Alcohol & FAS-Mediated Apoptosis in Polarized Liver Cell

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• 批准号: 7045785
• 负责人: BENITA L. MCVICKER
• 金额: $ 10.66万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7045785
• 关键词: CD95 molecule; JUN kinase; apoptosis; biological signal transduction; cell line; cellular polarity; chemosensitizing agent; confocal scanning microscopy; cytotoxicity; enzyme activity; ethanol; female; flow cytometry; hepatotoxin; immunocytochemistry; intracellular transport; laboratory mouse; liver cells; microinjections; phosphorylation; posttranslational modifications; protein kinase C; protein structure function; protein transport; tissue /cell culture; toxicology; zinc

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.

描述（由申请人提供）：贝尼塔·L·麦克维克（Benita L.从那时起，内布拉斯加州奥马哈弗吉尼亚州医疗中心的肝脏研究单位的迪恩·图马和卡罗尔·凯西（Dean Tuma and Carol Casey）。肝脏研究单元一直在确定慢性乙醇消耗可能导致各种病理后果，并进一步阐明乙醇会导致乙醇引起肝毒性疾病的机制。最近，麦克维克（McVicker）博士和同事确定使用成纤维细胞/肝癌杂交细胞系（WIF-B）作为研究乙醇对细胞过程的影响的模型。在存在与肝细胞极性和细胞增多症的改变有关的情况下，这种生理上重要的极化模型（无法使用常规分离的肝细胞无法完成）将使蛋白质运输事件（FAS/CD95死亡受体）评估。具体而言，本赠款中介绍的麦克维克（McVicker）研究的目标包括1）进一步表征乙醇对FAS贩运的影响； 2）确定特定的作用 参与乙醇诱导的FAS易位的调节剂以及这些作用与FAS诱导的凋亡机制的相关性。麦克维克博士对死亡受体贩运和信号传导以及使用WIF-B模型的使用的研究是新的感兴趣领域。在这些研究中，她建议使用几种技术（即免疫组织化学和显微注射测定法），这些技术将需要其他培训和专业教学。 McVicker博士可以在UNMC上访问共焦和流式细胞仪核心实验室，并支持这些方法中的培训咨询。此外，她还支持在华盛顿特区天主教大学的Pamela Tuma博士（使用WIF-B细胞的专家）的指导下学习特定技术。总体而言，这项拟议的工作的完成将为有指导的经验提供，以发展到乙醇治疗后对未来独立研究的肝功能和生存的独立研究。