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

四氯化碳(CCI{4})是一种超级基金毒物(CERCLA优先级#47)，通常以气体的形式逃逸到环境中。或者有时在水和土壤中发现它。肝脏是CCI4毒性的主要目标。暴露于高水平的CCI会导致肝脏损伤、炎症和纤维化。在健康人中，CCI引起的肝损伤和纤维化可以在停止接触后逆转。然而，患有慢性肝炎和脂肪肝等潜在肝病的人的反应可能会改变，他们的肝脏可能比健康的肝脏更容易受到毒物的影响。重要的是，人们经常对超级基金地点附近的脆弱社区提出健康担忧，包括慢性肝病。 因此，需要研究超级基金毒物的生物反应，并开发早期检测系统，以识别这些释放到环境中并在包括人体在内的生物体中积累的毒物。在此背景下，我们将使用具有潜在肝病的小鼠模型，例如我们实验室开发的Tak1[deltaHEP]小鼠，它模仿人类慢性肝病合并肝纤维化和癌症，以及喂食高脂饮食导致肥胖和脂肪肝疾病的小鼠。利用实验性的小鼠肝病模型，我们将研究潜在的肝病对长期持续接触CCI在肝纤维化和癌症方面的影响。除了通过已建立的方法学评估肝纤维化外，我们还将利用新的荧光蛋白和基因报告系统创建一个灵敏的新检测系统来监测肝纤维化。该系统还将评估另一种超级基金毒物在启动肝纤维化方面的效果。该项目将为环境CCI暴露对患有包括慢性肝炎和脂肪肝在内的潜在肝病的人的影响提供新的见解。潜在的肝病是脆弱社区的一个严重的健康问题，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。

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.