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Molecular mechanisms and therapeutic approach for ischemic brain damages

Research Project

Project/Area Number 12308040
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Neurochemistry/Neuropharmacology
Research InstitutionThe Tokyo Metropolitan Institute of Medical Science (TMIMS)

Principal Investigator

SHIBASAKI Futoshi  TMIMS, Molecular Cell Physiology, Depart. Chief, 東京都臨床医学総合研究所, 副参事研究員 (90300954)

Co-Investigator(Kenkyū-buntansha) NAKADA Hirohisa  Hujisawa Pharm. Co Ltd., 主任研究員
UCHINO Hiroyuki  Hachioji Medical Center, Tokyo Medical University, Lecture, 八王子医療センター・麻酔科, 講師 (60266476)
KATO Shiori  TMIMS, Molecular Cell Physiology, researcher, 東京都臨床医学総合研究所, 研究員 (10333460)
MATSUI Toru  Saitama Medical School, professor, 脳神経外科, 教授 (70199735)
UEDA Masatugu  YS institute, Snow-White Co Ltd., YS研究所, 研究所長
青木 一正  (財)東京都医学研究機構, 東京都臨床医学総合研究所, 研究員 (10184029)
大森 信彦  (財)東京都医学研究機構, 東京都臨床医学総合研究所, 研究員 (80311421)
星川 裕  (財)東京都医学研究機構, 東京都臨床医学総合研究所, 研究員 (80280626)
Project Period (FY) 2000 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥40,260,000 (Direct Cost: ¥36,000,000、Indirect Cost: ¥4,260,000)
Fiscal Year 2002: ¥9,230,000 (Direct Cost: ¥7,100,000、Indirect Cost: ¥2,130,000)
Fiscal Year 2001: ¥9,230,000 (Direct Cost: ¥7,100,000、Indirect Cost: ¥2,130,000)
Fiscal Year 2000: ¥21,800,000 (Direct Cost: ¥21,800,000)
Keywordsischemia / cell death / calcineurin / mitochondria / isomerase / hypoxia / 低酸素 / リン酸化 / サイクロスポリンA / アデノウイルス / 遺伝子導入
Research Abstract

In this research project, we pursued clarifying mechanisms by which calcineurin and cyclophilin D, specifically expressed in mitochondria, playes an important role in delayed neuronal cell death of CA1 sector of rat forebrain ischemic model. The series of results from this model with 10 min ischemia and reperfusion showed the drastic neuroprotective effect of an immunosuppressant cyclosporin A. These results clearly demonstrated that the mechams of the neuroprotection of cyclosporin A to ischemic brain damages were due to the inhibition of both calcineurin activity and cyclophilin D specifically expressed in mitochondrial matrix. The inhibition of cyclophilin D by CsA suppressed the assembly of MPT (mitochondrial permeability transition) pores through which cell death inducers such as cytochrome c and caspases were released. MPT pores were reported to be consisted of three components ; VDAC (voltage dependent anion channel), ANT (adenine nucleotide translocase), and cyclophilin D. We d … More emonstrated that cyclophilin D directly bind to ANT and/or VDAC using affinity colomn bound to cyclophilin D.
Under these information, we succeeded in development of the new anti-ischemic drug, FR901459 in collabaration with Fujisawa Pharm. CO. LTD., Japan. This new drug shows ideal characterization as an anti-ischemic drug, such as lower anti-immunosuppressive effect and a strong anti-isomerase activity. We are now developing this drug for a clinical use.
Furthermore, we focused on the critical event of hypoxia or anoxia during ischemic insult, and found hypoxic inducible factor HIF, which was a transcription factor and involved in the metabolic, angiogenetic, and erythropoietic pathway, played an critical role in regulatingneuronal cell deatrh. First, we have demonstrated that mRNA of HIF3, a subtype of the HIF family, mainly expressed in CA1 of hippocumpus 24 hours after ischemia, eventhough mRNA of HIF1 was responsive but much lower expressed than that of HIF3. In culture cells, calcineurin activity was suggested to be important in the HIF1 regulation by its dephosphorylatio.
These results prompt us to investigate the role of hypoxic pathway involving HIF as well as calcineurin/immunophilins. We plane to cralify the hypothesis that HIF family members would be critical factors in the pathway under calcium/calcineuin in ischemic events. Less

Report

(4 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • 2000 Annual Research Report
  • Research Products

    (64 results)

All Other

All Publications (64 results)

  • [Publications] Siesjo, BK, Uchino, H., Shibasaki, F.: "(Review Article) Post-treatment in transient global and focal ischemia : new pharmacological avenues"Pharamacology of Cerebral Ischemia. (in press). (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Omori, N., Mizuguchi, H., et al.: "Modification of a fiber protein in an adenovirus vector improves in vitro gene transfer efficiency to the mouse microglial cell line"Neurosci.Lett.. 324. 145-148 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] uchino, H., et al.: "Differential neuroproteiction by Cyclosporin A and FK506 following ischemia corresponds with differing abilities to inhibit calcineurin and the mitochondrial permeability transition"Neurobiol.Dis.. 10. 219-233 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yoshida, H., Yoshizawa, T.et al.: "Chemical chaperones reduce aggregate formation and cell death caused by the turncated Machado-Joseph disease gene product with an expanded polyglutamine stretch"Neurobiol.Dis.. 10. 88-99 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Shinoura, N., Sakurai, S, et al.: "Co-transduction of Apaf-1 and caspase-9 highly enhances p53-mediated apoptosis in gliomas"J.Biochem. 86. 587-595 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nomura, T., Yamamoto, H.et al.: "Enhancement by CsA of Taxol-induced apoptosis of human urinary bladder cancer cells"Urological Research. 30. 5102-5111 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] H.Uchino, BK Siesjo, F.Shibasaki: "Calcineurin and immunophilin are pivotal target for delayed neuronal cell death on the forebrain ischemia in the rat"Acta Neurochirugica Supplement Springer Verlag Wien New York. (in press). (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Uchino, H., Kawakami, M., Shibasaki, F., Siesjo B.K.: "Differential Alteration of Immediate early Gene, c-fos, fos B, c-jun, jun B, jun D in the rat brain following transient forebrain ischemia"Brain Res.. (in press). (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 内野博之, 芝崎 太: "Calsineurin/immunophilin情報伝達系制御と脳保護"蘇生. 21. 1-12 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 内野 博之, 芝崎 太, 石井 脩夫: "虚血性神経細胞死のメカニズムと脳保護"Lisa. 9. 330-350 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 内野 博之, 芝崎 太, 石井 脩夫: "薬理学的アプローチによる脳保護と21世紀における脳蘇生の展望"Lisa. 9. 331-362 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Siesjo BK, Uchino, H., and Shibasaki, F.: "(Review Article) Posttreatment in transient global and focal ischemia : new pharmacological avenues"Pharmacology of Cerebral Ischemia. (in press). (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Omori, N., Mizuguchi, H., Ohsawa, K., Kohsaka, S., Hayakawa,T., Abe, K., and Shibasaki, F.: "Modification of a fiber protein in an adenovirus vector improves in vitro gene transfer efficiency to the mouse microglial cell line"Neurosci. Lett.. 324. 145-148 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Uchino, H., Minamikawa-Tachino, R., Kristian, T., Perkins, G., Narazaki, M., Siesjo B.K., and Shibasaki, F.: "Differential neuroprotection by Cyclosporin A and FK506 following ischemia corresponds with differing abilities to inhibit calcineurin and the mitochondrial permeability transition"Neurobiol. Dis.. 10. 219-233 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yoshida, H., Yoshizawa, T., Shibasaki, F., Shoji, S., and Kanazawa, I.: "Chemical chaperones reduce aggregate formation and cell death caused by the truncated Machado-Joseph disease gene product with an expanded polyglutamine stretch"Neurobiol. Dis.. 10. 88-99 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Shinoura, N., Sakurai, S., Shibasaki, F., Asai, A., Kirino, T., Hamada, H.: "Co-transduction of Apaf-1 and caspase-9 highly enhances p53-mediated apoptosis in gliomas"Br. J. Cancer.. 86. 587-595 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nomura, T., Yamamoto, H., Mimata, H., Shitashige, M., Shibasaki, F., Mityamoto, E., and Nomura Y.: "Enhancement by CsA of Taxol-induced apoptosis of human urinary bladder cancer cells"Urological Research. 30. 102-111 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] H. Uchino, BK Siesjo and F. Shibasaki: "Calcineurin and immunophilin are pivotal target for delayed neuronal cell death on the forebrain ischemia in the rat"Acta Neurochirurgica Supplement Springer Verlag Wien New York. (in press). (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Uchino, H., Kawakami, M., Shibasaki, F., and Siesjo B. K.: "Differential Alteration of Immediate early Gene, c-fos, fos B, c-jun, jun B, jun D in the rat brain following transient forebrain ischemia"Brain Res.. (in press). (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Siesjo, BK, Uchino, H., Shibasaki, F: "(Review Article) Post-treatment in transient global and focal ischemia : new pharmacological avenues"Pharmacology of Cerebral Ischemia. (in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Omori, N., Mizuguchi, H.et al.: "Modification of a fiber protein in an adenovirus vector improves in vitro gene transfer efficiency to the mouse microglial cell line"Neurosci. Lett.. 324. 145-148 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Uchino, H., et al.: "Differential neuroprotection by Cyclosporin A and FK506 following ischemia corresponds with differing abilities to inhibit calcineurin and the mitochondrial permeability transition"Neurobiol. Dis.. 10. 219-233 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yoshida, H., Yoshizawa, T.et al.: "Chemical chaperones reduce aggregate formation and cell death caused by the truncated Machado-Joseph disease gene product with an expanded polyglutamine stretch"Neurobiol. Dis.. 10. 88-99 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Shinoura, N., Sakurai, S, et al.: "Co-transduction of Apaf-1 and caspase-9 highly enhances p53-mediated apoptosis in gliomas"J. Biochem. 86. 587-595 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Nomura, T., Yamamoto, H.et al.: "Enhancement by CsA of Taxol-induced apoptosis of human urinary bladder cancer cells"Urological Research. 30. 5102-5111 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] H.Uchino, BK Siesjo, F.Shibasaki: "Calcineurin and immunophilin are pivotal target for delayed neuronal cell death on the forebrain ischemia in the rat"Acta Neurochirurgica Supplement Springer Verlag Wien New York. (in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Uchino, H., Kawakami, M., Shibasaki, F., Siesjo B.K.: "Differential Alteration of Immediate early Gene, c-fos, fos B, c-jun, jun B, jun D in the rat brain following transient forebrain ischemia"Brain Res.. (in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] 内野博之, 芝崎 太: "Calcineurin/immunophilin情報伝達系制御と脳保護"蘇生. 21. 1-12 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 内野 博之, 芝崎 太, 石井 脩夫: "虚血性神経細胞死のメカニズムと脳保護"Lisa. 9. 330-350 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 内野 博之, 芝崎 太, 石井 脩夫: "薬理学的アプローチによる脳保護と21世紀における脳蘇生の展望"Lisa. 9. 331-362 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Shibasaki, F., Hallin, U., Uchino.H: "Review : Calcineurin as a multifunctional regulator"J. Biochem.. 131. 1-15 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Yoshimoto T, Uchino H, et al.: "Cyclosporm A, but not FK506 prevents the downregulation of pnos-phorylated Akt after transient focal ischemia in the rat."Brain Res.. 899. 148-158 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Uchino, H., et al.: "Differential neuroprotection by Cyclosporin A and FK506 following ischemia cor-renonds with differing abilities to inhibit calcineurin and the mitochondrial permeability transition"Neurobiol. Dis.. (in press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Miyata, K., Omori, N., Uchino, H., et al.: "Brain derived neurotrophic ftctor/TrkB mediates the neuroprotective effect of cyclosporin A in forebrain ischemia."Neuroscience. 105. 571-578 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Shitashige, M., et al.: "Phosphoryation of serine 70 of Bcl-2 as a possible prognostic maker in breast cancer."J. Biochem. 130. 741-748 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Uchino, H., et al.: "Differential Alteration of Immediate early Gene, c-fos, fos B, c-jun, jun B, jun D in the rat brain following transient forebrain ischemia"Brain Res. 2OO1. (in press).

    • Related Report
      2001 Annual Research Report
  • [Publications] Machida, K., et al.: "Inhibition of Cytochrome C release in Fas-mediated Signaling Pathway in transgenic mice induced to express hepatitis C viral Proteins."J. Biol. Chem.. 276. 12140-12146 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] ZOU, Y., et al.: "Calcineurin plays a critical role in the development of pressure overload-induced cardiac hypertrophy."Circulation. 104. 97-101 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Zou, Y., Yao, A., et al.: "Isoproterenol activates extracellular signal-regulated protein kinases in cardiomyocytes through calcineurin."Circulation. 104. 102-108 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Okamoto, K., et al.: "Adenovirus-mediated transfer of p53 augments hyperthermia-in-duced apoptosis in U251 glioma cells."Int. J. Radiat. Oncol. Biol. Phys.. 50. 525-531 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Siesjo B.K., et al.: "Mitochondrial dysfunction and maturation of brain damage after transient ischemia."Maturation Phenomenon in cerebral ischemia IV. Springer Velague U Ito (e. d. s) 2001. (in press).

    • Related Report
      2001 Annual Research Report
  • [Publications] Nomura, T., et al.: "Enhancement by cyclosporin A of Taxol-induced apoptosis of human urinary bladder cancer cells."Britsh J. Cancer. (in press).

    • Related Report
      2001 Annual Research Report
  • [Publications] Hakamata, Y., et al.: "Green fluorescent protein-transgenic rat : a tool for organ trans-plantation research."Biochem Biophys Res Commun. 286. 779-785 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Hirabayashi, M., T et al.: "A comparative study on the integration of exogenous DNA into mouse, rat rabbit, and pig genomes."Exp Anim. 50. 125-131 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Takahashi, R., Ueda, M.: "The milk protein promoter is a useful tool for developing a rat with tolerance to a human protein."Transgenic Res. 10. 571-575 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Yoshizawa T: "Cell cycle arrest enhances the in vitro cellular toxicity of the truncated Machado-Joseph disease gene product with an expanded polyglutamine stretch."Hum Mol Genetics. 9. 69-78 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Matsuda,S.: "Two distinct action mechanisms of immunophilin-ligand complexes for the blockade of T-cell activation."EMBO letter. 1. 428-434 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Simizu,S.: "Bcl-2 inhibits calcineurin-mediated Fas ligand expression in antitumor drug-treated Baby Hamster Kidney cells."Jpn.J Cancer Res. 91. 706-714 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Zhu,W.: "Ca2+/calmodulin-dependent kinase II and calcineurin play critical roles in endothelin-1-induced cardiomyocyte hypertrophy."J.Biol.Chem.. 275. 15239-15245 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Saito,S.: "b-adrenergic pathway induces apoptosis through calcineurin activation in cardiac myocytes."J.Biol.Chem.. 275. 34528-34533 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Omori,N.: "Nuclear factor of activated T-cells/calcineurin pathway in microglia.Neurochem.Res."Neurochem.Res.. 25. 983-1066 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Siesjo,B.K.: "Mitochondrial dysfunction and maturation of brain damage after transient ischemia."Maturation Phenomenon in cerebral ischemia IV.Springer Velague U Ito (e.d.s). (in press).

    • Related Report
      2000 Annual Research Report
  • [Publications] Miyata,K.: "Brain derived neurotrophic factor/TrkB mediates the neuroprotective effect of cyclosporin A in forebrain ishecmia."Neuroscience. (in press).

    • Related Report
      2000 Annual Research Report
  • [Publications] Machida,K.: "inhibition of cytochrome c release in Fas-mediated signaling Pathway by Hepatitis C viral protein in transgenic mice liver."J.Biol.Chem.. (in press).

    • Related Report
      2000 Annual Research Report
  • [Publications] Siesjo,B.K.: "Triggering events in ischemic brain damage."Pittsburg meeting for brain ischemia 2000. (in press).

    • Related Report
      2000 Annual Research Report
  • [Publications] Keep,M.: "Immunosuppressant as a neuroprotectant mechanisms of ischemic brain damage."Springer Velague Amsterdam 2000. (in press).

    • Related Report
      2000 Annual Research Report
  • [Publications] Yoshimoto,T.: "CsA preserve phosphorylation of ser 437 and the 308 AKT in focal ischemia."Neurology of Disease 2000. (in press).

    • Related Report
      2000 Annual Research Report
  • [Publications] Uchino,H: "Differential Alteration of Immediate early Gene, c-fos, fos B, c-jun, jun B, jun D in the rat brain following transient forebrain ischemia."Brain Res.. (in press).

    • Related Report
      2000 Annual Research Report
  • [Publications] 芝崎太: "カルシニューリンの生理的機能ム新しい展開に向けて-"生化学学会雑誌. 72. 527-538 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 芝崎太: "カルシニューリンの新しい役割"医学の歩み. 193. 298 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 内野博之: "虚血性脳神経細胞死におけるカルシニューリンの分子機序ム虚血性神経細胞障害に対する新規治療法確立を目指して-"医学のあゆみ. 193. 955-960 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 下重美紀: "カルシニューリン/イムノフィィン情報伝達系を介する細胞死制御"医学の歩み. 193. 931-936 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 内野博之: "虚血性脳神経細胞死制御に関わるメカニズムの解明"実験医学. 118. 842-851 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 近藤英作: "臨床免疫(in press)"Bcl-2のアポトーシス阻止機構. (2000)

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      2000 Annual Research Report

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Published: 2000-04-01   Modified: 2016-04-21  

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