| Budget Amount *help |
¥3,419,000 (Direct Cost: ¥2,630,000、Indirect Cost: ¥789,000)
Fiscal Year 2011: ¥1,469,000 (Direct Cost: ¥1,130,000、Indirect Cost: ¥339,000)
Fiscal Year 2010: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Research Abstract |
With persistent infection of Helicobacter pylori(H. pylori), gastric cancer develops by a multistep process occurring through the accumulation of genetic alterations in gastric epithelial cells. The mechanisms how the gastric epithelial cells with H. pylori infection and the resultant inflammatory response acquire the genetic changes leading to malignant transformation, however, remain unknown. Activation-induced cytidine deaminase(AID) induces somatic mutations in various host genes of non-lymphoid tissues, thereby contributing to carcinogenesis. Indeed, we demonstrated that H. pylori infection induced aberrant AID expression in gastric epithelial cells, resulting in the accumulation of p53 tumor suppressor gene mutations. Our findings suggested the novel link among H. pylori infection, accumulation of genetic changes and human gastric cancer development. The process of accumulation of genetic alterations induced by AID activity, however, have not yet been clarified.
We plan to investigate the role of AID in the occurrence of genetic alterations, including somatic mutations and chromosomal changes. We clarify the overall genetic alterations induced by aberrant AID activity using the genome-wide array comparative genomic hybridization(CGH) analyses as well as the comprehensive mutation assays. The results are also assessed in mouse models with the oral challenge of H. pylori and in AID transgenic mice to investigate whether aberrant AID expression induced by H. pylori infection in vivo could contribute to the occurrence of tumor-promoting genetic changes, leading to the gastric cancer development. A successful outcome of this research project would provide the novel insight into the molecular mechanisms of infection-and inflammation-associated carcinogenesis.
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