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Establishment and application of lentivector-based production of gene-rescue mouse for exploring gene functions

Research Project

Project/Area Number 19670003
Research Category

Grant-in-Aid for Young Scientists (S)

Allocation TypeSingle-year Grants
Research Field Neurophysiology and muscle physiology
Research InstitutionGunma University

Principal Investigator

HIRAI Hirokazu  Gunma University, 医学(系)研究科(研究院), 教授 (70291086)

Project Period (FY) 2007 – 2011
Project Status Completed (Fiscal Year 2011)
Budget Amount *help
¥103,480,000 (Direct Cost: ¥79,600,000、Indirect Cost: ¥23,880,000)
Fiscal Year 2011: ¥20,410,000 (Direct Cost: ¥15,700,000、Indirect Cost: ¥4,710,000)
Fiscal Year 2010: ¥20,280,000 (Direct Cost: ¥15,600,000、Indirect Cost: ¥4,680,000)
Fiscal Year 2009: ¥20,150,000 (Direct Cost: ¥15,500,000、Indirect Cost: ¥4,650,000)
Fiscal Year 2008: ¥19,630,000 (Direct Cost: ¥15,100,000、Indirect Cost: ¥4,530,000)
Fiscal Year 2007: ¥23,010,000 (Direct Cost: ¥17,700,000、Indirect Cost: ¥5,310,000)
Keywordsプルキンエ細胞 / 小脳 / レンチウイルス / 樹状突起 / 運動失調 / ニューロン / シナプス / 神経回路 / 神経発生 / 神経発達 / 神経再生 / Staggerer
Research Abstract

Staggererマウスの解析:Staggererマウスは、転写因子であるRORαのリガンド結合ドメインの欠損による転写障害が原因である。RORαは脳内ではプルキンエ細胞に豊富に発現している。Staggererマウスで見られるRORαの転写障害は、遺伝性脊髄小脳変性症1型(SCA1)と共通していることが報告されているため、Staggererマウスの小脳異常をスライスパッチクランプ法で解析し、SCA1の病態理解を深めることを目的とした。Staggererマウスのプルキンエ細胞ではmGluR1を介する遅いEPSC及び、mGluR1を介するシナプス前抑制が全く観察されなかった。
変異ataxin-1発現プルキンエ細胞の解析:レンチウイルスベクターを用いて変異ataxin-1を野生型マウスの小脳プルキンエ細胞に発現させた。その結果、プルキンエ細胞の形態、早いシナプス伝達、短期シナプス可塑性に異常は見られなかったが、mGluR1を介する遅いEPSC振幅の有意な減弱が観察された。さらにシナプス可塑性(LTD誘導)の障害も見られた。以上より、SCA1プルキンエ細胞では形態的及び通常のシナプス伝達に障害が見られる前に、mGluR1機能が障害され、これにより小脳失調を引き起こす可能性が考えられた。
INPP4A欠損マウスの線条体神経細胞死のレスキュー:脱リン酸化酵素INPP4Aを欠損するマウスは、線条体ニューロンが神経細胞死を起こして脱落する。そこでレンチウイルスベクターを用いてINPP4A遺伝子を線条体ニューロンに供給し、神経細胞死を防ぐことを目的とした。生後2日のINPP4A欠損マウスの線条体に、INPP4A発現レンチウイルスベクターを接種し、3週間後に観察したところ、ウイルス感染細胞において神経細胞死がほぼ完全に抑制されていた。

Report

(5 results)
  • 2010 Annual Research Report
  • 2009 Annual Research Report   Self-evaluation Report ( PDF )
  • 2008 Annual Research Report
  • 2007 Annual Research Report
  • Research Products

    (40 results)

All 2011 2010 2009 2008 Other

All Journal Article (16 results) (of which Peer Reviewed: 12 results) Presentation (20 results) Remarks (3 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] High Transgene Expression by Lentiviral Vectors Causes Maldevelopment of Purkinje Cells In Vivo.2010

    • Author(s)
      Sawada Y, Kajiwara G, Iizuka A, Takayama K, Shuvaev AN, Koyama C, Hirai H.
    • Journal Title

      The Cerebellum

      Volume: 9 Pages: 291-302

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The Ptdlns (3,4) P (2) phosphatase INPP4A is a suppressor of excitotoxic neuronal death.2010

    • Author(s)
      Sasaki J, Kofuji S, Itoh R, Momiyama T, Takavama K, Murakami H, Chida S, Tsuya Y, Takasuga Eguchi S, Asanuma K, Horie Y, Miura K, Davies EM, Mitchell C, Yamazaki M, Hirai H, Takenaa T, Suzuki A, Sasaki T.
    • Journal Title

      Nature

      Volume: 465 Pages: 497-501

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] High Transgene expression by lentiviral vectors causes maldevelopment of Purkinje cells in vivo2010

    • Author(s)
      Sawada Y, Kajiwara G, Iizuka A, Takayama K, Shuvaev AN, Koyama C, Hirai H
    • Journal Title

      Cerebellum (in press)

    • Related Report
      2009 Self-evaluation Report
  • [Journal Article] High transgene expression by lentiviral vectors causes maldevelopment of Purkinje cells in vivo.2010

    • Author(s)
      Sawada Y, Kajiwara G, Iizuka A, Takayama K, Shuvaev A, Koyama C, Hirai H
    • Journal Title

      The Cerebellum (In press)

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Lentiviral-vector-mediated rescue of motor behavior in spontaneously occurring hereditary ataxic mice2009

    • Author(s)
      Iizuka A, Takayama K, Torashima T, Yamasaki M, Koyama C, Mitsumura K, Watanabe M, Hirai H
    • Journal Title

      Neurobiol Disease 35 (3)

      Pages: 457-65

    • Related Report
      2009 Self-evaluation Report
  • [Journal Article] Rescue of abnormal phenotypes in delta2 glutamate receptor-deficient mice by the extracellular N-terminal and intracellular C-terminal domains of the delta2 glutamate receptor.2009

    • Author(s)
      Iizuka A, Takayama K, Torashima T, Yamasaki M, Koyama C, Mitsumura K, Watanabe M, Hirai H., akayama K, Torashima T, Horiuchi H, Hirai H
    • Journal Title

      Neurobiology of Disease 35

      Pages: 457-465

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Rescue of abnormal phenotypes in delta2 glutamate receptor-deficient mice by the extracellular N-terminal and intracellular C-terminal domains of the delta2 glutamate receptor.2009

    • Author(s)
      Torashima T, Iizuka A, Horiuchi H, Mitsumura K, Yamasaki M, Koyama C, Takayama K, Iino M, Watanabe M, Hirai H
    • Journal Title

      European Journal of Neuroscience 30

      Pages: 355-365

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] ウイルスベクターを用いた成熟マウス小脳皮質への遺伝子導入法2009

    • Author(s)
      平井宏和
    • Journal Title

      実験医学 27

      Pages: 499-506

    • Related Report
      2009 Annual Research Report
  • [Journal Article] Characterization of mutant mice that express polyglutamine in cerebellar Purkinje cells.2009

    • Author(s)
      One M, Mitsumura K, Toreshima T, Koyama C, Yamaguchi H, Furuya N, Hirai H
    • Journal Title

      Brain Research 1255

      Pages: 9-17

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Lentivector-mediated rescue from cerebellar ataxia in a mouse model of spinocerebellar ataxia2008

    • Author(s)
      Torashima T, Koyama C, Iizuka A, Mitsumura K, Takayama K, Yanagi S, Oue M, Yamaguchi H, Hirai H
    • Journal Title

      EMBO Rep 9 (4)

      Pages: 393-9

    • Related Report
      2009 Self-evaluation Report
  • [Journal Article] Purkinje-ce11-preferential tranduction by lentiviral vectors with the murine stem cell virus promoter.2008

    • Author(s)
      Takayama K, Tofashima T, Horiuchi H, Hirai H
    • Journal Title

      Neuroscience Letters 443

      Pages: 7-11

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Progress in transduction of cerebellar Purkinje, cells in vivo using viral vectors.2008

    • Author(s)
      Hirai H
    • Journal Title

      Cerebellum 7

      Pages: 273-278

    • NAID

      120000807297

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The scaffold protein JSAP1 regulates proliferation and differentiation of cerebellar granule cell precursors by modulating JNK signaling.2008

    • Author(s)
      Sato T, Torashima T, Sugihara K, Hrai H, Asano M, Yoshioka K
    • Journal Title

      Molecular & Cellular Neuroscience 39

      Pages: 569-578

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Inhibitory effects of the entiepileptic drug ethostiximide on G protein-activated inwardly rectifying K+channels.2008

    • Author(s)
      Kobayashi T, Hirai H, Iino M, Fuse I, Mitstimura K, Washiyama K, Kasai S, Ikeda K
    • Journal Title

      Neurepharmacology 56

      Pages: 499-506

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Potential usefulness of D2R reporter gene imaging by IBF as gene therapy monitoring for cerebellar neurodegene rative diseases.2008

    • Author(s)
      Shiba K, Torashima T, Hirai H, Ogawa K, Akhter N , Makajima K, Kinuya S, Mori H
    • Journal Title

      Journal of Cerebral Blood Flow & Metabolism 29

      Pages: 434-440

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Lentivector-mediated rescue from cerebellar ataxia in a mouse model of spinocerebellar ataxia2008

    • Author(s)
      Torashima T, Koyama C, Iizuka A, Mitsumura K, Takayama K, Yanagi S, Oue M, Yamaguchi H, Hirai H
    • Journal Title

      EMBO Reports

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Presentation] レンチ宅イルスベクターを利用した神経細胞への遺伝子導入で何ができるのか?2011

    • Author(s)
      平井宏和
    • Organizer
      第88回日本生理学会大会第116回日本解剖学会総会・全国学術集会合同大会
    • Place of Presentation
      横浜(中止により紙上発表のみ)
    • Year and Date
      2011-03-28
    • Related Report
      2010 Annual Research Report
  • [Presentation] レンチウイルスベクターを用いた小脳の発達・再生研究2010

    • Author(s)
      平井宏和、澤田悠輔、梶原剛
    • Organizer
      第33回日本神経科学大会
    • Place of Presentation
      神戸
    • Year and Date
      2010-09-02
    • Related Report
      2010 Annual Research Report
  • [Presentation] A PKCγ mutation in spinocerebellar ataxia type 14 impairs PKC functions in a dominant-negative manner in cerebellar Purkinje cells in vivo2010

    • Author(s)
      Anton Shuvaev, Tomohiko Irie, Hajime Horiuchi, Akira Iiduka, Masae lino, Takahiro Seki, Norio Sakai, Hirokazu Hirai
    • Organizer
      第87回日本生理学会
    • Place of Presentation
      盛岡
    • Year and Date
      2010-05-20
    • Related Report
      2010 Annual Research Report
  • [Presentation] Lentiviral vector-mediated rescue of cerebellar ataxia in a mouse model of spinocerebellar ataxia2009

    • Author(s)
      平井宏和
    • Organizer
      Annual Meeting of Chinese Medical Association
    • Place of Presentation
      Taipei Veterans General Hospital, Taipei, Taiwan
    • Year and Date
      2009-11-01
    • Related Report
      2009 Annual Research Report
  • [Presentation] Lentivector-mediated rescue from cerebellar ataxia in a mouse model of spinocerebellar ataxia2009

    • Author(s)
      平井宏和
    • Organizer
      5th International Symposium on Genomic Medicine of CCH
    • Place of Presentation
      Changhua Christian Hospital, Taichung, Taiwan
    • Year and Date
      2009-10-31
    • Related Report
      2009 Annual Research Report
  • [Presentation] レンチウイルスベクターを用いた遺伝性運動失調マウスの機能回復2009

    • Author(s)
      飯塚朗, 寅嶋崇, 三ツ村一浩, 小山知穂, 飯野昌枝, 平井宏和
    • Organizer
      第32回日本神経科学大会
    • Place of Presentation
      名古屋国際会議場(名古屋)
    • Year and Date
      2009-09-16
    • Related Report
      2009 Annual Research Report
  • [Presentation] 機能ドメインを土台としたδ2グルタミン酸受容体研究の進展2009

    • Author(s)
      平井宏和, 寅嶋崇, 飯塚朗
    • Organizer
      第32回日本神経科学大会
    • Place of Presentation
      名古屋国際会議場(名古屋)
    • Year and Date
      2009-09-16
    • Related Report
      2009 Annual Research Report
  • [Presentation] A PKCγ mutations in spinocerebellar ataxia type 14 impairs PKC functions in cerebellar Purkinje cells in vivo2009

    • Author(s)
      Shuvaev NA, Sakai N, Seki T, Iino M, Horiuchi H, Hirai H.
    • Organizer
      The 36th International Congress of Physiological Sciences
    • Place of Presentation
      京都国際会議場 (Kyoto)
    • Year and Date
      2009-07-28
    • Related Report
      2009 Self-evaluation Report
  • [Presentation] Rescue of abnormal phenotypes in σ2 glutamate-receptor-null mice by the extracellular N-terminal domain.2009

    • Author(s)
      Torashima T, 飯塚朗, 堀内始, 三ツ村一浩, Yamazaki M, 小山知穂, 高山清彦, 飯野昌枝, Watanabe M, 平井宏和
    • Organizer
      第36回国際生理学会世界大会
    • Place of Presentation
      京都国際会議場(京都)
    • Year and Date
      2009-07-28
    • Related Report
      2009 Annual Research Report
  • [Presentation] A PKC γ mutations in spinocerebellar ataxia type 14 impairs PKCfunctions in cerebellar Purkinje cells in vivo2009

    • Author(s)
      Shuvaev NA, Hirai H, Sakai N, Seki T, Iino M, Horiuchi H
    • Organizer
      第36回国際生理学会世界大会
    • Place of Presentation
      京都国際会議場(京都)
    • Year and Date
      2009-07-28
    • Related Report
      2009 Annual Research Report
  • [Presentation] 高力価レンチウイルスベクターの感染が小脳プルキンエ細胞の発達におよぼす影響の検討2009

    • Author(s)
      澤田悠輔, 梶原剛, 寅嶋崇, 高山清彦, 堀内始, 飯塚朗, 三ツ村一浩, 平井宏和
    • Organizer
      第32回日本神経科学大会
    • Place of Presentation
      名古屋国際会議場(名古屋)
    • Year and Date
      2009-06-16
    • Related Report
      2009 Annual Research Report
  • [Presentation] Purkinje-cell-selective transduction by the MSCV promoter incorporated in lentiviral vectors2008

    • Author(s)
      Takayama K, Torashima T, Horiuchi H, Hirai H.
    • Organizer
      Neuroscience 2008
    • Place of Presentation
      Convention Center, Washington DC
    • Year and Date
      2008-11-19
    • Related Report
      2009 Self-evaluation Report
  • [Presentation] Purkinje-cell-selective transduction by the MSCV promoter incorporated in lentiviral vectors2008

    • Author(s)
      KIYOHIKO TAKAYAMA, TAKASHI TORASHIMA, HAJIME HORIUCHI, HIROKAZU HIRAI
    • Organizer
      北米神経科学学会
    • Place of Presentation
      Washington DC
    • Year and Date
      2008-11-19
    • Related Report
      2008 Annual Research Report
  • [Presentation] レンチウイルスベクターを用いた神経科学研究と遺伝子治療2008

    • Author(s)
      平井宏和
    • Organizer
      「生体調節シグナルの統合的研究」第3回合同シンポジウム
    • Place of Presentation
      秋田
    • Year and Date
      2008-10-17
    • Related Report
      2008 Annual Research Report
  • [Presentation] レンチウイルスベクターの作製方法とその応用2008

    • Author(s)
      平井宏和
    • Organizer
      第33回組織細胞化学講習会
    • Place of Presentation
      神戸
    • Year and Date
      2008-08-06
    • Related Report
      2008 Annual Research Report
  • [Presentation] レンチウィルスベクターを用いたプルキン午細胞選択的なGFP発現2008

    • Author(s)
      高中清彦、寅嶋崇、堀内始、平井宏和
    • Organizer
      第31回日本神経科学大会
    • Place of Presentation
      東京
    • Year and Date
      2008-07-11
    • Related Report
      2008 Annual Research Report
  • [Presentation] レγチウイルスベクターの進歩-中枢神経系の病態生理解明と脳神経疾患の遺伝子治療への応用-2008

    • Author(s)
      平井宏和
    • Organizer
      第31回日本神経科学大会(シンポジウム)
    • Place of Presentation
      東京
    • Year and Date
      2008-07-09
    • Related Report
      2008 Annual Research Report
  • [Presentation] レンチウイルスベクターを用いたδ2グルタミン酸受容体欠損マウスのレスキュー-アミノ酸リガンド結合部位及びチャネルポアが欠損しても機能は障害されない-2008

    • Author(s)
      飯塚 朗, 三ツ村 一浩, 小山 知穂, 寅嶋 崇, 飯野 昌枝, 平井 宏和
    • Organizer
      第85回日本生理学会大会
    • Place of Presentation
      東京
    • Year and Date
      2008-03-26
    • Related Report
      2007 Annual Research Report
  • [Presentation] In vivo幼若ラット小脳皮質神経細胞へのレンチウイルスベクターを用いた遺伝子導入2008

    • Author(s)
      梶 原剛, 澤田 悠輔, 寅嶋 崇, 高山 清彦, 堀内 始, 飯塚 朗, 三ツ村 一浩, 飯野 昌枝, 小山 知穂, 平井 宏和
    • Organizer
      第85回日本生理学会大会
    • Place of Presentation
      東京
    • Year and Date
      2008-03-26
    • Related Report
      2007 Annual Research Report
  • [Presentation] レンチウイルスベクターを用いたCRAG発現による脊髄小脳変性症モデルマウスのシナプス伝達及び可塑性の回復2008

    • Author(s)
      三ツ村 一浩, 飯野 昌枝, 飯塚 朗, 寅嶋 崇, 小山 知穂, 高山 清彦, 堀内 始, 平井 宏和
    • Organizer
      第85回日本生理学会大会
    • Place of Presentation
      東京
    • Year and Date
      2008-03-26
    • Related Report
      2007 Annual Research Report
  • [Remarks]

    • URL

      http://synapse.dept.med.gunma-u.ac.jp/index.html

    • Related Report
      2009 Self-evaluation Report
  • [Remarks]

    • URL

      http://synapse.dept.med.gunma-u.ac.jp/index.html

    • Related Report
      2009 Annual Research Report
  • [Remarks]

    • URL

      http://synapse.dept.med.gunma-u.ac.jp/index.html

    • Related Report
      2008 Annual Research Report
  • [Patent(Industrial Property Rights)] 目的遺伝子を脳で小脳プルキンエ細胞、脳幹および嗅球特異的に過剰発現するトランスジェニック非ヒト哺乳動物2010

    • Inventor(s)
      平井宏和
    • Industrial Property Rights Holder
      群馬大学
    • Industrial Property Number
      2010-129021
    • Filing Date
      2010-06-04
    • Related Report
      2010 Annual Research Report

URL: 

Published: 2007-04-01   Modified: 2016-04-21  

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