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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：
8508747
负责人：
MICHELE T PRITCHARD
金额：
$ 22.27万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-11-20 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8508747
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 injury 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.

乙醇诱导的肝纤维化是一种严重的肝脏疾病。虽然在这方面取得了很大的进步，了解纤维化建立的机制及其如何解决，这些发现还没有带来更好的治疗策略。Egr-1是一种转录因子，它调节一系列广泛的与炎症和伤口愈合反应有关的基因。Egr-1是乙醇诱导的脂肪肝和急性肝脏炎症。由于Egr-1调节基因的能力，调节纤维化，我们假设Egr-1是毒素介导的肝纤维化后的重要贡献者，肝损伤事实上，最近发表的工作在K99部分完成的这一奖项显示，四氯化碳（CCl 4）诱导的肝纤维化在Egr-1缺陷的小鼠中增强。纤维化增强与肝保护作用降低、肝损伤更严重和肝细胞进入延迟相关在急性CCl 4暴露后，在BALB-1-/-小鼠中进入并通过细胞周期进展。激活椭圆在慢性CCW暴露后，BALB-1-/-小鼠的细胞反应与这些发现一致。总体而言，我们研究表明，Egr-1作为肝脏对肝毒素的反应的关键调节剂，纤维化过程向小鼠饲喂乙醇产生有限的纤维化，需要使用肝毒性剂如CC 14以探索纤维化的机制。为了更好地了解乙醇暴露对纤维化的影响，我们开发了一种新的模型，我们可以使用低水平的乙醇（2% v/v乙醇，天至2周）与急性或慢性CCW暴露组合。重要的是，CYP 2 E1，这种酶慢性乙醇暴露后，CCW生物活化所需的和在肝脏中诱导的，对照和乙醇喂养的小鼠暴露于该剂量的乙醇。使用该模型，以及原发性肝在星状细胞培养中，我们将继续剖析Egr-1有助于通过完成最初描述的三个特定目的来治疗纤维化。