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: ac207q@nih.gov
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: rr46w@nih.gov
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: GrantsInfo@nih.gov.
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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