Despite progress in elucidating neural stem cell properties and using them for transplantation, the challenges of neuronal cell replacement following CNS injury remain difficult to resolve. This proposal will use transplants of neuronal and glial restricted progenitors (NRP/GRP) to reconnect the disrupted sensory system after acute and chronic spinal cord injury (SCI). The experiments are designed to build neuronal relays across a dorsal column lesion reconnecting the denervated dorsal column nucleus (DCN). The proposal addresses important issues related to application of stem cell biology to CNS injury, including how to generate graft derived neurons, direct their axon growth, overcome the inhibitory environment of the injury, and, most importantiy, how to form functional synapses with the denervated target. We will continue our studies that demonstrated the principles of relay formation with NRP/GRP transplants by testing specific hypotheses for improving the functional aspects of the relay and advance this strategy to chronic SCI.
In Aim 1, we will test the role of synaptic density and activity-induced plasticity in producing stable and functional synaptic connections at the DCN target. We propose that a) synaptic activity with target neurons will improve through summation of the evoked potentials at the target site by increasing synaptic density (more axons) and reducing inhibition of perineuronal nets at the DCN, and b) synapse stability will improve with time, with task-specific activity, and with stimulation of the sensory relay.
In Aim 2 we will test the hypothesis that denervated targets can be reconnected and retrained to correctly interpret sensory information at a chronic injury stage. Specifically, we will test a) how to promote host sensory axons to grow into the site of a chronic injury, and b) how to promote connectivity at the target, where the DCN has been subject to prolonged deafferentation. To achieve connectivity in the chronic injury, we will use neurotrophins, chondroitinase (delivered by novel viral vectors), and exercise/training protocols. This relay model allows us to go beyond the current focus on regeneration, exploit the advantages of embryonic neurons produced by neural stem cells, and examine the steps needed to restore connectivity and improve function in a well-defined system.
Spinal cord injury has devastating effects on quality of life accompanied by a heavy financial burden to individuals and society. This proposal addresses potential therapies for spinal cord injury using transplants of neural stem cells to restore connectivity and function. The strategies developed in this project are also relevant to brain injury and other neuro-degenerative disorders that require neuronal cell replacement.
|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|
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|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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