Full Text PA-97-024
 
SPINAL CORD INJURY: EMERGING CONCEPTS
 
NIH GUIDE, Volume 26, Number 1, January 10, 1997
 
PA NUMBER:  PA-97-024
 
P.T. 34

Keywords: 
  Nervous System 
  Injury 
  Wound Healing 

 
National Institute of Neurological Disorders and Stroke
National Eye Institute
National Institute of Child Health and Human Development
National Institute of Nursing Research
 
Application Receipt Dates:  February 1, June 1, October 1
 
PURPOSE
 
The National Institute of Neurological Disorders and Stroke (NINDS),
National Eye Institute (NEI), National Institute of Child Health and
Human Development (NICHD), and  National Institute of Nursing
Research (NINR) invite applications for support of research that will
increase our knowledge of the mechanisms that underlie processes of
injury and repair in the central nervous system (CNS), including
optic nerve and other CNS tracts, and that will provide strategies
for therapeutic intervention in spinal cord 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 PA,
Spinal Cord Injury:  Emerging Concepts, is related to the priority
area of unintentional injuries.  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 domestic and foreign institutions,
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.
Foreign institutions are not eligible for First Independent Research
Support and Transition (FIRST) (R29) awards.  Applications from
minority institutions, minority individuals, and women are
particularly encouraged.
 
MECHANISM OF SUPPORT
 
The support mechanisms for grants in this area will be the
investigator-initiated research project grant (R01) and the FIRST
award (R29).  The principal investigator will plan, direct, and,
along with any co-investigators, perform the research.  Applicants
planning to submit a new (Type 1) investigator-initiated grant
application requesting $500,000 or more in direct costs for any year
must contact institute program staff before submitting the
application.  A cover letter that identifies the program staff member
who agrees to accept the assigned application must be sent with the
application.
 
RESEARCH OBJECTIVES
 
Background
 
Injury to the spinal cord tragically affects hundreds of thousands of
people in the United States, with approximately 10,000 new traumatic
injuries each year.  Early treatment and improved hospital care have
increased survival, but at great cost.  The estimated yearly cost of
long-term, specialized care for paralyzed patients exceeds $10
billion. The personal costs to patients and their families is beyond
calculation: planned education, career, marriage, and independence
are interrupted and often never regained.
 
The spinal cord, as part of the central nervous system (CNS),
coordinates movement and sensation for the entire body below the
head.  Specialized cell populations within the cord are the
substrates for these functions. Motoneurons extend long axons
peripherally to innervate skeletal muscle.  These motoneurons receive
information from descending tracts of the brain both directly and
indirectly via interneurons in the spinal cord gray matter.  Axons of
dorsal root ganglion cells connect peripheral sensory receptors to
spinal interneurons, to motoneurons, and to brain centers.  This
complex neuronal circuitry of the spinal cord is supported by the
glia of the CNS.  Radial glia enclose the cord like the rim and
spokes of a wheel, defining compartments for ascending and descending
fiber systems.  Astrocytes contribute to the blood-spinal cord
barrier and provide a wide variety of support functions.
Oligodendrocytes myelinate axons, and provide for rapid conduction of
neuronal signals.
 
Traumatic injury disrupts all of these cell types and changes their
functions.  Axons degenerate, neurons die, astrocytes proliferate and
become reactive, radial glia enclose large cysts, and
oligodendrocytes cannot remyelinate damaged areas.  The anatomy of an
injured spinal cord shows profound pathology, but also reveals the
sprouting of uninjured fibers, the regeneration of damaged
populations, the reorganization of glia, and clearing away of debris.
The neurophysiology of the spinal cord also changes, reflected by
altered responses to stimulation.  Without appropriate ascending and
descending input, remaining neural circuits change over time, and
this plasticity may contribute to permanently impaired function.
 
It is necessary to enhance initial regenerative responses, and much
can be learned from developmental neurobiology, where mechanisms that
underlie the generation of neural cells and their connections can be
examined directly.  A number of CNS regions, such as optic nerve,
provide accessible and well defined areas to elucidate fundamental
mechanisms.  Several trophic and inhibitory factors are known to
affect survival of neurons and extension of neurites, and naturally
occurring substances may enhance supportive glial functions.
Components of the extracellular matrix can support the growth of
axons.  The growing body of knowledge on genetic and cellular
mechanisms of survival and growth can be related directly to a
variety of injury paradigms to determine the most crucial events in
eventual outcome.
 
Clinical issues in spinal cord injury involve the entire person,
emotionally and physically, from the time of injury, through acute
hospital care, rehabilitation, and life changes.  Experimental
strategies to minimize damage in the early stages of injury include
hypothermia, antioxidants, neurotrophic factors, blockers of
excitoxicity, gangliosides, and steroid therapies; however, only one
treatment, high dose methylprednisolone, is in current use. Changes
in blood volume and maintenance of adequate ventilation during
initial treatment are also critical.  A myriad of chronic disorders,
from spasticity to depression to infection, plague the survivors of
spinal cord injury and require management by a variety of health care
professionals.
 
An NIH workshop entitled "Spinal Cord Injury: Emerging Concepts" was
held in Bethesda, Maryland on September 30- October 1, 1996.  Several
areas of relevance for further research were presented by the
participants, and form the basis for this program announcement.
 
Research Goals and Scope
 
Examples of investigator-initiated research grant applications for
basic, applied, and clinical studies related to the understanding of
the neurobiology of injury and regeneration may include, but should
not necessarily be limited to:
 
o  Mechanisms of Secondary Injury and Cell Death. Determine the
extent and time course of apoptosis in neuronal and glial populations
after trauma.  What gene families contribute to programmed cell death
after injury in the adult CNS?  What genes can contribute to cell
survival? What signals activate irreversible pathways and how are
these pathways regulated?  What are the links between immediate and
delayed cell death in the nervous system following injury?  To what
extent do the various mechanisms (i.e., excitotoxicity, free
radicals, cytokines) contribute to overall secondary damage?
 
o  Immune Responses.  Investigate the temporal profiles of cellular
and molecular changes in spinal cord that signal both the afferent
and efferent limbs of the immune response. What affects the
trafficking of immune cells across the blood/spinal cord barrier?
What aspects of the immune response contribute to healing after
spinal cord injury?
 
o  Cell Generation.  Explore the existence and properties of
multipotential stem cells that remain in the adult CNS. What signals
regulate the proliferation and differentiation of these cells?
 
o  Trophic Control Mechanisms.  Identify the peptide trophic factors
that signal survival and growth of specific types of neurons and
their processes.  How is production and release of such signals
regulated?  What confers responsiveness of neurons to trophic
stimulation?  What receptors and signal transduction pathways are
involved? What is the role of electrical activity in neuronal trophic
factor production and release?  Which trophic signals are made by
glial cells, and does neuronal activity regulate this production?  Do
glial cells from the central versus peripheral nervous system differ
in the mechanisms that regulate their production and release of
trophic factors?
 
o  Axonal Survival and Growth Signals.  What is the molecular and
cytoskeletal basis of axon growth?  Do the same intracellular
mechanisms that promote survival of the cell also promote
regeneration of the axon, or are novel molecular mechanisms involved?
 
o  Axonal Guidance Signals.  Elucidate novel chemotropic factors
(both soluble and contact-mediated) that guide growing axons, their
signaling mechanisms, and receptors. Do CNS and PNS differ in the
expression of these axonal guidance molecules?
 
o  Axonal Inhibitory Signals.  Identify molecules that inhibit axon
elongation and characterize their cell type specificity.  What
extracellular signals induce axons to stop growing during normal
development, and how is the signal transduced?  Is there cross-talk
between inhibitory and stimulatory axonal signals?
 
o  Function of Glia and Remyelination.  Astrocytes, microglia and
oligodendroglia all react to traumatic injury. What is the time
course and extent of glial reactivity?  To what extent do
demyelination and remyelination occur?  Do new myelinating cells
arise from surviving oligodendrocytes or from precursors found within
the CNS?  Are interactions among glial populations necessary for
myelination?
 
o  Synapse Formation.  Identify the mechanisms of synapse formation
in the central nervous system.  What factors contribute to site
recognition by growing axons?  What postsynaptic characteristics
result in permanent and stable synapses?  Is the exchange of
information between pre- and postsynaptic elements the same in
regenerating versus developing synapses?
 
o  Functional Plasticity.  Design interventions that can enhance or
build on intrinsic mechanisms of repair.  Can useful recovery of
function be achieved by driving the intrinsic rhythm generators of
the distal cord?  What minimum descending input, both quantitative
and qualitative, is required to drive these circuits?  Study the
potential for adaptive change in the spinal cord that remains after
injury.  Evaluate the efficacy of neuromodulator or transmitter
replacement in terms of modified segmental circuitry.  How is
motoneuron excitability below a lesion altered?  What changes occur
in sensory circuits that can contribute to chronic effects after
injury?  Will rescue of cells that have been damaged improve
function?
 
o  Neural Prostheses.  Investigate the feasibility of using neural
prostheses to restore bowel and bladder function, upper and lower
extremity functional movement, and upper and lower extremity
sensation.  Develop new microelectrodes capable of providing chronic
ingoing and outgoing connections with sensory and motor neurons in
the spinal cord.  Investigate biomaterials and bioactive surfaces to
permit the integration of neural prostheses with spinal cord tissue.
 
o  Chronic Injury and Rehabilitation.  Emphasize systematic analyses
of rehabilitation as adjuncts to biological or pharmacological
treatment of damaged spinal cord.  Define "windows of opportunity"
for functional repair.  Enhance understanding of the neurobiology of
the chronically injured cord.  Develop improved animal models for
both acute and chronic spinal cord and CNS injury. Study therapeutic
interventions aimed at the various functional consequences of spinal
cord injury such as spasticity and exaggerated reflexes, respiratory
compromise, pain, pressure ulcers, bone deterioration, or
bowel/bladder control.  Investigate issues of nutrition, physical
conditioning, and sleep in individuals with spinal cord
injury.
 
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 new
policy results from the NIH Revitalization Act of 1993 (Section 492B
of Public Law 103-43) and supersedes and strengthens the previous
policies (Concerning the Inclusion of Women in Study Populations, and
Concerning the Inclusion of Minorities in Study Populations) which
have been in effect since 1990.  The new policy contains some new
provisions that are substantially different from the 1990 policies.
 
All investigators proposing research involving human subjects should
follow the "NIH Guidelines for Inclusion of Women and Minorities as
Subjects in Clinical Research", which have been published in the
Federal Register of March 28, 1994 (FR 59 14508-14513), and reprinted
in the NIH GUIDE FOR GRANTS AND CONTRACTS of March 18, 1994, Volume
23, Number 11.
 
Investigators also may obtain copies of the policy from the program
staff listed under INQUIRIES.  Program staff may also provide
additional relevant information concerning the policy.
 
APPLICATION PROCEDURES
 
Applications are to be submitted on the grant application form PHS
398 (rev. 5/95) according to the instructions included in the
application package.  These application packages are available at
most institutional offices of sponsored research and 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:
ASKNIH@odrockm1.od.nih.gov.
 
Receipt dates for new research grant applications are February 1,
June 1, and October 1.
 
On page 1 of form PHS 398, check "YES" in Item 2 and enter the number
and title of this Program Announcement in the space provided.
 
Use the mailing label provided in the application package to mail the
completed, signed original and five exact copies to:
 
DIVISION OF RESEARCH GRANTS
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)
 
A number of other Institutes, Centers, and Divisions (ICD) at the NIH
may be interested in the general subject of this program
announcement.  Applications submitted in response to this PA that
propose research in scientific areas that overlap ICD interests will
receive a funding component assignment in accord with existing
referral guidelines and procedures established by the Division of
Research Grants, NIH.
 
REVIEW CONSIDERATIONS
 
Applications will be assigned on the basis of established PHS
referral guidelines.  Applications will be reviewed for scientific
and technical merit by an appropriate study section in the Division
of Research Grants.  Applications for multicentered clinical trials
will be reviewed by the institute designated for primary assignment.
The standard review criteria will be used to assess the scientific
merit of applications.  The second level of review will be by the
appropriate National Advisory Council.
 
AWARD CRITERIA
 
Applications will compete for available funds with all other
applications.  The following will be considered when making funding
decisions:
 
o  quality of the proposed projects as determined by peer review;
o  availability of funds; and
o  program balance among research areas.
 
INQUIRIES
 
Inquiries are encouraged.  The opportunity to clarify any issues or
questions from potential applicants is welcome.
 
Direct inquiries regarding programmatic issues to:
 
Dr. Mary Ellen Cheung
Division of Stroke, Trauma, and Neurodegenerative Disorders
National Institute of Neurological Disorders and Stroke
Federal Building, Room 8A13
Bethesda, MD  20892
Telephone:  (301) 496-4226
FAX:  (301) 480-1080
Email:  MM108W@NIH.GOV
 
Dr. Michael D. Oberdorfer
Strabismus, Amblyopia, and Visual Process Branch
National Eye Institute
6120 Executive Boulevard, Suite 350, MSC 7164
Bethesda, MD  20892-7164
Telephone:  (301) 496-5301
FAX:  (301) 496-0528
Email:  MO5R@NIH.GOV
 
Dr. Danuta Krotoski
National Center for Medical Rehabilitation Research
National Institute of Child Health and Human Development
Building 6100, Room 2A03, MSC 7510
Bethesda, MD  20892
Telephone:  (301) 402-2242
FAX:  (301) 402-0832
Email:  DK58P@NIH.GOV
 
Dr. Mary D. Leveck
Scientific Program Administrator
National Institute of Nursing Research
Building 45, Room 3AN-12, MSC 6300
Bethesda, MD  20892
Telephone:  (301) 594-5963
FAX:  (301) 480-8260
Email:  MLEVECK@EP.NINR.NIH.GOV
 
Direct inquiries regarding fiscal aspects to:
 
Ms. Gladys Bohler
Division of Extramural Activities
National Institute of Neurological Disorders and Stroke
Federal Building, Room 1004
Bethesda, MD  20892
Telephone:  (301) 496-9231
FAX:  (301) 402-0219
 
Ms. Carolyn Grimes
Extramural Services Branch
National Eye Institute
Executive Plaza South, Suite 350
Bethesda, MD  20892
Telephone:  (301) 496-5884
 
Ms. Mary Ellen Colvin
Grants Management Branch
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 8A07
Bethesda, MD  20892
Telephone:  (301) 496-5001
 
Mr. Jeff Carow
Grants Management Officer
National Institute of Nursing Research
Building 45, Room 3AN12 MSC 6301
Bethesda, MD  20892
Telephone:  (301) 594-5974
FAX:  (301) 480-8256
Email:  JCAROW@EP.NINR.NIH.GOV
 
AUTHORITY AND REGULATIONS
 
This program is described in the Catalogue of Federal Domestic
Assistance Number:  93.853-93.854, 93.868, 93.864- 93.865, and
93.361.  Grants will be awarded under the authority of the Public
Health Service Act, Title IV, Section 301 (Public Law 78-410, as
amended: 42 USC 241) and administered under PHS grant policies and
Federal Regulations 42 CFR Part 52 and 45 CFR 74.  This program is
not subject to Health Services Agency Review of the intergovernmental
review requirements of Executive Order 12372.
 
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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