human Development
 (http://www.nichd.nih.gov/)

THIS PA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS.  THIS PA INCLUDES 
DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED 
WHEN PREPARING AN APPLICATION IN RESPONSE TO THIS PA.

PURPOSE

The National Institute of Neurological Disorders and Stroke (NINDS), the 
National Institute of Mental Health (NIMH), the National Institute on 
Deafness and Other Communication Disorders (NIDCD), the National Institute on 
Aging (NIA) and the National Institute of Child Health and Human Development 
(NICHD) are committed to the discovery of effective treatments for 
neurological disorders, and invite applications for studies on the biology of 
non-human stem cells and regulation of their replication, development and 
function in the nervous system.  The tremendous plasticity exhibited by stem 
and progenitor cells raises the possibility that they can be used to replace 
components and restore function to parts of the brain that have been 
compromised by congenital disorders, developmental malfunction, injury or 
disease. There is, however, little understanding of the behavior and 
regulation of these cells in the environment of the healthy brain, or in the 
nervous system altered by such conditions as stroke, trauma, spinal cord 
injury, sensory loss, Muscular Dystrophy, Amyotrophic Lateral Sclerosis, 
Parkinson’s Disease, Huntington’s Disease, Alzheimer’s Disease, Multiple 
Sclerosis or mental illness. There are few studies on the long-term fates of 
transplanted cells within the nervous system or at other sites within the 
host. An understanding of environmental cues, age-dependent processes and 
genetic factors that govern the activities of these cells is crucial in order 
to develop safe and effective cell-replacement treatments. This Program 
Announcement encourages applications for support of ground-breaking research 
on non-human stem cells that address these issues. 

RESEARCH OBJECTIVES

Background

One of the most exciting frontiers in medicine is the potential use of stem 
cells for treating congenital or degenerative disorders.  In the central 
nervous system (CNS), cell-replacement strategies are of particular interest 
because, unlike other tissues, the mature brain and spinal cord have little 
capacity for self-repair.  CNS neurons are very restricted in their ability 
to regrow in situ, and the adult brain appears to have a limited ability to 
produce new neurons. Recent reports of multipotent cells that are able to 
generate cells with neuronal properties have raised expectations that such 
cells might be used to replace lost neurons and glia, repair defective 
circuits, and restore functions compromised by age, physical damage or 
disease. The hope is that, when exposed to the optimal microenvironment, stem 
cells will differentiate in a manner appropriate to the local brain region, 
and integrate seamlessly with the existing circuits of the host. For this to 
occur, the stem or progenitor cell should respond to proliferative and/or 
guidance cues that are either induced by the injury or degeneration, or 
supplied exogenously, but subsequently turn off these programs once normal 
cell numbers and circuitry have been attained. 

Whether stem cells can fulfill all these criteria in all areas of the nervous 
system remains to be determined; however, recent results obtained from 
studies in non-human model systems are encouraging.  Transplanted neuroblasts 
appear responsive to local cues. They can migrate to and repopulate 
degenerating parts of the adult brain, express the correct transmitters and 
make synaptic contacts with host neurons.  In the diseased retina, precursor 
cells differentiate into new neurons that appear to incorporate into local 
circuitry. In rodent models of Parkinson’s Disease, precursor cells induce 
functional recovery, if differentiated into dopaminergic neurons before 
transplantation into the striatum.   Oligodendrocytes derived from murine 
embryonic stem cells replaced lost myelin in the injured adult spinal cord. 
Together, these results demonstrate the ability of stem cells to differentiate 
and integrate appropriately into the damaged or diseased CNS. 

Another promising area of research lies in exploring the extent to which 
precursor cells derived from non-neural tissues, or from different stages of 
development, can generate specific classes of neurons and glia that can be 
used to repair particular neural circuits. While it is not surprising that 
murine embryonic stem cells can differentiate spontaneously into heart, 
blood, bone, and neuronal cells, unspecialized cells derived from adult 
sources as diverse as muscle, brain and bone marrow have recently been shown 
to “trans-differentiate” and acquire properties of cells from other lineages. 
Most intriguing, cells that appear committed to a particular lineage may “de-
differentiate” to a more pluripotent state.  These aspects of plasticity 
raise the hope for autologous transplants. The concern, however, also arises 
that transplanted cells could be triggered by the local environment to change 
once again into an undesired phenotype with unpredictable consequences. 

Examples of the enormous plasticity exhibited by stem cells raise fundamental 
questions regarding the comparative potential of precursor cells derived from 
different species, tissue sources and stages of development; the nature of 
the local environment that regulates stem cell behavior, and the genetic, 
molecular and cellular mechanisms that result in functional integration 
within the host. Understanding the normal process of stem cell 
differentiation during development provides a crucial “baseline” to assess 
their behavior in the environment provided by an adult host.  This type of 
information could be obtained from studies conducted in vitro as well as in 
appropriate animal models. 

Recent findings demonstrate that in select regions of the avian and mammalian 
nervous systems, endogenous neural stem and precursor cells continue to 
produce new neurons and circuits throughout adulthood, and indeed over the 
entire lifespan. Hair cells of the inner ear can be replaced following 
acoustic and drug-induced damage in the adult avian and amphibian nervous 
systems. Interestingly, behavior and experience can have profound effects on 
neurogenesis in the adult and the aging brain. These preliminary findings 
have important implications for development, learning, memory and the 
maintenance of a healthy and functional nervous system into old age.  The 
processes that regulate the native production of new neurons may be deployed 
to repair disordered regions of the brain. In addition, elucidation of these 
processes may provide insight into the functional basis of neurodevelopmental 
disorders, as well as errors in the establishment of neural circuitry leading 
to malfunction during puberty, adulthood and in old age. New research into 
mechanisms that influence neurogenesis and gliogenesis will provide 
fundamental information on the capacity of the nervous system to adapt in 
response to pharmacological and behavioral therapy throughout life. 

Objectives and Scope

This Program Announcement is intended to promote the exploration of non-human 
stem cell biology in the nervous system.   Research efforts on cellular, 
molecular and genetic mechanisms that influence the lineage choices of stem 
cells are of particular interest, as are studies that explore the long-term 
fates of stem cell-derived populations in animal models. The following 
examples illustrate areas that are of high interest; other innovative 
projects are also encouraged. 

o  Comparison of the mitotic potential and fates of different types of neural 
and non-neural progenitor cells in vitro and in vivo.

o  Comparison of the structural and functional integration of different types 
of progenitor cells into host nervous system, and in hosts of different ages. 

o  Comparison of the functional properties of neural precursor cells 
implanted at different stages of differentiation.

o  Characterization of the migratory properties of stem cells in the 
developing, adult or aging nervous system.

o  Investigation of the ability of progenitor cells to revert to a more 
plastic, multipotent state.

o  Examination of changes in gene and protein expression as stem and 
progenitor cells differentiate along specific lineages.

o  Identification of signals, signaling pathway components and 
transcriptional factors that regulate the fate(s) of transplanted cells in 
the nervous system.

o  Development of in vivo and in vitro assays that permit accurate and 
reliable characterization of the state of differentiation of stem or 
precursor cells.

o  Development of informatics models that integrate the results from studies 
of different stem and precursor cell types, and provide reliable predictions 
about changes in the state of the cells as a result of environmental cues.

o  Identification, characterization and validation of animal model systems, 
including models of disease and aging for screening and comparing the 
functional capabilities of implanted stem cells.

o  Comparison of the efficacy and risks of different modes of cell delivery 
in large and small mammals, and in animals of different ages.

o  Assessment of the ability of transplanted cells to integrate with the host 
nervous system and modify dysfunctional states.

o  Development of novel techniques such as non-invasive methods to track the 
integration and/or function of transplanted cells.

o  Assessment of the long-term fates of and the consequences of transplanted 
cells and their progeny in ectopic sites within the host. 

o  Assessment of the effects of environmental changes, therapies, or 
rehabilitation strategies on the production, differentiation and survival of 
endogenous stem cells across the lifespan. 
 
MECHANISM OF SUPPORT

The Exploratory/Developmental Grants (R21) mechanism and the Research Project 
(R01) grant mechanism will be used to support projects under this Program 
Announcement (PA).  Under these mechanisms, responsibility for the planning, 
direction, and execution of the proposed project will be solely that of the 
applicant.  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) generate pilot data to 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. Support for the R21 grants is limited to two years with a maximum of 
$100,000 direct costs requested per 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.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign, for-profit and non-
profit organizations, public and private, such as universities, colleges, 
hospitals, laboratories, units of State and local governments, and eligible 
agencies of the Federal government. Racial/ethnic minority individuals, 
women, and persons with disabilities are encouraged to apply as principal 
investigators.

INQUIRIES

Inquiries are encouraged.  The opportunity to clarify any issues or questions 
from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Arlene Y. Chiu, Ph.D.
Program Director, 
Repair and Plasticity Program
National Institute of Neurological Disorders and Stroke
Neuroscience Center, Room 2206, MSC 9525
Bethesda, MD  20892-9525
Telephone:  (301) 496-1447
FAX: (301) 480-1080
Email:  chiua@ninds.nih.gov

Beth-Anne Sieber, Ph.D.
Chief, Developmental Neurobiology Program
Division of Neuroscience and Basic Behavioral Science
National Institute of Mental Health
Neuroscience Center, Room 7186
Bethesda, MD  20892
Telephone:  (301) 443-5288
FAX:  (301) 402-4740
Email: sieberb@helix.nih.gov

Nancy L. Freeman, Ph.D.
Scientific Program Director
National Institute on Deafness and Other Communication Disorders
National Institutes of Health
Executive Plaza South-400C
6120 Executive Blvd. MSC-7180
Rockville, MD 20892-7180
Telephone:	(301) 402-3458
FAX:	(301) 402-6251
Email:	Nancy_Freeman@NIH.gov

Bradley C Wise, Ph.D.
Program Director, Fundamental Neuroscience
Neuroscience and Neuropsychology of Aging Program
National Institute of Aging
Gateway Building, Suite 3C307
7201 Wisconsin Avenue MSC 9205
Bethesda, MD 20892-9205
Telephone:	(301) 496-9350
FAX:	(301) 496-1494
Email: WiseB@nia.nih.gov
 
Ralph M. Nitkin, Ph.D.
Biological Sciences and Career Development Program
National Center for Medical Rehabilitation Research
National Institute of Child Health and Human Development
Executive Building, Room 2A03
6100 Executive Blvd, MSC 7510
Bethesda, MD 20892-7510
Telephone: (301) 402-4206
FAX: (301) 402-0832
Email: rn21e@nih.gov

Direct inquiries regarding fiscal matters to:

Rita Sisco
Grants Management Specialist
Grants Management Branch , DER 
National Institute of Neurological Disorders and Stroke
Neuroscience Center, Room 3290, MSC 9537
Telephone: (301) 496-7488
FAX: 301-402-0219
Email: rr46w@nih.gov

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

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

Linda Whipp
Grants Management Officer
Grants and Contracts Management Office
Gateway Building, Suite 2N212
Bethesda, Maryland 20892-9205
Telephone:	(301) 496-1472
FAX:	(301) 402-3672
Email:WhippL@nia.nih.gov

Christopher Myers
Grants Management Branch
National Institute of Child Health and Human Development
Building 61E, Room 8A01, MSC 7510
6100 Executive Boulevard
Bethesda, MD 20892-7510
Telephone: 301-435-6996
Email: cm143g@nih.gov
  
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 Division of 
Extramural Outreach and Information Resources, National Institutes of Health, 
6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/435-
0714, email: GrantsInfo@nih.gov.  

For R21 applications, use form PHS 398, with the following modifications:
1. Face Page of the application:
Item 2, Check the box marked "Yes" and type the title (R21 Program). The 
title and number of the program announcement must also be typed on line 2 of 
the face page of the application form.

2. Description:
As part of the description, explain briefly how this application relates to 
the purpose of the R21 mechanism as stated in this program (i.e. generating 
pilot data in a potentially important area or developing innovative 
methodologies or concepts that will produce significant breakthroughs in an 
area of established importance.

3. Research Plan:
Color/glossy photos may be submitted as an appendix, however, the appendix 
may not be used to circumvent the page limitation.  Letters of recommendation 
are not considered appendices, and do not count towards the 15-page limit. 

Applicants planning to submit an investigator-initiated R01 application 
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 Institute or Center who agreed to accept assignment of the 
application.  

This policy requires an applicant to obtain agreement for acceptance of both 
any such 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 title and number of the program announcement must be typed on line 2 of 
the face page of the application form and the YES box must be marked.

Submit a signed, typewritten original of the application, including the 
Checklist, and 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)

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS

Complete and detailed instructions and information on Modular Grant 
applications can be found at 
http://grants.nih.gov/grants/funding/modular/modular.htm.

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 all 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 all 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.

REVIEW CONSIDERATIONS

Applications will be assigned on the basis of established PHS referral 
guidelines.  Applications will be evaluated for scientific and technical 
merit by an appropriate scientific 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

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  In 
the written comments reviewers will be asked to discuss the following aspects 
of the application in order to judge the likelihood that the proposed 
research will have a substantial impact on the pursuit of these goals.  Each 
of these criteria will be addressed and considered in assigning the overall 
score, weighting them as appropriate for each application.  Note that the 
application does not need to be strong in all categories to be judged likely 
to have major scientific impact and thus deserve a high priority score.  For 
example, an investigator may propose to carry out important work that by its 
nature is not innovative but is essential to move a field forward.

(1) Significance:  Does this study address an important problem?  If the aims 
of the application are achieved, how will scientific knowledge be advanced?  
What will be the effect of these studies on the concepts or methods that 
drive this field?

(2) Approach:  Are the conceptual framework, design, methods, and analyses 
adequately developed, well-integrated, and appropriate to the aims of the 
project?  Does the applicant acknowledge potential problem areas and consider 
alternative tactics?

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

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

(5) Environment:  Does the scientific environment in which the work will be 
done contribute to the probability of success?  Do the proposed experiments 
take advantage of unique features of the scientific environment or employ 
useful collaborative arrangements?  Is there evidence of institutional 
support.

(6) For R21 grants:  Could these high risk experiments lead to a breakthrough 
in the field? Could the proposed studies demonstrate the feasibility of new 
technologies that could have a major impact in a specific area?

AWARD CRITERIA

Applications will compete for available funds with all other recommended 
applications. 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.

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.  Reviewers are cautioned that their anonymity may 
be compromised when they directly access an Internet site.
     
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 Program Announcement 
(PA), “ The biology of stem cells in the environment of the nervous system,” 
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 No. 
93.853, 93.242, 93.173, 93.866 and 93.929.  Awards are made under 
authorization of sections 301 and 405 of the Public Health Service Act as 
amended (42 USC 241 and 284) and administered under NIH grants policies and 
Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92.  This program is 
not subject to the intergovernmental review requirements of Executive Order 
12372 or Health Systems Agency review.

The PHS strongly encourages all grant and contract 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, and 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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