Project Description: |
In living organisms, routine metabolic processes result in the formation of many free radicals within the cellular environment that can be toxic to the cells themselves. My research tests the hypothesis that free radicals produced in metabolism regulate a membrane transport system, System xc-, that provides neurons and glia with the precursors required to synthesize a cellular antioxidant called glutathioine. System xc- is a plasma membrane transport system that catalyzes the stoichiometric exchange of extracellular cystine for intracellular glutamate in the brain, retina, kidney and duodenum. The internalized cystine is then used for glutathione synthesis. While several groups have demonstrated transcriptional regulation of System xc- within 24 hours of exposure of cells to oxidants there have been essentially no studies which have examined the short-term regulation of transporter activity. My students and I have shown that oxidants appear to acutely (within minutes) regulate System xc- by modulating the cell surface expression of the transporter. These exciting findings suggest a novel form of regulation of System xc- that may serve as an extremely important component of the cellular defense system in protecting cells from oxidative insults. We are currently using biochemical and cell biological techniques 1) to describe the cellular signaling pathways that are involved in the hydrogen peroxide-regulated activity of system xc- in cultured glioma cells and dopaminergic cells and 2) to identify the cellular compartments involved in the constitutive trafficking pathways of System xc-. Each student in the Chase lab has their own independent research project that fits into the overall research aims of the lab. Students also assist in formulating testable hypotheses and constructing appropriate experimental designs to test their hypotheses. |
