| Co-Investigator(Kenkyū-buntansha) |
KAMOTO Toshiyuki Dept. Vrdogy., Kyoto University Assist. Prof., 医学研究科, 助手 (00281098)
TOYOKUNI Shinya Dept. Pathol., Kyoto Univ., Assoc. Prof., 医学研究科, 助教授 (90252460)
FUKUMOTO Manabu Dept. Pathol., Tohoko Univ., Professor, 加齢医学研究所, 教授 (60156809)
ISHIMOTO Akinori Virus Inst. Kyoto Univ., Professor, ウイルス研究所, 教授 (50073127)
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| Research Abstract |
We studied effects of genetic background of host on various diseases. Defect in lpr gene causes a spectrum of autoimmunities in MRL mice, but not in C3H mice. Analyzing(MRL-lpr x C3H-lpr)FィイD22ィエD2 mice, we could show several host genes or their combinations to determine the spectrum of autoimmunities. Similar polygenic trait was found in SL/Kh pre-B lymphoma system. Lymphomas were induced by somatic integration of endogenous ecotropic MuLV to Slv1-8 hot spots, their host-junctional fragments were cloned with a modified inverse PCR technique. SL/Kh mice showed a unique pre-B cell expansion in pre-lymphoma BM. Such expansion was induced by Bomb1 host locus on Chr. 3 mapped us. A candidate gene for Bomb1 is Lef1, a transcription factor in Wnt/Frzl pathway, expressed in both T and pre-B cells. SL/Kh thymocytes showed very low responsiveness to Con A. Immunological abnormalities in B-lineage may induce expansion of the target cells for virus integration. We could identify several other host genes affecting type of lymphomas, length of latent period, and resistance to lymphoma development. These studies clearly indicate that lymphomagenesis is tightly bound to host modifying genes that regulate steps of carcinogenesis. In addition to lymphomas, we could map modifier genes for tongue cancer, bladder cancer, lung cancer and liver cancers using quantitative trait mapping. In these studies, we showed that the recombinant inbred strains is a highly useful tool to analyze complicated trait such as cancer susceptibility.
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