ETHANOL OXIDATION EFFECTS ON EGF SIGNAL TRANSDUCTION

乙醇氧化对 EGF 信号转导的影响

• 批准号: 6371408
• 负责人: Dahn Louis Clemens
• 金额: $ 10.59万
• 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 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6371408
• 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：（改编自研究者摘要） 在长期喂食乙醇的动物中观察到明显的肝功能障碍 是受体介导的内吞作用的损伤。 受体介 内吞作用负责许多蛋白质的吸收和降解， 生物学上重要的分子，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调节 表面受体的表达和信号传导。 因此，在本发明中， 肝脏受体介导的内吞作用的改变可能对 肝脏 虽然，受体介导的内吞作用的损害是很好的， 在从乙醇喂养的动物中分离的肝细胞中建立， 这种损害的机制尚未阐明。 而且 乙醇代谢在这一缺陷中的直接参与还有待进一步研究。 演示。 肝细胞损伤的许多机制与肝细胞损伤有关。 已经提出了慢性乙醇滥用。 一个有吸引力的，虽然未经证实 机理，提出乙醛形成乙酰丙酮-蛋白质加合物， 通过它们的积累最终导致肝功能障碍。 之一 这些慢性乙醇中毒的潜在机制 氧化尚未确定一直缺乏一个稳定的体外 肝脏模型系统用于慢性乙醇氧化的研究。 的PI 最近开发了一种肝源性细胞系，其代谢乙醇， 乙醛并产生乙醛-蛋白质加合物，并建议使用 该细胞系（HAD细胞）研究表皮生长障碍 因子信号转导 假设酒精脱氢酶 介导的乙醇氧化损害了 表皮生长因子受体 该受体的失活 显著改变了肝细胞对 细胞外信号 表皮生长因子是一种重要的肝 促分裂原 表皮生长因子与其受体的结合激活 一种内在酪氨酸激酶，启动信号转导级联反应 导致细胞增殖。 该提案的具体目标是： 1)确定表皮生长因子受体介导的 乙醇氧化和暴露于乙醛会损害内吞作用; 2)探讨乙醇氧化对信号转导的影响 重组HAD中表皮生长因子受体的途径 细胞; 3）研究乙酰丙酮-蛋白加合物是 导致观察到的乙醇诱导的表皮损伤 生长因子受体;和4）研究乙醇氧化的影响 重组人表皮生长因子的促有丝分裂活性 HAD细胞。 通过完成这些研究，希望研究人员能够 可以确定慢性乙醇氧化和暴露于 乙醛对表皮生长因子信号转导的影响， 从而更好地理解诱导肝的机制 损伤

项目成果

Autophagy reduces acute ethanol-induced hepatotoxicity and steatosis in mice.

• DOI: 10.1053/j.gastro.2010.07.041
• 发表时间: 2010-11
• 期刊: Gastroenterology
• 影响因子: 29.4
• 作者: Ding WX;Li M;Chen X;Ni HM;Lin CW;Gao W;Lu B;Stolz DB;Clemens DL;Yin XM
• 通讯作者: Yin XM