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Liver fibrosis and ethanol: role of the transcription factor, Egr-1

肝纤维化和乙醇：转录因子 Egr-1 的作用

基本信息

批准号：
8329621
负责人：
MICHELE T PRITCHARD
金额：
$ 3.76万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-05-08 至 2012-08-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8329621
关键词：
Acute Acute Hepatitis Address Antioxidants Attenuated Award Biological Models CCL2 gene COL1A2 gene CXCL2 gene CYP2E1 gene Carbon Tetrachloride Cell Culture Techniques Cell Cycle Cell Cycle Progression Cell physiology Cells Characteristics Chronic Cirrhosis Collagen Collagen Diseases Data Development Disease Dose Early Gene Transcriptions Endothelial Cells Endotoxemia Enzymes Ethanol Extracellular Matrix Fatty Liver Fibrosis Gene Expression Generations Genes Growth Health Hepatic Hepatic Stellate Cell Hepatocyte Immediate-Early Genes Inflammation Inflammatory Injury Injury to Liver Instruction Intercellular adhesion molecule 1 Ischemia Kupffer Cells Lead Literature Liver Liver Fibrosis Liver diseases Maintenance Matrix Metalloproteinases Mediating Mediator of activation protein Modeling Molecular Mus Outcome Patients Phenotype Platelet-Derived Growth Factor Play Process Production Publishing Recovery Reperfusion Therapy Resolution Role Staging Steatohepatitis TIMP1 gene Therapeutic Toxin United States Work Wound Healing alcohol exposure base cell type chronic alcohol ingestion design feeding fibrogenesis hepatotoxin improved injury and repair liver cell proliferation liver transplantation novel novel therapeutics oval cell response transcription factor

项目摘要

Ethanol-induced hepatic fibrosis is a severe form of liver disease. Although great strides have been made in understanding the mechanisms by which fibrosis is established and how it resolves, these discoveries have not yet lead to improved therapeutic strategies. Egr-1 is a transcription factor that regulates a broad array of genes involved in inflammation and the wound-healing response. Egr-1 is a critical modulator of ethanolinduced fatty liver and acute hepatic inflammation in mice. Due to the ability of Egr-1 to regulate genes that modulate fibrosis, we hypothesize that Egr-1 is an important contributor to liver fibrosis after toxin-mediated liver injury. Indeed, recently published work completed during the K99 portion of this award revealed that carbon tetrachloride (CCI4)-induced liver fibrosis is enhanced in mice deficient in Egr-1. Enhanced fibrosis was associated with reduced hepatoprotection, more severe liver injury and a delay in hepatocyte entrance into and progression through the cell cycle in egr-1-/- mice after acute CCI4 exposure. Activation of the oval cell response in egr-1-/- mice after chronic CCW exposure is consistent with these findings. Collectively, our studies suggest novel roles for Egr-1 as a critical modulator the liver's response to hepatotoxins and the fibrogenic process. Ethanol feeding to mice produces limited fibrosis necessitating the use of hepatotoxicants such as CCi4 to explore mechanisms of fibrosis. To better understand the effects of ethanol exposure on fibrogenesis, we developed a new model with which we can 'accelerate' fibrosis using low-level ethanol (2% v/v ethanol for 5 days to 2 weeks) in combination with acute or chronic CCW exposure. Importantly, CYP2E1, the enzyme required for CCW bioactivation and induced in liver after chronic ethanol exposure, is not different between control and ethanol-fed mice exposed to this dose of ethanol. Using this model, as well as primary hepatic stellate cell cultures, we will continue to dissect the molecular mechanisms by which Egr-1 contributes to fibrosis through completion of the three Specific Aims as originally described.

乙醇性肝纤维化是一种严重的肝脏疾病。尽管已经取得了很大的进步