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Application of disease-model mice with mutant mtDNA for precise investigation of its pathogenesis

Research Project

Project/Area Number 14GS0305
Research Category

Grant-in-Aid for Creative Scientific Research

Allocation TypeSingle-year Grants
Research InstitutionUniversity of Tsukuba

Principal Investigator

HAYASHI Jun-Ichi  University of Tsukuba, Graduate School of Life and Environmental Sciences, Professor (60142113)

Co-Investigator(Kenkyū-buntansha) YONEKAWA Hiromichi  The Tokyo Metropolitan Institute of Medical Science, Department of Laboratory Animal Science, Vice President (30142110)
Project Period (FY) 2002 – 2006
Project Status Completed (Fiscal Year 2006)
Budget Amount *help
¥447,070,000 (Direct Cost: ¥370,930,000、Indirect Cost: ¥76,140,000)
Fiscal Year 2006: ¥73,580,000 (Direct Cost: ¥56,600,000、Indirect Cost: ¥16,980,000)
Fiscal Year 2005: ¥73,580,000 (Direct Cost: ¥56,600,000、Indirect Cost: ¥16,980,000)
Fiscal Year 2004: ¥73,580,000 (Direct Cost: ¥56,600,000、Indirect Cost: ¥16,980,000)
Fiscal Year 2003: ¥109,200,000 (Direct Cost: ¥84,000,000、Indirect Cost: ¥25,200,000)
Fiscal Year 2002: ¥117,130,000 (Direct Cost: ¥117,130,000)
Keywordsmitochondrial diseases / mouse mtDNA mutation / disease model mice / gene therapy by nuclear transplantation / clone mice / ミトコンドリア遺伝子病 / 病態モデルマウス(ミトマウス) / 受精卵遺伝子治療 / ミトコンドリア間相互作用 / 臨床症状の多様性 / ミトコンリア間相互作用
Research Abstract

Purpose 1 : Precise investigation of pathogenesis.
Results : We provided first evidence that the mutated mtDNA is responsible for male infertility, which had been published in PNAS 103 : 15148-15153, 2006.
Purpose 2 : Transmission profiles of the mtDNA to following generations.
Results : It has been controversial of whether there is recombination in mammalian mtDNA. Our study provided convincing evidence that mouse mtDNA rarely recombine each other by creating mice carrying heteroplasmic mtDNAs, which had been published in PNAS 102 : 6057-6062, 2005. Moreover, we showed that the mitochondrial bottleneck is not generated due to a mtDNA copy number drastic decline in early oogenesis rather to a small effective number of segregation units for mtDNA in mouse germ cells, which had been published in Nature Genet. 39 : 386-390, 2007.
Purpose 3 : Development of gene therapy for mito-mice expressing respirtion defects.
Results : We can provide the first report of the success of gene therapy by application of nuclear transplantation technique to firtilized eggs of mito-mice, which had been published in PNAS 102 : 16765-16770, 2005.

Report

(6 results)
  • 2006 Annual Research Report   Final Research Report Summary
  • 2005 Annual Research Report
  • 2004 Annual Research Report
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • Research Products

    (54 results)

All 2007 2006 2005 2004 2002 Other

All Journal Article (38 results) Book (3 results) Publications (13 results)

  • [Journal Article] The mitochondrial bottleneck occurs without reduction of mtDNA content in female mouse germ cells2007

    • Author(s)
      Cao L, Shitara H, Horii T, Nagao Y, Imai H, Abe K, Hara T, Hayashi J, Yonekawa H.
    • Journal Title

      Nat Genet 39(3)

      Pages: 386-90

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] The mitochondrial bottleneck occurs without reduction of mtDNA content in female mouse germ cells.2007

    • Author(s)
      Cao L, Shitara H, Horii T, Nagao Y, Imai H, Abe K, Hara T, Hayashi J, Yonekawa H.
    • Journal Title

      Nat Genet. 39(3)

      Pages: 386-90

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] The mitochondrial bottleneck occurs without reduction of mtDNA content in female mouse germ cells.2007

    • Author(s)
      Cao L, Shitara H, Horii T, Nagao Y, Imai H, Abe K, Hara T, Hayashi J, Yonekawa H.
    • Journal Title

      Nat Gent. 39(3)

      Pages: 386-90

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Mitochondria-related male infertility2006

    • Author(s)
      Nakada K, Sato A, Yoshida K, Morita T, Tanaka H, Inoue S, Yonekawa H, Hayashi J.
    • Journal Title

      Proc Natl Acad Sci U S A. 103(41)

      Pages: 15148-53

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Suppression of disease phenotypes of adult mito-mice carrying pathogenic mtDNA by bone marrow transplantation2006

    • Author(s)
      Inoue S, Ishikawa K, Nakada K, Sato A, Miyoshi H, Hayashi J.
    • Journal Title

      Hum Mol Genet 15(11)

      Pages: 1801-7

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Generation of trans-mitochondrial mice carrying homoplasmic mtDNAs with a missense mutation in a structural gene using ES cells2006

    • Author(s)
      Kasahara A, Ishikawa K, Yamaoka M, Ito M, Watanabe N, Akimoto M, Sato A, Nakada K, Endo H, Suda Y, Aizawa S, Hayashi J.
    • Journal Title

      Hum Mol Genet 15(6)

      Pages: 871-81

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Mitochondria-related male infertility.2006

    • Author(s)
      Nakada K, Sato A, Yoshida K, Morita T, Tanaka H, Inoue S, Yonekawa H, Hayashi J.
    • Journal Title

      Proc Natl Acad Sci U S A. 103(41)

      Pages: 15148-53

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Annual Research Report 2006 Final Research Report Summary
  • [Journal Article] Suppression of disease phenotypes of adult mito-mice carrying pathogenic mtDNA by bone marrow transplantation.2006

    • Author(s)
      Inoue S, Ishikawa K, Nakada K, Sato A, Miyoshi H, Hayashi J.
    • Journal Title

      Hum Mol Genet. 15(11), 1

      Pages: 801-7

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Generation of trans-mitochondrial mice carrying homoplasmic mtDNAs with a missense mutation in a structural gene using ES cells.2006

    • Author(s)
      Kasahara A, Ishikawa K, Yamaoka M, Ito M, Watanabe N, Akimoto M, Sato A, Nakada K Endo H, Suda Y, Aizawa S, Hayashi J.
    • Journal Title

      Mol Genet. 15(6)

      Pages: 871-81

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Suppression of disease phenotypes of adult mito-mice carrying pathogenic mtDNA by bone marrow transplantation.2006

    • Author(s)
      Inoue S, Ishikawa K, Nakada K, Sato A, Miyoshi H, Hayashi J.
    • Journal Title

      Hum Mol Genet. 15(11)

      Pages: 1801-7

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Generation of trans-mitochondrial mice carrying homoplasmic mtDNA with a missense mutation in a structural gene using ES cells2006

    • Author(s)
      Atsuko Kasahara, Jyunichi Hayashi
    • Journal Title

      Hum. Mol. Genet. 15

      Pages: 871-881

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Mitochondria dynamics and aging2006

    • Author(s)
      Akitsugu Sato, Jyunichi Hayashi
    • Journal Title

      Biochim. Biophys. Acta in press

    • Related Report
      2005 Annual Research Report
  • [Journal Article] 哺乳類ミトコンドリアDNAにおける組換え2006

    • Author(s)
      佐藤晃嗣, 林 純一
    • Journal Title

      細胞工学 25

      Pages: 54-59

    • Related Report
      2005 Annual Research Report
  • [Journal Article] ミトコンドリア病モデルマウスを用いた受精卵遺伝子治療2006

    • Author(s)
      佐藤晃嗣, 林 純一
    • Journal Title

      実験医学 24

      Pages: 842-845

    • Related Report
      2005 Annual Research Report
  • [Journal Article] 動物モデルと治療戦略 : ミトコンドリア病の動物モデル2006

    • Author(s)
      笠原敦子, 林 純一
    • Journal Title

      Clinical Neuroscience 印刷中

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Gene therapy for progeny of mito-mice carrying pathogenic mtDNA by nuclear transplantation2005

    • Author(s)
      Sato A, Kono T, Nakada K, Ishikawa K, Inoue S, Yonekawa H, Hayashi J.
    • Journal Title

      Proc Natl Acad Sci U S A. 102(46)

      Pages: 16765-70

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Rare creation of recombinant mtDNA haplotypes in mammalian tissues2005

    • Author(s)
      Sato A, Nakada K, Akimoto M, Ishikawa K, Ono T, Shitara H, Yonekawa H, Hayashi J.
    • Journal Title

      Proc Natl Acad Sci U S A. 102(17)

      Pages: 6057-62

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Gene therapy for progeny of mito-mice carrying pathogenic mtDNA by nuclear transplantation.2005

    • Author(s)
      Sato A, Kono T, Nakada K, Ishikawa K, Inoue S, Yonekawa H, Hayashi J.
    • Journal Title

      Proc Natl Acad Sci U S A. 102(46)

      Pages: 16765-70

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Rare creation of recombinant mtDNA haplotypes in mammalian tissues.2005

    • Author(s)
      Sato A, Nakada K, Akimoto M, Ishikawa K, Ono T, Shitara H, Yonekawa H, Hayashi J.
    • Journal Title

      Proc Natl Acad Sci U S A. 102(17)

      Pages: 6057-62

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Rare creation of recombinant mtDNA haplotypes in mammalian somatic tissues.2005

    • Author(s)
      Akitsugu Sato, Jyunichi Hayashi
    • Journal Title

      Proc. Natl. Acad. Sci. USA 102

      Pages: 6057-6062

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Gene therapy for progeny of mito-mice carrying pathogenic mtDNA by nuclear transplantation2005

    • Author(s)
      Akitsugu Sato, Jyunichi Hayashi
    • Journal Title

      Proc. Natl. Acad. Sci. USA 102

      Pages: 16765-16770

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Application of ES cells for generation of respiration-deficient mice carrying mtDNA with a large-scale deletion.2005

    • Author(s)
      Kaori Ishikawa, Jyunichi Hayashi
    • Journal Title

      Biochem. Biophys. Res. Commun. 333

      Pages: 590-595

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Nuclear DNA but not mtDNA controls tumor phenotypes in mouse cells.2005

    • Author(s)
      Miho Akimoto, Jyunichi Hayashi
    • Journal Title

      Biochem. Biophys. Res. Commun. 327

      Pages: 1028-1035

    • Related Report
      2005 Annual Research Report
  • [Journal Article] ミトコンドリア DNA 変異の機能的評価 : サイブリッド作製2005

    • Author(s)
      石川 香, 林 純一
    • Journal Title

      臨床検査 49

      Pages: 51-58

    • Related Report
      2005 Annual Research Report
  • [Journal Article] ミトマウスを用いた糖尿病発症における変異型ミトコンドリアゲノムの病原性の検証2005

    • Author(s)
      中田和人, 林 純一
    • Journal Title

      細胞工学 24

      Pages: 820-824

    • Related Report
      2005 Annual Research Report
  • [Journal Article] 哺乳類ミトコンドリアゲノムの遺伝と進化;オーバービュー2005

    • Author(s)
      林 純一
    • Journal Title

      蛋白質核酸酵素 50

      Pages: 1742-1743

    • Related Report
      2005 Annual Research Report
  • [Journal Article] 哺乳類ミトコンドリアゲノムの遺伝と進化;ミトコンドリアDNAの母性遺伝と組換え2005

    • Author(s)
      佐藤晃嗣, 林 純一
    • Journal Title

      蛋白質核酸酵素 50

      Pages: 1744-1748

    • Related Report
      2005 Annual Research Report
  • [Journal Article] 哺乳類ミトコンドリアゲノムの変異と疾患 : ミトコンドリア遺伝子病モデルマウス2005

    • Author(s)
      中田和人, 林 純一
    • Journal Title

      蛋白質核酸酵素 50

      Pages: 1774-1777

    • Related Report
      2005 Annual Research Report
  • [Journal Article] オルガネラダイナミックス研究の実態と展望2005

    • Author(s)
      坂本 亘, 林 純一
    • Journal Title

      蛋白質核酸酵素 50

      Pages: 1861-1862

    • Related Report
      2005 Annual Research Report
  • [Journal Article] 動物オルガネラダイナミックス : ミトコンドリアゲノムの相補作用2005

    • Author(s)
      佐藤晃嗣, 林 純一
    • Journal Title

      蛋白質核酸酵素 50

      Pages: 1863-1867

    • Related Report
      2005 Annual Research Report
  • [Journal Article] 動物ミトコンドリアゲノムのテクノロジー : ミトコンドリア移植による病原性ミトコンドリアDNAの診断2005

    • Author(s)
      石川 香, 林 純一
    • Journal Title

      蛋白質核酸酵素 50

      Pages: 1904-1906

    • Related Report
      2005 Annual Research Report
  • [Journal Article] 動物ミトコンドリアゲノムのテクノロジー : 生きているGFPミトコンドリアの長期観察2005

    • Author(s)
      設楽浩志, 林 純一
    • Journal Title

      蛋白質核酸酵素 50

      Pages: 1909-1911

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Nuclear DNA but not mtDNA controls tumor phenotypes in mouse cells.2005

    • Author(s)
      Miho Akimoto
    • Journal Title

      Biochem.Biophys.Res.Commun. 327

      Pages: 1028-1035

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Rare creation of recombinant mtDNA haplotypes in mammalian somatic tissues2005

    • Author(s)
      Akitsugu Sato
    • Journal Title

      Proc.Natl.Acad.Sci.USA (In press)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] In vivo interaction between mitochondria carrying mtDNAs from different mouse species.2004

    • Author(s)
      Akitsugu Sato
    • Journal Title

      Genetics 167

      Pages: 1855-1861

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Accumulation of pathogenic ΔmtDNA induced deafness but not diabetic phenotypes in mito-mice.2004

    • Author(s)
      Kazuto Nakada
    • Journal Title

      Biochem.Biophys.Res.Commun. 323

      Pages: 175-184

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Determination of normal ranges of mitochondrial respiratory activities by mtDNA transfer from 54 human subjects to mtDNA-less HeLa cells for identification of the pathogenicities of mutated mtDNAs2004

    • Author(s)
      Chu-Shih Chen
    • Journal Title

      J.Biochem. 135

      Pages: 237-243

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Presence of interaction but not complementation between human mtDNAs carrying different mutations within a tRNALeu (UUR) gene2004

    • Author(s)
      Tomoko Ono
    • Journal Title

      Biochem.Biophys.Res.Commun. 314

      Pages: 1107-1112

    • Related Report
      2004 Annual Research Report
  • [Book] 二層膜オルガネラの遺伝学2005

    • Author(s)
      林 純一
    • Total Pages
      221
    • Publisher
      共立出版
    • Related Report
      2005 Annual Research Report
  • [Book] 二層膜オルガネラの遺伝学2005

    • Author(s)
      林 純一
    • Publisher
      共立出版(印刷中)
    • Related Report
      2004 Annual Research Report
  • [Book] ミトコンドリア・ミステリー2002

    • Author(s)
      林 純一
    • Total Pages
      297
    • Publisher
      講談社
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Publications] Akitsugu Sato: "Interaction theory of mitochondria : a new paradigm for the mammalian mitochondrial genetic system."Genetics. (In press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Tomoko Ono: "Presence of interaction but not complementation between human mtDNAs carrying different mutations within a tRNALeu(UUR) gene."Biochem.Biophys.Res.Commun.. 314. 1107-1112 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Chu-Shin Chen: "Determination of normal ranges of mitochondrial respiratory activities by mtDNA transfer from 54 human subjects to mtDNA-less HeLa cells for identification of the pathogenicities of mutated mtDNAs."J.Biochem.. 135. 237-243 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Mayumi Okamoto: "Ditercalinium chloride, a pro-anticancer drug, intimately associates with mammalian mitochondrial DNA and inhibits its replication."Curr.Genet.. 43. 364-370 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 中田和人: "ミトコンドリア遺伝子疾患モデルマウスの病態発症とミトコンドリア連携説"蛋白質核酸酵素. 48. 487-492 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 中田和人: "特集 多彩な機能をもつオルガネラ「ミトコンドリア」 ミトコンドリア遺伝子疾患モデルマウスとミトコンドリア病"実験医学. 21. 1724-1729 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Jun-Ichi Hayashi: "In reply to inter-mitochondrial complementation of mtDNA mutations"Nature Genetics. 30. 361 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kimiko Inoue: "Production of mitochondrial DNA transgenic mice using zygotes"Methods. 26. 358-363 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Noriko Enomoto: "Hypoxic induction of hypoxia-inducible factor-1a and oxygen-regulated gene expression in mitochondrial DNA-depleted HeLa cells"Biochem. Biophys. Res. Commun. 297 : 346-352. 297. 346-352 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yoshinori Takahashi: "Mammalian copper chaperone Cox17p has an essential role in activation of cytochrome c oxidase and embryonic development"Mol. Cell. Biol. 22. 7614-7621 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kazuto Nakada: "A novel defence system of mitochondria in mice and human subjects for preventing expression of mitochondrial dysfunction by pathogenic mutant mtDNAs"Mitochondrion. 2. 59-70 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 中田 和人: "RNAの細胞生物学:ミトコンドリアtRNA変異マウス"蚤白質 核酸 酵素. (印刷中). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] 林 純一: "ミトコンドリア・ミステリー"講談杜ブルーバックス. 297 (2002)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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