CELLULAR THERAPY IN CHRONIC SPINAL CORD INJURY

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The long-term goal is to improve residual function and to prompt central nervous system regeneration in regions of chronic spinal cord injury (SCI) in man. We propose to use the broad scope of the facilities of The Miami Project to Cure Paralysis to initiate an eight part attack on this difficult and unresolved clinical problem. Because recent research has shown that central neurons have the capacity to regenerate if provided with an altered cellular environment we will seek specific ways in which to provide a cellular environment salutary for regeneration in regions of SCI. To rationally develop this approach for human SCI we must first document the clinical course after various types of injury in the human in order to better predict eventual outcome (Project 1). We must also better understand the pathology of the various kinds of human cord injury, and learn how this pathology correlates with images obtained with modern imaging techniques, such as magnetic resonance imaging (Project 2). A more precise understanding of the physiology of the injured human cord as assayed with modern clinical electrophysiologic techniques is also necessary in devising therapeutic approaches (Project 3). Only against this background can we select suitable lesions in animals that successfully mimic aspects of the human lesion. Consideration of how the cellular environment of the human cord injury might be altered requires answers to several questions. What are the potential sources of cellular material for transplantation; will it be possible and/or necessary to use cell lines (Project 4)? Can in vitro studies mimic in vivo conditions and thus define cellular interactions that may be permissive or inhibitory for a regenerative response (Project 4)? Do human tissues follow the rules derived from animal studies in regenerative responses (Project 4)? How important a role will immunological rejection play in transplantation strategies in SCI? Having devised suitable lesion models and designed and transplanted promising cellular constructs, we must assess the consequences on both sensory and motor systems. This will require better definition of selected sensory and motor mechanisms in the rat spinal cord (Projects 5 and 6). We will then be in a position to assess the long-term functional effects of cellular transplants designed to influence the status of myelination and new fiber growth. We emphasize the possible use of the Schwann cell in designing cellular implants because use of this cell type would make it possible to use the patient's own tissues to facilitate CNS regeneration. The work proposed in these six projects will be supported by Core facilities for Administration, Histology/Electron Microscopy, Animal Care/Behavioral Testing, and Statistics.