| Project/Area Number |
16590329
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Experimental pathology
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| Research Institution | National Institute of Health Sciences |
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Principal Investigator |
HIRABAYASH Yoko National Institute of Health Sciences, Center for Biological Safety and Research, Cellular and Molecular Toxicology Division, Section Chief, 安全性生物試験研究センター毒性部, 室長 (30291115)
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| Co-Investigator(Kenkyū-buntansha) |
INOUE Tohru National Institute of Health Sciences, Center for Biological Safety and Research, Director, 安全性生物試験研究センター, センター長 (50100110)
松下 智哉 中外製薬株式会杜, 研究本部・安全性研究部, 研究員
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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 |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2006: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2005: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2004: ¥1,200,000 (Direct Cost: ¥1,200,000)
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| Keywords | Thioredoxin / hematopoietic stem cell / Thioredoxin overexpression mice / cell cycle / Thioredoxin knockout mice / BUUV method / suppression of hematopoiesis / benzene |
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| Research Abstract |
Three-year-research subject on the major participated molecules in xenobiotic responses focusing on the oxidative stress has been conducted specifically on the hematopoietic system as a target organ. Not only wild-type mice, thioredoxin (Trx) overexpression (Tg) and Trx hemizygous deficiency (KO) mice were used for reference animals.
1.Responses to oxidative stress in the level of in vivo and in vitro at the steady-state were studied with respect to the following aspects.
1)Cellular systems, both non-cycling post mitotics and cycling proliferative system, were focused in the study ; the former includes primary culture system of myocardial cells for studying mitochondrial intracellular respiration and apoptosis ; the latter includes cell-kinetics of the hematopoietic stem/progenitor system.
2)Study on the cell kinetics of the hematopoietic progenitor cells disclosed that the stem cell kinetics in Trx-Tg mice was persistently down-regulated, thus, attenuation of the oxidative stress is assumed to decelerate the stem cell cycling. When mice at 2-month-old were compared with those 21-month-old senescent mice, xenobiotic responses during the senescent stage were seemingly comparable to the state after prolonged oxidative stresses.
2.Global gene chip microarray was conducted to learn hematopoietic system-specific gene expressions. Data from expression genes were analyzed by multivariative principal component analyses to reduce dimensionality which consequently generated most pertinent responsible genes or gene ontology (GO). The GOs elucidated were found to consist of those related to oxidative stresses and of cell cycling and anti-inflammatory responsive genes in unsupervised manner. These oxidative-stress responsive genes directly regulate cell cycle of hematopoietic stem cells, thereby, maintain the stem cell compartment.
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