Mouse Strain With Elevated Sensitivity to Chemical

对化学物质敏感性升高的小鼠品系

• 批准号: 6897641
• 负责人: Michael Karin
• 金额: $ 27.7万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6897641
• 关键词: RNA interference; arsenic; benzene; bioassay; biphenyl compounds; bromine; cancer risk; carbon tetrachloride; chemical carcinogenesis; chemical hypersensitivity; chemical related neoplasm /cancer; diethylnitrosamine; disease /disorder model; free radical oxygen; genetic strain; genetically modified animals; hazardous substances; laboratory mouse; liver neoplasms; mass spectrometry; microarray technology; neoplasm /cancer genetics; oxidative stress; site directed mutagenesis; tumor promoters

DESCRIPTION (provided by applicant): During the previous funding period the investigators have generated mice that lack the DCKP subunits, of the IKB kinase (IKK) complex only in hepatocytes. As a result these mice, called Ljver-IKKp-Knockout (LIKKO) mice, are unable to mount an NF-icB activation response in their hepatocytes. Challenge of LIKKO mice with certain hepatotoxins results in fulminant liver failure associated with a massive increase in the production of reactive oxygen species (ROS). When challenged with the chemical carcinogen diethyl nitrosamine (DEN), LIKKO mice develop 3 times as many hepatocellular carcinomas (HCC) as normal mice. The investigators proposed that LIKKO mice provide an outstanding and highly sensitive system for examining the in vivo consequences of oxidative stress caused by Superfund chemicals and for assessing their ability to cause liver cancer and/or act as tumor promoters. In addition to assessing the effect of the LIKKO mutation on the carcinogenic and tumor promoting activity of six different Superfund chemicals:arsenite, benzene, carbon tetrachloride, hexabromobiphenyl, dimethyl nitrosomine (which is closely related to DEN) and benzo(a)pyrene-7, 8-dihydrodiol-9, 10-epoxide (BPDE), they will examine the mechanism responsible for the elevated susceptibility of LIKKO mice to chemical carcinogenesis. A combination of reverse genetic and biochemical analysis will be used to examine the hypothesis that increased cell injury to the liver coupled to regenerative proliferation is the major mechanism responsible for the observed increase in chemical carcinogenesis in LIKKO mice. The researchers will examine the role played by ROS in this process and also test the hypothesis that ROS-mediated inhibition of INK phosphatases leads to prolonged INK activation after challenge of LIKKO mice with pro-apoptotic stimuli, leading to a coordinate increase in both cell death and compensatory liver regeneration. They will also test the ability of anti-oxidants to prevent these changes and reduce the incidence of liver cancer. Finally, hepatocytes from LIKKO mice will be used to develop an in vitro system for testing the hepatocarcinogenic activity of Superfund toxicants, that if successful will greatly reduce the time required for assessing the carcinogenic potential of various chemicals.

描述（由申请人提供）：在上一个资金期间，调查人员拥有 仅在肝细胞中的IKB激酶（IKK）复合物的缺乏DCKP亚基的小鼠。 结果，这些老鼠称为ljver-ikkp-knockout（likko）小鼠，无法安装NF-ICB 肝细胞中的激活反应。 具有某些肝毒素的LIKKO小鼠的挑战会导致与活性氧（ROS）大量增加有关的暴发性肝衰竭。 当用化学致癌二乙基硝基胺（DEN）挑战时，LIKKO小鼠的发展肝细胞癌（HCC）是正常小鼠的3倍。 研究人员提出，LIKKO小鼠提供了一个出色且高度敏感的系统，用于检查由超级基金化学物质引起的氧化应激的体内后果，并评估其引起肝癌和/或充当肿瘤启动子的能力。 除了评估LIKKO突变对六种不同超级基金化学物质的致癌和肿瘤活性外，砷，苯，四氯化碳，六邻苯甲基苯基，二甲基硝基胺，与DEN与DEN密切相关（与DEN）和苯甲酸（A）Pyrene-7，8-Dioldiol-dodiol-dodiol-dodiol-dodiol-yydodiol-ddrodydodiol dodrdiol-ddrodydodydodiol-doddiol ddrodioldiol-ddrodydodiol dodrdiol-dodrdiol-dodrdiol-dodrdiol，将检查造成likko小鼠对化学癌变的敏感性升高的机制。 反向遗传分析和生化分析的结合将用于检查以下假设：伴随着再生增殖的肝脏损伤增加是导致LIKKO小鼠化学癌变增加的主要机制。 研究人员将研究ROS在此过程中所起的作用，并测试ROS介导的墨水磷酸酶抑制的假设导致在具有促凋亡刺激的Likko小鼠挑战后，墨水激活延长，从而导致细胞死亡和补偿性肝脏再生的协调增加。他们还将测试抗氧化剂防止这些变化并降低肝癌的发生的能力。 最后，LIKKO小鼠的肝细胞将用于开发一种体外系统，用于测试超级基金有毒物质的肝癌活性，如果成功的话， 减少评估各种化学物质的致癌潜力所需的时间。