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.
Showing the most recent 10 out of 404 publications
