REGULATION OF PERIPHERAL NERVE-SPECIFIC NA CHANNEL, PN1

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The long-term goal of this research is to understand the mechanisms that regulate the temporal and tissue specific expression of the peripheral nervous system specific Na channel, PN1. Na channels, expressed in the axons and cell bodies of peripheral nervous system (PNS) neurons, are in large part responsible for making these cells electrically excitable. The PN1 Na channel has the following unique properties: first, it is one of the only genes expressed predominantly in the PNS; and second, PN1 is rapidly and dramatically upregulated upon brief (1 min.) exposure to nerve growth factor (NGF) and interferon gamma (IFNgamma) by an as yet unknown mechanism. Our research plan is to: 1) Use genetic and biochemical techniques to identify PN1 regulatory DNA elements that confer the PN1 expression pattern on reporter genes transfected into several cell lines. 2) Determine the mechanism-immediate early genes and response elements-by which PN1 is upregulated by NGF and IFNgamma. The yeast one hybrid screen developed In the Pls lab will be used to isolate immediate early genes. 3) Test the constructs isolated in 1 and 2 for their ability to drive expression of a reporter gene in vivo by creating transgenic mice expressing the different constructs. Results from these experiments should be applicable in an experimental or therapeutic context to drive gene expression specifically PNS.