Long term rehabilitation is often required for patients who have suffered traumatic and ischemic brain injury. The requirement for long-term rehabilitation is directly determined by the extent of permanent neuron loss. Since neuron loss occurs during a delayed as well as an acute phase, one approach to improving the outcome in such patients is to develop therapies that limit delayed neuron destruction. We propose the development of a herpes virus based gene therapy approach in which the expression of neuroprotective proteins in the peri-injury period will reduce the extent of neuron death and limit the loss of function of surviving neurons. Specifically, we will test the efficacy of gene transfer and expression of neurotrophic factors in an in vivo model of traumatic injury, and the gene for bcl2 in an organotypic hippocampal slice culture system and an in vivo model of ischemic injury. A role for neurotrophic factors in the maintenance of neuron function in experimental traumatic injury has been previously suggested. We hypothesize that delayed neuron loss following ischemic injury to the hippocampal formation to be a form of apoptosis. For this reason, we will transfer the gene for bcl2, because its expression has been shown to be neuroprotective in other apoptotic models.
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