ETHANOL OXIDATION EFFECTS ON EGF SIGNAL TRANSDUCTION

乙醇氧化对 EGF 信号转导的影响

• 批准号: 2396687
• 负责人: Dahn Louis Clemens
• 金额: $ 8.52万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-25 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2396687
• 关键词: acetaldehyde; alcohol dehydrogenase; biological signal transduction; cell growth regulation; cell line; cellular pathology; epidermal growth factor; ethanol; hepatotoxin; liver cells; oxidation reduction reaction; receptor mediated endocytosis; toxin metabolism

DESCRIPTION: (Adapted from Investigator's Abstract) One of the more pronounced hepatic dysfunctions observed in animals chronically fed ethanol is a impairment in receptor-mediated endocytosis. Receptor-mediated endocytosis is responsible for the uptake and degradation of many biologically important molecules including hormones, growth factors and cytokines. Receptor-mediated endocytosis is also involved in the regulation of the expression of surface receptors and signal transduction. Thus, alterations in hepatic receptor-mediated endocytosis could be detrimental to the liver. Although, impairment in receptor-mediated endocytosis is well established in hepatocytes isolated from ethanol fed animals, the mechanism(s) of this impairment have yet to be elucidated. Furthermore, the direct involvement of ethanol metabolism in this defect has yet to be demonstrated. Many mechanisms for the hepatic cell injury associated with chronic ethanol abuse have been proposed. One attractive, though unproven mechanism, proposes that acetaldehyde forms acetaldehyde-protein adducts and through their accumulation eventually causes hepatic dysfunction. One of the main reasons that these underlying mechanisms of chronic ethanol oxidation have not been determined has been the lack of a stable in vitro hepatic model system for the study of chronic ethanol oxidation. The PI recently developed a cell line of hepatic origin that metabolized ethanol to acetaldehyde and produces acetaldehyde-protein adducts and proposes to use this cell line (HAD cells) to investigate impairments in epidermal growth factor signal transduction. The hypothesis is that alcohol dehydrogenase mediated oxidation of ethanol impairs the biological activities of the epidermal growth factor receptor. Inactivation of this receptor dramatically alters the ability of hepatocytes to respond appropriately to extracellular signals. Epidermal growth factor is an important hepatic mitogen. The binding of epidermal growth factor to its receptor activates an intrinsic tyrosine kinase, which initiates a signal transduction cascade resulting in cell proliferation. The Specific Aims of this proposal are: 1) Determine what processes of epidermal growth factor receptor-mediated endocytosis are impaired by ethanol oxidation and exposure to acetaldehyde; 2) Investigate the effect of ethanol oxidation on the signal transduction pathway of the epidermal growth factor receptor in the recombinant HAD cells; 3) Investigate the possibility that acetaldehyde-protein adducts are responsible for the observed ethanol induced impairment of the epidermal growth factor receptor; and 4) Investigate the effects of ethanol oxidation on the mitogenic activities of epidermal growth factor in the recombinant HAD cells. By completing these studies, it is hoped that the investigators can determine the effects of chronic ethanol oxidation and exposure to acetaldehyde on the signal transduction of epidermal growth factor, thus leading to a greater understanding of the mechanisms of induced liver injury.

描述：(改编自《调查者摘要》) 长期饲喂乙醇的动物出现明显的肝功能障碍 是受体介导的内吞作用的一种损害。受体介导 内吞作用负责摄取和降解许多 重要的生物分子，包括激素、生长因子和 细胞因子。受体介导的内吞作用也参与了这种调节。 表面受体的表达和信号转导。因此， 肝脏受体介导的内吞作用的改变可能对 肝脏。然而，受体介导的内吞作用的损害是很好的。 建立在乙醇喂养的动物的肝细胞中， 这种损伤的机制(S)尚不清楚。此外， 乙醇代谢在这一缺陷中的直接参与尚未得到证实。 演示了。与肝细胞损伤相关的多种机制 有人提出了长期滥用乙醇的建议。一件诱人的事，尽管未经证实 机理，提出乙醛形成乙醛-蛋白质加合物和 通过它们的积累最终导致肝功能障碍。其中之一 慢性乙醇的这些潜在机制的主要原因 氧化作用尚未确定，在体外缺乏稳定的 慢性乙醇氧化研究的肝脏模型系统。《少年派》 最近开发了一种源于肝脏的细胞系，它能将乙醇代谢成 乙醛产生乙醛-蛋白质加合物，并建议使用 这种细胞系(有细胞)研究表皮生长的损害。 信号转导因子。假设是酒精脱氢酶 乙醇介导的氧化作用损害细胞的生物活性 表皮生长因子受体。该受体失活 戏剧性地改变肝细胞对 细胞外信号。表皮生长因子是一种重要的肝脏 有丝分裂原。表皮生长因子与其受体的结合被激活 一种内在的酪氨酸激酶，它启动了一系列信号转导 导致细胞增殖。这项建议的具体目标是： 1)确定表皮生长因子受体介导的过程 内吞作用因乙醇氧化和暴露于乙醛而受损； 2)研究乙醇氧化对信号转导的影响 表皮生长因子受体在重组HAD中的作用途径 细胞；3)研究乙醛-蛋白质加合物 对观察到的酒精引起的表皮损伤负责 生长因子受体；4)研究乙醇氧化的影响 重组人表皮生长因子促分裂活性的研究 有细胞。通过完成这些研究，希望调查人员 可以确定慢性乙醇氧化和暴露的影响 乙醛对表皮生长因子信号转导的影响 使我们对诱导肝的机制有了更深入的了解 受伤。