PILOT STUDIES FOR RE-ESTABLISHING CONNECTIVITY IN SPINAL CORD INJURY

Release Date:  March 9, 2000

RFA:  NS-01-001

National Institute of Neurological Disorders and Stroke

Letter of Intent:          August 15, 2000
Application Receipt Date:  October 11, 2000

THIS RFA 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 RFA.

PURPOSE

Motor vehicular accidents, sports accidents, and assaults result in 
about 10,000 new cases of spinal cord injury (SCI) every year in the 
United States. Damaged nerve fibers within the cord cease to relay 
signals between the brain and the rest of the body, depending on the 
site of damage along the spinal cord, these injuries can interfere with 
breathing, bowel and bladder function, and result in paraplegia or 
quadriplegia. New findings on the molecular regulation of axonal 
pathfinding and synapse formation during development suggest that 
similar mechanisms could lead to more robust and directed nerve regrowth 
in adulthood, and the restoration of connections within the damaged 
spinal cord.  However, more information is needed on the expression of 
such signals in the normal and injured adult spinal cord.  In order to 
stimulate research in this area, the National Institute of Neurological 
Disorders and Stroke (NINDS) invites applications for support of pilot 
studies that extend the new discoveries in developmental neurobiology to 
stimulate axonal regeneration, guidance, and synaptogenesis within the 
injured spinal cord.  Researchers with expertise in development and 
other disciplines are encouraged to initiate exploratory studies leading 
to a better understanding of the basic mechanisms that contribute to 
repair and plasticity after spinal cord injury.

RESEARCH OBJECTIVES

Background

In the adult mammalian central nervous system (CNS), damage to white 
matter tracts results in the complete failure of the severed axons to 
regenerate.  Restoration of function depends on overcoming endogenous 
obstacles to regeneration, and re-establishing neural connections across 
the lesion site.  Recent research indicates that multiple factors - the 
trophic environment within the CNS, the inhibitory nature of myelin 
debris and the glial scar, secondary damage, cavitation within the 
spinal cord, and even the responsive state of the injured neuronal 
population - all contribute to the failure to regenerate. Although 
studies that target individual components have had limited success in 
coaxing some axonal growth across or around lesion sites, it is 
increasingly clear that no single molecule or mechanism is responsible 
for the lack of regeneration within the CNS. In addition, research on 
the development of the nervous system reveal that a variety of guidance 
cues help growing axons locate and form synapses with their appropriate 
targets.  Families of diffusible and contact-mediated attractant and 
repellant molecules, and their receptors, are being discovered in worms, 
flies and mammals, and the intracellular signaling cascades mediating 
their activities are being identified.  In addition, new studies on 
synaptogenesis implicate the unique roles of organizing molecules, such 
as nARIA, agrin, gephyrin, PSD95, GRIP and other proteins with PDZ 
domains that act to recruit and assemble the synaptic apparatus at 
appropriate sites. 

These and other exciting results from development need to be brought to 
bear on the study of SCI.  Compared to embryogenesis, however, 
regeneration poses unique challenges.  The mature CNS must adopt new 
strategies that can operate within the confines of damaged or scarred 
neural architecture.  Successful regeneration may require navigation 
through foreign or inappropriate terrain within the mature nervous 
system, and novel reorganization of circuits. Accomplishing these goals 
may involve the selective reactivation of signaling molecules and 
mechanisms that operate primarily in embryogenesis. 

Objectives and Scope

This RFA seeks proposals from investigators who study navigational cues 
that regulate neurite outgrowth and synaptogenesis in development, to 
apply their findings to the task of re-establishing functional 
connectivity in the damaged spinal cord.  Areas of interest include:

O Studies to determine the presence in normal and injured adult spinal 
cord of guidance molecules or other molecular signals, within growing 
axons, the axonal environment or target areas that are known to 
influence neurite outgrowth and synapse formation during development.

O Studies to determine the responsiveness of different classes of 
regenerating axons in the mature spinal cord to trophic factors, 
guidance molecules, and mechanisms of target selection. 

O Studies on the synergism of multiple trophic factors and/or 
extracellular matrices in promoting and guiding axonal regeneration 
and collateral sprouting within damaged and undamaged regions of the 
mature spinal cord.

O Examination of synaptogenesis within the normal and injured adult 
spinal cord   the classes of synapses formed, the accuracy of re-
connectivity, the mechanism and specificity of action of agents, such 
as trophic factors and small molecules, that regulate synapse re-
formation.

O Studies on the role of glia and other support cells in the normal 
maintenance of spinal tracts as well as in regeneration following 
injury.

O Development of improved and versatile implantable materials and cell 
lines to facilitate the growth of regenerating axons over and beyond 
the lesion site.

O The translation of results obtained from studies on rodents to larger 
mammals where the dimensions of the spinal cord and requirements for 
regeneration more closely mimic the situation in human patients.

SPECIAL REQUIREMENTS

The NINDS invites applications for R21 grants to extend new findings in 
development to promote regeneration in the mature CNS.  The purpose of 
this RFA is to encourage collaboration between developmental 
neuroscientists and investigators in the spinal cord field in applying 
cellular and molecular insights from development to the understanding 
and eventual treatment of SCI.  For this announcement, the R21 mechanism 
will have a cap of $150,000 direct costs and a maximum term of 3 years.

The purpose of this RFA is to encourage new collaborations in spinal cord 
injury research.  It offers an opportunity for young investigators, as 
well as researchers established in other disciplines, to begin to 
address problems in SCI, and to generate preliminary data in this new 
enterprise.  Of particular interest are proposals with in vivo models of 
spinal cord injury in mature mammals that will yield potential 
strategies to improve regeneration and eventual functional recovery 
within the adult spinal cord.  Collaborations may take the form of 
sharing of personnel (i.e. research fellows), resources, animal models, 
and facilities.  Travel for investigators to accomplish such 
collaborations should be budgeted in the applications.  Meetings with 
NINDS staff to discuss progress and share information will be planned 
separately from the RFA.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) R21, 
Individual Exploratory/ Developmental Research Grant, award mechanism.  
Responsibility for the planning, direction, and execution of the 
proposed project will be solely that of the applicant.  The total 
project period for an application submitted in response to this RFA may 
not exceed three years.  This RFA is a one-time solicitation.  Future 
unsolicited competing continuation applications will compete with all 
investigator-initiated applications and be reviewed according to the 
customary peer review procedures.  The anticipated award date is July 1, 
2001.

FUNDS AVAILABLE

The NINDS will allocate up to $2.0 million in total costs to support 
grants in FY 2001.  It is anticipated that between 8 and 10 grants may 
be awarded at an annual direct cost level of $150,000.  Applicants may 
request up to three years of support.  In all cases, facilities and 
administrative (indirect) costs will be awarded based on the negotiated 
rates. Because the nature and scope of the research proposed may vary, 
it is anticipated that the size of each award will also vary.  Although 
the financial plans of NINDS provide support for this program, awards 
pursuant to this RFA are contingent upon the availability of funds and 
the receipt of a sufficient number of meritorious applications.  

ELIGIBILITY REQUIREMENTS

Applications may be submitted by foreign or 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.

INQUIRIES

Inquiries concerning this RFA are strongly 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, NINDS	
Neuroscience Center, Room 2209, MSC 9525
6001 Executive Boulevard
Bethesda, MD 20892-9525
Telephone: 301-496-1447
FAX: 301-480-1080
Email: [email protected] 

Direct inquiries regarding fiscal matters to:

Rita Rollins-Hickey
Grants Management Specialist
Grants Management Branch, DER, NINDS
Neuroscience Center, Room 3249, MSC 9537
Telephone:  (301) 496-9231
FAX:  301-402-0219
Email: [email protected]

LETTER OF INTENT

Prospective applicants are asked to submit, by August 15, 2000, a Letter 
of Intent that includes a descriptive title of the proposed research, the 
name, address, and telephone number of the Principal Investigator, the 
identities of other key personnel or participating institutions, and the 
number and title of this RFA.  Although a Letter of Intent is not 
required, is not binding, and does not enter into the review of a 
subsequent application, the information that it contains allows Institute 
staff to estimate the potential review workload and avoid conflict of 
interest in the review.

The Letter of Intent is to be sent to:

Arlene Y. Chiu, Ph.D.
Program Director, Repair and Plasticity
National Institute of Neurological Disorders and Stroke
National Institutes of Health
Neuroscience Center, Room 2202, MSC 9525
6001 Executive Boulevard
Bethesda, MD 20892-9525
Rockville, MD 20852 (for courier service)
FAX: 301-480-1080

SCHEDULE SUMMARY

Letter of Intent Receipt Date: August 15, 2000
Application Receipt Date: October 11, 2000 
Peer Review Date: March 2001 
Council Review:  May 24-25, 2001 
Earliest Anticipated Start Date: July 1, 2001

APPLICATION PROCEDURES

The Research grant application form PHS 398 (rev. 4/98) is to be used in 
applying for these grants.  These forms are available at most 
institutional offices of sponsored research, from the Division of 
Extramural Outreach and Information Resources, National Institutes of 
Health 6701 Rockledge Drive, Room MSC 7910, Bethesda, MD 20892, 
telephone 301/710-0267, email: [email protected]. 

The RFA label available in the PHS (rev. 4/98) application form must be 
affixed to the bottom of the face page of the application.  Type the RFA 
number on the label.  Failure to use this label could result in delayed 
processing of the application such that it may not reach the review 
committee in time for review.  In addition, the RFA title and number 
must be typed on line 2 of the face page of the application form and the 
YES box must be marked. 

The sample RFA label available at: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been 
modified to allow for this change.  Please note this is in pdf format.

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS

PHS 398

Budget Instructions

Modular Grant applications  will request direct costs in $25,000 
modules, up to a total direct cost request of $150,000 per year.   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:

o FACE PAGE: Items 7a and 7b should be completed, indicating Direct 
Costs (in $25,000 increments up to a maximum of $150,000) 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, typewritten original of the application, including the 
Checklist, and three 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)

At the time of submission, two additional copies of the application must 
be sent to: 

Dr. Lillian M. Pubols
Chief, Scientific Review Branch, NINDS, NIH
Neuroscience Center, Suite 3208, MSC 9529
6001 Executive Boulevard
Bethesda, MD 20892-9529
Rockville, MD 20852 (for express, courier service)

Applications must be received by the receipt date designated in this 
announcement.  If an application is received after that date, it will be 
returned to the applicant without review.  The Center for Scientific 
Review (CSR) will not accept any application in response to this RFA 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 substantial revisions of 
applications already reviewed, but such applications must include an 
introduction addressing the previous critique.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by CSR and 
responsiveness by NINDS. Incomplete applications will be returned to the 
applicant without further consideration.

Applications will be reviewed for scientific and technical merit by a 
review group convened by the Scientific Review Branch, NINDS.  As part of 
the initial merit review, all applications will receive a written 
critique, undergo a process in which only those applications deemed to 
have the highest scientific merit (generally the top half of the 
applications received for review) will be discussed, assigned a priority 
score, and receive a second level review by the NINDS Advisory Council. 

REVIEW CRITERIA FOR RESEARCH GRANT APPLICATIONS: 

The R21 mechanism for exploratory/developmental studies was chosen for 
this RFA to encourage young investigators and investigators not currently 
engaged in spinal cord injury research to enter the field.  Since new 
avenues are to be explored, extensive preliminary data specific to spinal 
cord injury may not necessarily be a part of the application, however, 
the significance of the work, approach to the selected study, and 
qualifications of the investigators should be apparent.  Reviewers will 
concentrate on the potential of the proposed project to provide 
information on axonal regrowth and synaptogenesis in the adult spinal 
cord that can lead to new directions for spinal cord injury research.

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 review, comments on the following aspects of the 
application will be made 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 the 
assignment of the overall score.

(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?

In addition to the above criteria, in accordance with NIH policy, 
applications will also be reviewed with respect to the following:

o  The reasonableness of the proposed budget and duration in relation to 
the proposed research.
o  The adequacy of the proposed protection for animals and the 
environment, to the extent they may be adversely affected by the project 
proposed in the application.

AWARD CRITERIA 

Funding decisions will be based on scientific and technical merit as 
determined by the Initial Review Group, Program balance and need, review 
by the National Advisory Neurological Disorders and Stroke Council, and 
the availability of funds.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women and members of minority groups 
and their subpopulations must be included in all NIH supported 
biomedical and behavioral research projects involving human subjects, 
unless a clear and compelling rationale and justification 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 was published in the Federal 
Register of March 28, 1994 (FR 59 14508-14513) and in the NIH Guide For 
Grants and Contracts, Vol. 23, No. 11, March 18, 1994, available on the 
web at: http://grants.nih.gov/grants/guide/notice-files/not94-100.html

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.

Investigators may also obtain copies of these policies from the program 
staff listed under INQUIRIES. Program staff may also provide additional 
relevant information concerning the policy.

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 RFA, "Pilot 
projects for spinal cord injury research," is related to the priority 
area of unintentional injuries: spinal cord injury.  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.  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.

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, 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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