The main objective of this application is to begin to develop a new therapeutic approach for traumatic brain injury - neurotrophic factor gene therapy with adenoviral vectors. While great strides have been made in the management of traumatic brain injury, no treatments exist which prevent and minimize neuronal loss following brain injury, the main cause of long-term disabilities in head-injured patients. Animal studies have revealed many potential therapeutic agents for brain injury, however, these compounds are administered in a global manner, producing possible side effects detrimental to the maintenance of the trauma patient. Gene therapy is a way in which to chronically present these therapeutic agents to a specific area of the brain, using genetically engineered viruses, without major global side effects. In order to develop gene therapy for traumatic brain injury, two factors must be addressed: 1) the production of novel genes in injured brain tissue, induced by an adenoviral vector, must be demonstrated, measured, and optimized in the rat and 2) the neuroprotective ability of a therapeutic gene in an animal model of brain injury must be demonstrated. These are the focus of the specific aims of this proposal. They are: 1) to determine the optimal viral vector concentration that will provide the greatest number of infected brain cells with minimal amounts of neural toxicity when injected into the normal and injured cortex, 2) to examine the neuroprotective effects of virally mediated glial cell line-derived neurotrophic factor (GDNF) or brain-derived neurotrophic factor (BDNF) expression in the cortex following a cortical contusion, and 3) to explore whether a virally mediated neurotrophic factor (either GDNF or BDNF) injected after a cortical contusion can rescue and protect neurons and behavioral function. In addition, this proposal will measure transgene expression in compromised cortical tissue. Together, these studies will develop a framework for further investigations of gene therapy for traumatic brain injury. Future questions will address the therapeutic windows of opportunity, long-term behavioral and cognitive function, and the optimization of new therapeutic genes and viral vectors for traumatic brain injury. In addition, these studies will provide a comprehensive research-training program for undergraduates in the fields of neurobiology, molecular biology, and animal behavior.
| Degeorge, M L; Marlowe, D; Werner, E et al. (2011) Combining glial cell line-derived neurotrophic factor gene delivery (AdGDNF) with L-arginine decreases contusion size but not behavioral deficits after traumatic brain injury. Brain Res 1403:45-56 |
| Minnich, Jennie E; Mann, Sarah L; Stock, Megan et al. (2010) Glial cell line-derived neurotrophic factor (GDNF) gene delivery protects cortical neurons from dying following a traumatic brain injury. Restor Neurol Neurosci 28:293-309 |
