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) 710-0267, 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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