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New strategy for drug development of cerebral ischemia; zinc signal is a potential target

Research Project

Project/Area Number 23590644
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Applied pharmacology
Research InstitutionGifu Pharmaceutical University

Principal Investigator

HARA Hirokazu  岐阜薬科大学, 薬学部, 准教授 (30305495)

Co-Investigator(Kenkyū-buntansha) ADACHI Tetsuo  岐阜薬科大学, 薬学部, 教授 (40137063)
KAMIYA Tetsuro  岐阜薬科大学, 薬学部, 助教 (60453057)
Project Period (FY) 2011 – 2013
Project Status Completed (Fiscal Year 2013)
Budget Amount *help
¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2013: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2012: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2011: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
Keywords亜鉛 / 脳梗塞 / 神経細胞死 / アポトーシス / スプライシング / 脳虚血
Research Abstract

There is increasing evidence that excessive zinc release from presynaptic terminals following cerebral ischemia induces neuronal cell death. It was reported that the blockade of free zinc by zinc chelators abolishes the neurodegeneration induced by cerebral ischemia. These findings support the concept that zinc is one of mediators of ischemic neuronal cell death. However, the mechanism is not fully understood. In this study, we addressed molecular mechanisms of zinc-induced neurotoxicity. We demonstrated here that zinc-induced apoptosis might be regulated, at least in part, through alterations in splicing pattern of pro-apoptotic factor Bim. To our knowledge, this is first report showing a novel function of zinc as a splicing regulator. In addition, we provided evidence that apomorphine, a dopamine receptor agonist, protects against zinc-induced neurotoxicity independently of dopamine receptors.

Report

(4 results)
  • 2013 Annual Research Report   Final Research Report ( PDF )
  • 2012 Research-status Report
  • 2011 Research-status Report
  • Research Products

    (32 results)

All 2014 2013 2012 2011 Other

All Journal Article (6 results) (of which Peer Reviewed: 6 results) Presentation (18 results) (of which Invited: 1 results) Book (2 results) Remarks (4 results) Patent(Industrial Property Rights) (2 results) (of which Overseas: 1 results)

  • [Journal Article] Newly Synthesized ‘Hidabeni’ Chalcone Derivatives Potently Suppress LPS-Induced NO Production <i>via</i> Inhibition of STAT1, but Not NF-κB, JNK, and p38, Pathways in Microglia2014

    • Author(s)
      Hara H, Ikeda R, Ninomiya M, Kamiya T, Koketsu M, Adachi T
    • Journal Title

      Biological and Pharmaceutical Bulletin

      Volume: 37 Issue: 6 Pages: 1042-1049

    • DOI

      10.1248/bpb.b14-00116

    • NAID

      130004147351

    • ISSN
      0918-6158, 1347-5215
    • Related Report
      2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] Newly synthesized ‘hidabeni’ chalcone derivatives potently suppress LPS-induced NO production via inhibition of STAT1, but not NF-&#61547;B, JNK, and p38, pathways in microglia2014

    • Author(s)
      Hara H, Ikeda R, Ninomiya M, Kamiya T, Koketsu M, Adachi T
    • Journal Title

      Biol Pharm Bull

      Volume: 印刷中

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Zinc- induced modulation of SRSF6 activity alters Bim splicing to promote generation of the most potent apoptotic isoform BimS2013

    • Author(s)
      Hara H, Takeda T, Yamamoto N, Furuya K, Hirose K, Kamiya T, Adachi T
    • Journal Title

      FEBS J

      Volume: 280 Issue: 14 Pages: 3313-3327

    • DOI

      10.1111/febs.12318

    • Related Report
      2013 Annual Research Report 2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] Protective Effects of Apomorphine against Zinc-Induced Neurotoxicity in Cultured Cortical Neurons2013

    • Author(s)
      Hara H, Maeda A, Kamiya T, Adachi T
    • Journal Title

      Biological and Pharmaceutical Bulletin

      Volume: 36 Issue: 4 Pages: 585-591

    • DOI

      10.1248/bpb.b12-00962

    • NAID

      130003361389

    • ISSN
      0918-6158, 1347-5215
    • Related Report
      2013 Final Research Report 2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Inhibitory effects of chalcone glycosides isolated from Brassica rapa L.' hidabeni' and their synthetic derivatives on LPS-induced NO production in microglia2011

    • Author(s)
      Hara H, Nakamura Y, Ninomiya M, Mochizuki R, Kamiya T, Aizenman E, Koketsu M, Adachi T
    • Journal Title

      Bioorg. Med. Chem

      Volume: 19 Issue: 18 Pages: 5559-5568

    • DOI

      10.1016/j.bmc.2011.07.036

    • NAID

      120006341206

    • Related Report
      2013 Final Research Report 2011 Research-status Report
    • Peer Reviewed
  • [Journal Article] Endoplasmic reticulum stress inducers provide protection against 6-hydroxydopamine-induced cytotoxicity2011

    • Author(s)
      Hara H, Kamiya T, Adachi T
    • Journal Title

      Neurochem. Int

      Volume: 58 Issue: 1 Pages: 35-43

    • DOI

      10.1016/j.neuint.2010.10.006

    • Related Report
      2011 Research-status Report
    • Peer Reviewed
  • [Presentation] ミクログリアにおけるLPS誘導性IL-23発現に対するアポモルフィンの抑制作用2014

    • Author(s)
      木元大,原宏和,梶田実穂,高田知里,神谷哲朗,足立哲夫
    • Organizer
      日本薬学会第134年会
    • Place of Presentation
      熊本
    • Related Report
      2013 Annual Research Report 2013 Final Research Report
  • [Presentation] ミクログリアにおいて亜鉛はIL-23発現を誘導する2013

    • Author(s)
      梶田実穂,原宏和,土井卓也,神谷哲朗,足立哲夫
    • Organizer
      第59回日本薬学会東海支部大会
    • Place of Presentation
      名古屋
    • Year and Date
      2013-07-06
    • Related Report
      2013 Final Research Report
  • [Presentation] 亜鉛によるSRSF6の活性低下がBim遺伝子のスプライシング変化を惹起する2013

    • Author(s)
      廣瀬和也,原宏和,鳥居薫,神谷哲朗,足立哲夫
    • Organizer
      日本生化学会中部支部例会・シンポジウム
    • Place of Presentation
      名古屋
    • Year and Date
      2013-05-25
    • Related Report
      2013 Final Research Report
  • [Presentation] Pretreatment with apomorphine protects cultured cortical neurons from zinc-induced neurotoxicity2013

    • Author(s)
      Hirokazu Hara, Tetsuro Kamiya, Tetsuo Adachi
    • Organizer
      Neuroscience 2013
    • Place of Presentation
      San Diego, USA
    • Related Report
      2013 Annual Research Report 2013 Final Research Report
  • [Presentation] 脳内亜鉛の恒常性破綻と神経細胞死2013

    • Author(s)
      原宏和
    • Organizer
      メタルバイオサイエンス2013
    • Place of Presentation
      静岡
    • Related Report
      2013 Final Research Report
  • [Presentation] ミクログリアにおける亜鉛誘導性IL-23発現にはATF4が関与している2013

    • Author(s)
      土井卓也,原宏和,梶田実穂,神谷哲朗,足立哲夫
    • Organizer
      第86回日本生化学会大会
    • Place of Presentation
      横浜
    • Related Report
      2013 Annual Research Report 2013 Final Research Report
  • [Presentation] 亜鉛神経毒性に対するアポモルフィンの保護作用2013

    • Author(s)
      原宏和,前田明日香,神谷哲朗,足立哲夫
    • Organizer
      第66回日本酸化ストレス学会
    • Place of Presentation
      名古屋
    • Related Report
      2013 Annual Research Report 2013 Final Research Report
  • [Presentation] 脳内亜鉛の恒常性破綻と神経細胞死2013

    • Author(s)
      原 宏和
    • Organizer
      メタルバイオサイエンス研究会2013
    • Place of Presentation
      静岡
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] 飛騨紅かぶカルコン誘導体のミクログリアにおける抗炎症作用とその構造活性相関2012

    • Author(s)
      池田諒子,原宏和,神谷哲朗,二ノ宮真之,纐纈守,足立哲夫
    • Organizer
      第58回日本薬学会東海支部大会
    • Place of Presentation
      静岡
    • Year and Date
      2012-07-07
    • Related Report
      2013 Final Research Report
  • [Presentation] 酸化・ニトロ化ストレス細胞障害を抑制する保護物質の探索研究2012

    • Author(s)
      原宏和,足立哲夫
    • Organizer
      日本酸化ストレス学会東海支部設立シンポジウム
    • Place of Presentation
      名古屋
    • Year and Date
      2012-02-18
    • Related Report
      2013 Final Research Report
  • [Presentation] 亜鉛によるBimのスプライシングパターン変化におけるSRp55の関与2012

    • Author(s)
      原宏和,武田樹也,古谷佳祐,神谷哲朗,足立哲夫
    • Organizer
      第85回日本生化学会大会
    • Place of Presentation
      福岡
    • Related Report
      2013 Final Research Report 2012 Research-status Report
  • [Presentation] ミクログリアにおけるiNOS発現誘導を阻害する飛騨紅かぶカルコンの構造活性相関2012

    • Author(s)
      原宏和,池田諒子,神谷哲朗,二ノ宮真之,纐纈守,足立哲夫
    • Organizer
      第65回日本酸化ストレス学会
    • Place of Presentation
      徳島
    • Related Report
      2013 Final Research Report 2012 Research-status Report
  • [Presentation] 亜鉛による神経細胞障害に対するアポモルフィンの保護作用2011

    • Author(s)
      前田明日香,原宏和,神谷哲朗,足立哲夫
    • Organizer
      第84回日本生化学会大会
    • Place of Presentation
      京都
    • Related Report
      2013 Final Research Report
  • [Presentation] ミクログリアにおいて亜鉛はIL-23発現を誘導する

    • Author(s)
      梶田実穂,原 宏和,土井卓也,神谷哲朗,足立哲夫
    • Organizer
      第59回日本薬学会東海支部大会
    • Place of Presentation
      名古屋
    • Related Report
      2013 Annual Research Report
  • [Presentation] 亜鉛によるSRSF6の活性低下がBim遺伝子のスプライシング変化を惹起する

    • Author(s)
      廣瀬和也,原 宏和,鳥居 薫,神谷哲朗,足立哲夫
    • Organizer
      日本生化学会中部支部例会・シンポジウム
    • Place of Presentation
      名古屋
    • Related Report
      2013 Annual Research Report
  • [Presentation] 飛騨紅かぶカルコン誘導体のミクログリアにおける抗炎症作用とその構造活性相関

    • Author(s)
      池田諒子,原 宏和,神谷哲朗,二ノ宮真之,纐纈 守,足立哲夫
    • Organizer
      第58回日本薬学会東海支部大会
    • Place of Presentation
      静岡
    • Related Report
      2012 Research-status Report
  • [Presentation] 亜鉛による神経細胞障害に対するアポモルフィンの保護作用

    • Author(s)
      前田明日香、原 宏和、神谷哲朗、足立哲夫
    • Organizer
      第84回日本生化学会大会
    • Place of Presentation
      京都
    • Related Report
      2011 Research-status Report
  • [Presentation] 酸化・ニトロ化ストレス細胞障害を抑制する保護物質の探索研究

    • Author(s)
      原 宏和、足立哲夫
    • Organizer
      日本酸化ストレス学会東海支部設立シンポジウム(招待講演)
    • Place of Presentation
      名古屋
    • Related Report
      2011 Research-status Report
  • [Book] Zinc Signals in Cellular Functions and Disorders2014

    • Author(s)
      Hirokazu Hara and Elias Aizenman
    • Publisher
      Oxidative Stress and Neuronal Zinc Signaling
    • Related Report
      2013 Annual Research Report
  • [Book] Oxidative Stress and Neuronal Zinc Signaling; Zinc Signals in Cellular Functions and Disorders

    • Author(s)
      Hirokazu Hara, Elias Aizenman
    • Publisher
      Springer (in press)
    • Related Report
      2013 Final Research Report
  • [Remarks]

    • URL

      http://www.gifu-pu.ac.jp/research/research_rinyaku.html

    • Related Report
      2013 Final Research Report
  • [Remarks] 岐阜薬科大学

    • URL

      http://www.gifu-pu.ac.jp/top.html

    • Related Report
      2013 Annual Research Report
  • [Remarks] 岐阜薬科大学

    • URL

      http://www.gifu-pu.ac.jp/

    • Related Report
      2012 Research-status Report
  • [Remarks] 岐阜薬科大学HP

    • URL

      http://www.gifu-pu.ac.jp/

    • Related Report
      2011 Research-status Report
  • [Patent(Industrial Property Rights)] アポトーシス促進因子Bimのスプライシングパターン変化を指標とした新規抗がん剤のスクリーニング法2012

    • Inventor(s)
      原 宏和、足立哲夫
    • Industrial Property Rights Holder
      岐阜薬科大学
    • Industrial Property Rights Type
      特許
    • Filing Date
      2012-03-05
    • Related Report
      2013 Final Research Report
    • Overseas
  • [Patent(Industrial Property Rights)] アポトーシス促進因子Bimのスプライシングパターン変化を指標にした新規抗がん剤のスクリーニング法2012

    • Inventor(s)
      原 宏和、足立哲夫
    • Industrial Property Rights Holder
      岐阜市
    • Industrial Property Number
      2012-048222
    • Filing Date
      2012
    • Related Report
      2011 Research-status Report

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Published: 2011-08-05   Modified: 2019-07-29  

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