Spinal Cord Injury, Plasticity and Transplant Mediated Repair

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DESCRIPTION (provided by applicant): Our long-term goal is to develop treatments for acute and chronic spinal cord injury (SCI) that can be translated into the clinic. Therapeutic interventions, such as transplantation and exercise (EX), lead to reorganization of the spinal cord, as shown by anatomical, physiological and behavioral assays. Our Projects will address transplant (TP)-mediated effects on recovery of function and the reliance of recovery on actions at local and/or distant sites. Project 1 will focus on the benefits offered by transplantation of neural restricted precursor cells (neuronal and glial) after adult rat SCI. Basic mechanisms by which stem cell IPs promote neuroprotection, long distance axonal growth, relay information across a lesion and support recovery of function will be explored. Project 2 will use spinalized cats to test whether behavioral recovery attained with neurotrophin-producing IPs results from axonal regeneration or local trophic effects. Experiments will test for recovery of function when transplantation is delayed after injury and will define sensory and motor influences on reorganization of lumbar locomotor circuits (i.e. CPG) after training or transplantation. Project 3 will use spinalized rats to address mechanisms of IP- and EX-mediated reorganization of spinal cord circuitry. Whether activity-dependent plasticity creates an environment more conducive to axonal regeneration and if plasticity of neuromuscular junctions relates to improved functional capabilities will be examined. The Administration Core will organize weekly meetings of PPG participants, prepare progress reports and maintain the entire PPG budget. The Behavior and Biomechanics Core will conduct established and novel behavioral assessments of SCI animals to specify the effects of lesions and treatments and to provide insights into recovery mechanisms. The Cell and Molecular Biology Core will provide stem cells and modified fibroblasts for transplantation and assist with PCR and protein assays. The Histology Core will prepare tissue sections for tract tracing and immunocytochemical reactions and perform image analysis of TP-mediated axonal regeneration and sprouting. The Surgery Core will assist with preparation of SCI animals and transplantation procedures. Our strategy is to employ multiple injury models and combinations of treatments to promote repair and to understand mechanisms of functional recovery. This program has direct relevance to the design and implementation of future treatment programs for SCI.