Alcohol & FAS-Mediated Apoptosis in Polarized Liver Cell

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DESCRIPTION (provided by applicant): Benita L. McVicker received her PhD from The University of Nebraska Medical Center (UNMC) in 1997 and has worked in the laboratories of Drs. Dean Tuma and Carol Casey in the Liver Study Unit at the VA Medical Center in Omaha, Nebraska since that time. The Liver Study Unit has been instrumental in establishing that chronic ethanol consumption can lead to a variety of pathological consequences, yet further clarification of the mechanism(s) by which ethanol causes hepatotoxic conditions is required. Recently, Dr. McVicker and co-workers have identified the use of a fibroblast/hepatoma hybrid cell line (WIF-B) as a model for studying the effects of ethanol on cellular processes. The generation of such a physiologically important polarized model (that cannot be accomplished with regular isolated hepatocytes) will enable the evaluation of protein trafficking events (Fas/CD95 death receptor) in the presence of alcohol in relation to alterations in hepatocyte polarity and apoptosis. Specifically, the goals of Dr. McVicker's research presented in this grant include 1) further characterization of ethanol's effects on Fas trafficking and 2) to identify the role of specific regulators that are involved in ethanol-induced Fas translocation and the correlation of these effects with Fas-induced apoptosis mechanisms. The study of death receptor trafficking and signaling as well as the use of the WIF-B model are new areas of interest to Dr. McVicker. For these studies, she has proposed to use several techniques (i.e. immunohistochemistry and microinjection assays) that will require additional training and specialized instruction. Dr. McVicker has access to the confocal and flow cytometry core labs at UNMC and has support for training consultations in those methods. In addition, she has support to learn specific techniques under the direction of Dr. Pamela Tuma (an expert in the use of WIF-B cells) at The Catholic University in Washington D.C. Overall, the completion of this proposed work will provide the mentored experience to progress to future independent study of liver function and survival following ethanol treatment.