Helicobacter pylori, the type species of a growing genera of bacterial pathogens, is strongly linked on epidemiological grounds with gastric cancer. However, experimental evidence indicating a causal relationship between Helicobacter and induction of cancer is lacking. The recent isolation and identification by our laboratory of a novel bacterium, Helicobacter hepaticus from A/J mouse livers with hepatitis and hepatocellular carcinoma strongly implicates this organism plays a primary role in hepatocarcinogenesis. We have subsequently developed reliable and sensitive diagnostic tests to identify H. hepaticus infected mice, determined that H. hepaticus causes a persistent infection and have fulfilled Koch's postulates in A/J and outbred Swiss mice. We are therefore proposing experiments designed to delineate the oncogenic potential of H. hepaticus. Specifically, we will 1) elucidate the pathogenesis and oncogenic potential of H. hepaticus in a long term carcinogenesis bioassay; 2) determine liver tumor mutational spectra in H. hepaticus infected mice and compare the results to mutational spectra in carcinogen induced liver tumors; and 3) by using H. hepaticus infected F1 hybrid mice determine loss of heterozygosity (LOH) in selected genomic markers. This information should provide important information that will ultimately lead to advances in prevention and treatment of H. pylori associated gastric cancer.
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