| Project/Area Number |
16390025
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Biological pharmacy
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| Research Institution | Showa University |
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Principal Investigator |
NOSE Kiyoshi Showa Univ., Sch.Pharm.Sci., Professor, 薬学部, 教授 (70012747)
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| Co-Investigator(Kenkyū-buntansha) |
SHIBANUMA M. Showa Univ., Sch.Pharm.Sci., Associate Professor, 薬学部, 助教授 (60245876)
EGAWA K. Showa Univ., Sch.Pharm.Sci., Lecturer, 薬学部, 講師 (00095879)
KANEYAMA S. Showa Univ., Sch.Pharm.Sci., Research Fellow, 薬学部, 助手 (10338535)
MORI K. Showa Univ., Sch.Pharm.Sci., Research Fellow, 薬学部, 助手 (60349040)
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| Project Period (FY) |
2004 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥14,000,000 (Direct Cost: ¥14,000,000)
Fiscal Year 2006: ¥4,500,000 (Direct Cost: ¥4,500,000)
Fiscal Year 2005: ¥4,500,000 (Direct Cost: ¥4,500,000)
Fiscal Year 2004: ¥5,000,000 (Direct Cost: ¥5,000,000)
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| Keywords | TGFb / reactive oxygen species / NADPH oxidase / mitochondria / TGF-β / Nox4 / DNAアレイ / プロテオーム / EMT / 間葉系遺伝子 |
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| Research Abstract |
(1)Sources of reactive oxygen species produced by TGFβ-stimulation :
Reactive oxygen species (ROS) are produced from mouse mammary epithelial cells stimulated with TGFβ, and scavengers of ROS inhibited expression of several mesenchymal markers. We identified mitochondria as a major source of ROS. Deprivation of mitochondria abolished expression of several TGFβ-inducible genes such as MMP-10. We also found that Nox4 that is a catalytic subunit of NADPH oxidase was induced by TGFβ through mitochondria-dependent pathway, and knock-down of Nox4 with siRNA inhibited the induction of MMP-10. These results indicate that mitochondria and ROS play a critical role in signal transduction of TGFβ, especially in expression of mesenchymal phenotypes.
(2)DNA chip analysis of gene expression regulated by mitochondria-dependent ROS :
DNA chip analysis was carried out for comprehensive understand of gene expression that was regulated by ROS produced from mitochondria. Among about 30,000 mouse genes, 671 genes were identified to be up-regulated by TGFβ, and 105 genes of which were dependent on ROS produced from mitochondria. Transcription factors such as CHOP, ATF3, E2F7 and p107 were up-regulated more than 3-fold, and several stress-response genes such as TRB3, Gadd45a, and GSTα1 were also up-regulated. Results of experiments using siRNA against CHOP indicated that some of the stress-response genes were regulated by CHOP.
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