Project 5: Effect of Underlying Liver Diseases on Fibrosis Induced by Superfund T

项目5：潜在肝病对Superfund T诱导的纤维化的影响

• 批准号: 8263101
• 负责人: EKIHIRO SEKI
• 金额: $ 15.49万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8263101
• 关键词: Animals; Antioxidants; Bilirubin; Biological; CYP2E1 gene; Carbon Tetrachloride; Cells; Characteristics; Chronic Hepatitis; Cirrhosis; Collaborations; Communities; Data; Detection; Diet; Disease; Disease Progression; Dose; Early Diagnosis; Environment; Evaluation; Exposure to; Fatty Liver; Fatty acid glycerol esters; Fibroblasts; Fibrosis; Free Radicals; Gases; Gene Proteins; Generations; Goals; Growth; Health; Healthcare; Hepatic Stellate Cell; Hepatocyte; Human; Human body; Hyperbilirubinemia; Image; In Vitro; Individual; Inflammation; Injury; Instruction; Kupffer Cells; Laboratories; Lipid Peroxidation; Liver; Liver Fibrosis; Liver diseases; Low income; MAP3K7 gene; Malignant Neoplasms; Malignant neoplasm of liver; Mediating; Metabolism; Methodology; Modeling; Monitor; Mus; Mutant Strains Mice; Myofibroblast; Necrosis; Neptune; Obese Mice; Obesity; Organism; Predisposition; Primary carcinoma of the liver cells; Proteins; Reactive Oxygen Species; Reporter; Reporter Genes; Reporting; Research; Resolution; Role; Soil; Superfund; System; TGFB1 gene; Testing; Time; Toxic effect; Toxicant exposure; Transgenic Mice; Translational Research; UGT1A1 gene; Water; Xenobiotics; antibody conjugate; chronic liver disease; feeding; in vivo; insight; mouse model; non-alcoholic fatty liver; novel; programs; promoter; protein profiling; receptor; response; superfund site; toxicant; tumor; tumor growth

Carbon tetrachloride (CCI{4}) is a superfund toxicant (CERCLA Priority #47) that usually escapes into the environment as a gas. or it is sometimes found in water and soil. The liver is a primary target of the toxicity of CCI4. Exposure to high levels of CCI{4} induces liver damage, inflammation and fibrosis. In healthy people CCI{4} -induced liver injury and fibrosis can reverse when the exposure is discontinued. However, the response of people with underlying liver diseases, such as chronic hepatitis and fatty liver disease, may change, and their livers could be more susceptible to toxicants than healthy livers. Importantly, the health concerns, including chronic liver disease, are often raised regarding vulnerable communities near the Superfund sites. Therefore, the biological response for Superfund toxicants needs to be studied and eariy detection systems need to be developed for identifying these toxicants released into the environment and accumulating in organisms, including the human body. In this context, we will use mouse models with underlying liver diseases, such as Tak1[deltaHEP] mice which have been developed by our laboratory, which mimic human chronic liver disease with liver fibrosis and cancer and mice fed high fat diet that induce obesity and fatty liver disease. Using experimental murine models of liver diseases, we will examine the effect of underlying liver diseases on long-term continuous exposure to CCI{4} with respect to liver fibrosis and cancer. In addition to the evaluation of liver fibrosis by established methodology, we will create a sensitive new detection system for monitoring liver fibrosis using a new fluorescent protein and gene reporter system. This system will also evaluate the effect of another Superfund toxicant in the initiation of liver fibrosis. This project will provide new insights into the effect of environmental CCI{4} exposure on people with underlying liver diseases, including chronic hepatitis and fatty liver. Underlying liver disease is a serious health concern in vulnerable communities, including tribal and low-income border communities that are the targets of our Superfund Research Program. We will share and disseminate our results through the Research Translation and Community Engagement Cores.

四氯化碳（CCI{4}）是一种超级基金有毒物质（CERCLA优先级#47），通常以气体形式逃逸到环境中。有时也存在于水和土壤中。肝脏是CCl 4毒性的主要靶点。暴露于高水平的CCI{4}会导致肝损伤、炎症和纤维化。在健康人中，CCI{4}诱导的肝损伤和纤维化可以在停止暴露时逆转。然而，患有慢性肝炎和脂肪肝等潜在肝脏疾病的人的反应可能会发生变化，他们的肝脏可能比健康的肝脏更容易受到有毒物质的影响。重要的是，健康问题，包括慢性肝病，经常被提出来，涉及超级基金地点附近的脆弱社区。 因此，需要研究对超级基金毒物的生物反应，并且需要开发早期检测系统来识别释放到环境中并在生物体（包括人体）中积累的这些毒物。在这种情况下，我们将使用具有潜在肝脏疾病的小鼠模型，例如我们实验室开发的Tak 1 [deltaHEP]小鼠，其模拟具有肝纤维化和癌症的人类慢性肝病，以及喂食高脂肪饮食诱导肥胖和脂肪肝疾病的小鼠。使用实验性肝病小鼠模型，我们将检查潜在肝病对长期连续暴露于CCI{4}的肝纤维化和癌症的影响。除了通过已建立的方法学评估肝纤维化外，我们还将使用新的荧光蛋白和基因报告系统创建一种用于监测肝纤维化的灵敏的新检测系统。该系统还将评估另一种超级基金毒物在肝纤维化起始中的作用。该项目将为环境CCI{4}暴露对潜在肝病患者（包括慢性肝炎和脂肪肝）的影响提供新的见解。潜在的肝病是脆弱社区的一个严重健康问题，包括部落和低收入边境社区，这些社区是我们超级基金研究计划的目标。我们将通过研究翻译和社区参与核心分享和传播我们的成果。