INTERNEURONAL CIRCUITS UNDERLYING VOLUNTARY MOVEMENTS IN NORMAL AND INJURED
SPINAL CORD

Release Date:  September 27, 1999

RFA NUMBER:  NS-99-008

National Institute of Neurological Disorders and Stroke

SOME APPLICATIONS UNDER THIS RFA USE THE "MODULAR GRANT" AND 
"JUST-IN-TIME" CONCEPTS.  THE RFA INCLUDES DETAILED 
MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST 
BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THE RFA.

Letter of Intent Receipt Date:     December 15, 1999
Application Receipt Date:          February 16, 2000 

PURPOSE

Traumatic spinal cord injury currently affects approximately 250,000
Americans.  Many functional changes can result, including the loss of
voluntary movements below the level of the spinal lesion.  Research from a
variety of animal models has shown that various spinal circuits, with
appropriate ascending and descending input, are critical for coordinated
voluntary and reflex movements including not only standing and walking, 
but also control of bladder, bowel, and sexual functions.  Since many spinal
cord injuries leave much of the spinal cord intact, reactivation of the
"spinal pattern generators" to control at least some of these lost functions
seems possible.  Fundamental research, in mammalian systems, on the anatomy
and physiology of intrinsic spinal circuits that are involved in volitional
movements will play a key role in unlocking the potential to restore 
function after injury.  

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health promotion
and disease prevention objectives of "Healthy People 2000," a PHS-led national
activity for setting priority areas.  This RFA, "Interneuronal Circuits
Underlying Voluntary Movements in Normal and Injured Spinal Cord", is related
to the priority area of unintentional injuries: spinal cord injury.  Potential
applicants may obtain a copy of "Healthy People 2000" (Full Report:  Stock No.
017-001-00474-0 or Summary Report:  Stock No. 017-001-00473-1) through the
Superintendent of Documents, Government Printing Office, Washington, DC 
20402-9325 (telephone 202/512-1800).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by foreign 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.

MECHANISM OF SUPPORT

The mechanism of support for this RFA will be the investigator initiated
research project grant (R01).  Responsibility for planning, direction and
execution of the proposed research will rest solely with the applicant.   This
RFA is a one time solicitation.  Future applications will compete with all
investigator-initiated applications and be reviewed according to the 
customary peer review procedures. 

For applications requesting $250,000 or less in direct costs, specific
application instructions have been modified to reflect "MODULAR GRANT" and
"JUST-IN-TIME" streamlining efforts being examined by the NIH.  Complete and
detailed instructions and information on Modular Grants can be found at 
http://grants.nih.gov/grants/funding/modular/modular.htm

FUNDS AVAILABLE

The NINDS will allocate up to 2.5 million dollars in total costs to support
grants responding to this RFA in FY 2000.  It is anticipated that between five
and seven grants may be awarded.  Applicants may request up to five years of
support.  In all cases, facilities and administrative (F&A) costs will be
awarded based on the negotiated rates. The award of grants pursuant to this
RFA is contingent upon the receipt of a sufficient number of high quality
applications and the availability of funds for this purpose.  Policies that
govern research grant programs of the National Institutes of Health are 
applicable to all procedures in the receipt, review and support of this RFA.

RESEARCH OBJECTIVES

Background

The spinal cord gray matter contains a variety of highly specialized neurons. 
Large alpha motoneurons and smaller gamma motoneurons send long axons to
activate muscles of the limbs and trunk in both reflex and volitional
movements.  The axons of intrinsic spinal projection neurons extend into the
brain, transmitting a variety of sensory information.  Preganglionic autonomic
neurons reach the sympathetic chain or the visceral ganglia to control
functions of smooth and striated muscle. 

In addition to these projection neurons with long axons, the spinal gray
matter contains many interneurons with axons that project entirely within the
spinal cord.  These interneurons make up networks that are involved in
sensation and motor activity within the segmental levels of the cord.  Such
networks of interneurons receive both descending information from the brain
and afferents from the periphery, and communicate with the brain through
ascending axon systems.  Rhythmic patterns of coordinated movements, 
such as stepping, can be produced by "central pattern generators," which are
cellular circuits or networks consisting of interneurons linked to
motoneurons.  Descriptions of the distributions of interneurons associated
with hindlimb activity have been presented for a variety of limbed vertebrates
(Kiehn and Kjaerulff, 1998).  In this work, lesion studies point to a
distributed network located in the lateral and ventral cord.  Activity-
dependent labeling has suggested that the medial portion of the intermediate
gray and the area around the central canal are important for rhythm-generation
during locomotion.  Other rhythmic behaviors such as scratching or backward
walking reveal additional areas of activity in various regions of the gray
matter.  However, the precise interneuronal networks that are involved in
generation of rhythmic activity remain to be elucidated.

Coordinated rhythmic activity depends on the integration of descending
pathways, reflex activity, and sensory inputs (Hultborn et al, 1998).  This
unification or processing of information is also necessary for appropriate
function of bowel and bladder sphincters (de Groat, 1998), and of sexual
function.  The convergence of interneurons onto the output motoneurons may
help to control the coordination of visceral and somatic functions that is
necessary for voluntary control of bladder and bowel function.

Objectives and Scope

This RFA seeks basic science applications for research in a mammalian system
aimed at identification of the interneuronal circuits involved in the
coordination and expression of voluntary limb movements and of bladder, bowel,
and sexual functions.  Further research is needed to explore the physiological
characteristics, neurotransmitters, and connectivity of this essential
component of the spinal circuitry underlying complex functions.  

Research interests include, but are not limited to:

o Identification of spinal cord circuitry involved in voluntary movement by
methods such as electrophysiology, functional imaging, activity dependent and
trans-synaptic labeling of interneurons, and/or optical recording using
voltage-sensitive or ion-sensitive dyes.  

o Identification of the spinal cord circuitry involved in the coordination of
smooth and striated muscles subserving bladder, bowel or sexual functions
using activity-dependent or trans-synaptic labeling of interneurons,
electrophysiology, and/or functional imaging.

o Identification of the role of interneurons in the coordination of activities
from afferent, descending, and reflex pathways; the involvement of
interneurons, or groups of interneurons, in more than one functional circuit;
the anatomical/physiological characteristics of these interneurons.

o Development or use of new mammalian animal models, such as transgenic,
knock-out, or mutant animals to elucidate the role of interneurons in
voluntary movements.

o Development of new methods to assess interneuronal circuits involved in
voluntary movements. 

o In mammalian models of spinal cord injury: Identification of anatomical and
functional plasticity in spinal cord circuitry that occurs rostral and caudal
to an injury; identification of anatomical and functional plasticity following
spinal cord injury resulting from activation, inhibition or other modulation
of sensory afferents; development of specific blocking or stimulation
paradigms to eliminate or activate components of a pattern-generating circuit.

De Groat, W.C. 1998.  Anatomy of the central neural pathways controlling the
lower urinary tract.  Eur. Urol. 34 Suppl 1: 2-5.

Kiehn, O. and O. Kjaerulff.  1998. Distribution of central pattern generators
for rhythmic motor outputs in the spinal cord of limbed vertebrates.  Ann. NY
Acad. Sci.: 110-130.

Hultborn, H., et al.  1998.  How do we approach the locomotor network in the 
mammalian spinal cord?  Ann. NY Acad. Sci.: 70-82.

LETTER OF INTENT

Prospective applicants are asked to submit, by December 15, 1999, 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 NINDS staff to estimate the potential review workload 
and avoid conflict of interest in the review.

The Letter of Intent is to be sent to:

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

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,
MSC 7910, Bethesda, MD 20892; telephone 301/435-0714; email:
GrantsInfo@nih.gov and on the internet at
http://grants.nih.gov/grants/forms.htm.

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.  In addition, the RFA label
available in the PHS 398 (rev. 4/98) application form must be affixed to the
bottom of the face page of the application.  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. 

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. 

Applications requesting $250,000 or less in direct costs per year should
conform to modular grant application procedures as announced in the NIH Guide,
December 15, 1998. The modular grant concept establishes specific modules in
which direct costs may be requested as well as a maximum level for requested
budgets.  Only limited budgetary information is required under this approach. 
The just-in-time concept allows applicants to submit certain information only
when there is a possibility for an award.  It is anticipated that these
changes will reduce the administrative burden for the applicants, reviewers
and Institute staff. 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 accordane
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 $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:  Use a Modular Grant Budget Narrative 
page (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.  

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.

o   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. 

o  Provide an additional narrative budget justification for any variation in
the number of modules requested beyond the first year.

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

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)

In order to facilitate the review of applications, please mail or deliver one
copy of the application when completed to:

Dr. Lillian 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 February 16, 2000.  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 

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,
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?

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.

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:

William J. Heetderks, M.D., Ph.D.
Program Director, Repair and Plasticity, NINDS    
Neuroscience Center, Room 2208, MSC 9525
6001 Executive Boulevard
Bethesda, MD 20892-9525
Telephone: 301-496-1447
FAX: 301-480-1080
Email: wh7q@nih.gov 

Direct inquiries regarding fiscal matters to:

Rita Rollins-Hickey
Grants Management Specialist
Grants Management Branch, DEA, NINDS
NSC Room 3249, MSC 9537
Telephone:  (301) 496-9231
FAX:  301-402-0219
Email: rr46w@nih.gov

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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