The etiology of certain acute insults and chronic neuro-degenerative disorders has been advanced by the finding that these diseases are possibly manifested fully or in part through glutamate receptor activation. These diseases include stroke, Alzheimer's and Huntington's disease. Unfortunately, very little is known about the intracellular mechanisms responsible for glutamate-induced cell death. The power of molecular genetics will be used to probe signal transduction mechanisms. The catalytic or regulatory (inhibitory) domain of protein kinase C, calcium/calmodulin-dependent protein kinase II, and calcium activated neutral proteinase will be expressed in cultured neurons using a HSV-1 vector system. Infected cells will then be challenged with toxic doses of various glutamate agonists to determine the role of these enzymes in mediating neuronal death. The development of the HSV-1 vector system to study glutamate neurotoxicity could have broad implications: 1) An understanding of these intracellular processes may suggest clinical therapeutic strategies for stroke. 2) The HSV-1 vector may provide a novel therapeutic approach in treating chronic neurologic disorders by restoring function through gene therapy.
