Stroke is a devastating disorder that leads to neuronal death and neurologic disability. The brain's inherent ability to form new neuronal connections and restore lost function can be enhanced by neutralizing the inhibitory nature of the adult CNS through antibody therapy targeting the protein Nogo-A. We have shown that anti-Nogo-A immunotherapy results in neuronal plasticity and functional recovery after ischemic stroke in adult rats. A better understanding of the mechanism underlying anti-Nogo-A immunotherapy would lead to improved therapeutic approaches for clinical use. Additionally, since stroke is more prevalent in the aged, ischemic stroke is best studied in a model, which incorporates the aged animal, as we propose here. We hypothesize that interfering with the growth inhibitory protein Nogo-A induces specific genomic changes and enhances functional recovery after stroke by increasing axonal and dendritic plasticity in brain regions important for sensorimotor function. We will test our hypothesis in the following specific aims:
Specific aim 1 - Determine whether anti-Nogo-A immunotherapy after stroke results in increased axonal and dendritic plasticity in the aged rat. We will also determine the appropriate treatment time for therapy, and examine genomic changes that occur after stroke and anti-Nogo-A therapy in order to better understand the other important gene products important for stroke recovery in our model.
Specific aim 2 - Determine whether contralesional forelimb cortex mediates recovery after stroke and anti-Nogo-A immunotherapy. We will use both large and small stroke volumes to determine the effects of lesion size on mechanisms of stroke recovery and also use intracortical microstimulation to map the remaining cortical tissue by examining evoked forelimb movements.
Specific aim 3 - Determine whether global or oligodendrocyte-specific Nogo-A knockout mice demonstrate spontaneous neuroplasticity after ischemic stroke, and also perform genomic analysis to determine other important gene products for plasticity after stroke. The results of these studies will lead to new therapeutic approaches to return lost function to patients suffering from ischemic, as well as other causes of brain damage by giving new insight into repair mechanisms in the aged brain, and lead to appropriate design for the translation into clinical trials using anti-Nogo-A immunotherapy after stroke. Relevance: Stroke is a devastating disorder that leaves millions of individuals neurologically impaired and severely decreases their quality of life. We have discovered a novel immunotherapy that will improve functional recovery after ischemic stroke in adult rats, and now propose studies to elucidate the mechanisms by which this recovery occurs in order to better translate these findings to a useful therapy for human stroke patients.
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