Thioredoxin and ethanol-induced liver injury

硫氧还蛋白和乙醇诱导的肝损伤

• 批准号: 7154969
• 负责人: Jessica Cohen
• 金额: $ 3.8万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7154969
• 关键词: Kupffer' s cell; RNA interference; alcoholism /alcohol abuse; biological signal transduction; buthionine sulfoximine; enzyme activity; ethanol; free radical oxygen; gene expression; glutathione; laboratory mouse; laboratory rat; lipopolysaccharides; liver disorder; mitogen activated protein kinase; molecular pathology; phosphorylation; polymerase chain reaction; predoctoral investigator; protein transport; serine threonine protein kinase; thioredoxin; tissue /cell culture; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): Chronic ethanol exposure can result in hepatic injury. This injury is exacerbated in part through an LPSdependent signaling cascade. Our lab found that chronic ethanol exposure increases the IPS response of Kupffer cells leaing to the activation LPS-induced activation of p38. Ultimately the activation of p38 will lead to TNFa mRNA stability. LPS and TNFalpha stimulate the production of reactive oxygen species. The ROS causes the redox-sensing molecule thioredoxin (Trx) to dissociate from ASK1 leading to apoptosis. Glutathione is another redox-sensing molecule that protects the cell against oxidative damage. As a result of ethanol-induced oxidative stress, mitochondrial levels of GSH drastically deplete. The specific aims of this proposal will determine (1) effects of chronic ethanol on LPS dependent signal transduction leading to increased p38 phosphorylation (2) identify how Trx and GSH contribute to increased p38 activation in response chronic ethanol exposure (3) if overexpression of Trx-1 protects mice from ethanol-induced liver injury. Results from our studies will further our understanding of cellular antioxidant systems and possibly the prevention of ethanol-induced liver disease.

描述（由申请人提供）：慢性乙醇暴露会导致肝损伤。这种损伤通过LPS依赖性信号级联反应而加剧。我们的实验室发现，慢性乙醇暴露会增加跃升至激活LPS诱导的p38激活的库普弗细胞的IPS响应。最终，p38的激活将导致TNFA mRNA稳定性。 LPS和TNFALPHA刺激活性氧的产生。 ROS会导致氧化还原分子硫氧还蛋白（TRX）与ASK1分离导致细胞凋亡。谷胱甘肽是另一种氧化还原的分子，可保护细胞免受氧化损伤。由于乙醇诱导的氧化应激，线粒体水平的GSH水平急剧消耗。该提案的具体目的将确定（1）慢性乙醇对LPS依赖性信号转导的影响，从而导致p38磷酸化增加（2）确定TRX和GSH如何在反应慢性乙醇暴露时增加p38激活（3）如果TRX-1的过表达可保护小鼠免受乙醇诱导的Liver诱导的Liver诱导的损伤。我们的研究结果将进一步了解细胞抗氧化剂系统，并可能预防乙醇诱导的肝病。