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Trafficking of a Membrane Transport System

Project Full Title:

Regulation of System xc- trafficking by hydrogen peroxide

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Project Description:

This interdisciplinary project will incorporate the disciplines of biology, chemistry and neuroscience. The project is specifically housed within the Hope College Departments of Biololgy and Chemistry. Therefore, interested students can elect to participate in either summer research program.

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. The internalized cystine is then used for glutathione synthesis which protects the brain from oxidative damage. 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 molecular techniques 1to identify important trafficking motifs within the C-terminus of System xc- and 2) to describe the cellular signaling pathways that are involved in the hydrogen peroxide-regulated activity of System xc-. Ultimately, this work will provide us with a better understanding of molecular processes which acutely regulate System xc- and identify key proteins which regulate transporter trafficking. As such, this work may provide direction for future studies aimed at pharmacological manipulation of System xc- activity for therapeutic benefit.

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.

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