Our long-term goal is to develop treatments for acute and chronic spinal cord injury (SCI) that can be translated into clinical care. The combination of therapeutic interventions, such as transplantation and exercise (EX), can lead to reorganization of the spinal cord, as shown by anatomical, physiological and behavioral assays. Our Projects will address the general areas of regeneration and activity dependent plasticity after SCI, focusing on transplant-mediated effects on recovery of function and the proposition that exercise will facilitate further recovery by promoting connectivity of regenerating axons at local and/or distant sites. Project 1 will provide a mechanistic examination of the effects of activity dependent or transplant dependent changes in the spinal cord microenvironment on regenerating axons as signified by changes in intra-axonal signaling. Project 2 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 cells promote neuroprotection, long distance axonal growth, relay of information across a lesion and support recovery of function will be explored. Project 3 will use spinalized rats to address mechanisms of transplant and EX-mediated reorganization of spinal cord circuitry. Whether activity-dependent plasticity creates an environment more conducive to axonal regeneration will be determined. These studies then will be advanced into a cat model of SCI. Project 4 will use spinalized cats to test whether transplant-derived neurotrophins modify excitability of afferent pathways during locomotion and whether locomotor circuitry can be re-engaged in a chronic injury paradigm. Throughout the Projects multiple injury models, combinations of treatments to promote repair and study of acute vs. chronic treatment will be used to explore the potential for functional recovery. The Administration Core will monitor research progress through weekly meetings of PPG participants, will review changes in research design initiated by project results and foster project interactions. The Behavior and Biomechanics Core will conduct established 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, modified fibroblasts and viral vectors for transplantation and assist Projects with PCR and protein assays. The Histology Core will prepare tissue sections for tract tracing and immunocytochemical reactions and perform image analysis of transplant-mediated axonal regeneration and sprouting. The Surgery Core will instruct Projects with procedures of transplantation in SCI animals. The Electrophysiology Core will provide training and support in techniques necessary to demonstrate functional connectivity and recovery after SCI. This Program Project has direct relevance to the design and implementation of future treatment programs for acute and delayed intervention after SCI.

Public Health Relevance

Neural tissue and cell transplantation and exercise will be tested for efficacy in promoting regeneration after spinal cord injury. We will explore when a treatment might be most effective by delaying treatment for weeks to months after injury. This approach directly impacts the overwhelming number of chronically injured spinal cord injured patients. In a preclinical study we will pursue studies in a large animal model, spinal cord injured cats, examining the potential to promote structural and functional recovery after an acute or chronic injury and the ability to foster greater recovery through aggressive physical rehabilitation training. We feel that results of this study will have direct clinical relevance.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Jakeman, Lyn B
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Drexel University
Anatomy/Cell Biology
Schools of Medicine
United States
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Ollivier-Lanvin, Karen; Fischer, Itzhak; Tom, Veronica et al. (2015) Either brain-derived neurotrophic factor or neurotrophin-3 only neurotrophin-producing grafts promote locomotor recovery in untrained spinalized cats. Neurorehabil Neural Repair 29:90-100
Lee, Seung Joon; Kalinski, Ashley L; Twiss, Jeffery L (2014) Awakening the stalled axon - surprises in CSPG gradients. Exp Neurol 254:12-7
Jin, Ying; Bouyer, Julien; Haas, Christopher et al. (2014) Behavioral and anatomical consequences of repetitive mild thoracic spinal cord contusion injury in the rat. Exp Neurol 257:57-69
Singh, Anita; Krisa, Laura; Frederick, Kelly L et al. (2014) Forelimb locomotor rating scale for behavioral assessment of recovery after unilateral cervical spinal cord injury in rats. J Neurosci Methods 226:124-31
Graziano, Alessandro; Foffani, Guglielmo; Knudsen, Eric B et al. (2013) Passive exercise of the hind limbs after complete thoracic transection of the spinal cord promotes cortical reorganization. PLoS One 8:e54350
Houle, John D; Cote, Marie-Pascale (2013) Axon regeneration and exercise-dependent plasticity after spinal cord injury. Ann N Y Acad Sci 1279:154-63
Haas, Christopher; Fischer, Itzhak (2013) Human astrocytes derived from glial restricted progenitors support regeneration of the injured spinal cord. J Neurotrauma 30:1035-52
Liu, Gang; Detloff, Megan Ryan; Miller, Kassi N et al. (2012) Exercise modulates microRNAs that affect the PTEN/mTOR pathway in rats after spinal cord injury. Exp Neurol 233:447-56
Keeler, Benjamin E; Liu, Gang; Siegfried, Rachel N et al. (2012) Acute and prolonged hindlimb exercise elicits different gene expression in motoneurons than sensory neurons after spinal cord injury. Brain Res 1438:8-21
Ketschek, A R; Haas, C; Gallo, G et al. (2012) The roles of neuronal and glial precursors in overcoming chondroitin sulfate proteoglycan inhibition. Exp Neurol 235:627-37

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