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Molecular mechanism of cerebral ischemia through Jak-Stat signaling

Research Project

Project/Area Number 16591444
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Cerebral neurosurgery
Research InstitutionEhime University

Principal Investigator

HATA Ryuji  Ehime University, School of Medicine, Associate Professor, 医学部, 助教授 (90258153)

Co-Investigator(Kenkyū-buntansha) OHNISHI Takanori  Ehime University, School of Medicine, Professor, 医学部, 教授 (70233210)
KUMON Yoshiaki  Ehime University, School of Medicine, Associate Professor, 医学部, 助教授 (80127894)
TANAKA Junya  Ehime University, School of Medicine, Professor, 医学部, 教授 (70217040)
Project Period (FY) 2004 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2005: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2004: ¥1,800,000 (Direct Cost: ¥1,800,000)
Keywordscerebral ischemia / cytokine / Stat3 / Neuronal death / apoptosis
Research Abstract

Introduction :
Cerebral ischemia induces the expression of a number of growth factors and cytokines that can protect neurons against ischemic brain injury. For example, ciliary neurotrophic factor (CNTF), epidermal growth factor (EGF) and interleukin-6 (IL-6) have been shown to promote Stat3 activation. These growth factors and cytokines can activate Janus protein tyrosine kinases (Jaks)/signal transducers and activators of transcription (Stat) pathways. Recently, we reported that Stat3 was activated following cerebral ischemia in mouse [1]. However, little is known about the function of activated Stat3 in the ischemic brain. Here we demonstrate the increased expression of activated Stat3 promotes cell death in cultured astrocyres.
Methods & Results :
Astrocytes from the forebrains of newborn rats were cultured. Recombinant adenovirus expressing Stat3 wild type (St3.Wt), Stat3 dominant negative type (St3.DN) and LacZ were constructed as described previously [2]. Astocytes were exposed to … More adenovirus vector expressing Stat3.Wt, Stat3.DN or LacZ (multiplicity of infection 10) for 2h and incubated with a virus free fresh medium up to 72h. Three days later, inoculation with the virus vectors expressing St3.wt and St3.DN remarkably induced Stat3 protein compared with the control (LacZ). Western blots also revealed that Ad.St3.wt remarkably induced p-Stat3(Tyr-705) while Ad.St3.DN and Ad.LacZ did not. These results demonstrated that both Ad.St3.Wt and Ad.St3.DN induced Stat3 protein in cultured astrocytes and that only Ad.St3.Wt could phosphorylate Stat3 at Tyr-705 site and activate Stat3. LDH assay revealed that overexpression of St3.wt promoted cell death while overexpression of St3.DN and LacZ did not. In addition, caspase-3 like activity of the St3.Wt treated group was significantly increased than that of the St3.DN group at 2d after virus inoculation.
Conclusion :
We have shown that over-expression of Stat3 promotes cell death in cultured astrocytes, and activation of caspase-3 activity may be involved in this cell death mechanism. These data have revealed that activation of Stat3 can play a crucial role in the mechanism of ischemic cell death.
References :
[1]Wen et al. ; Neurosci Lett, 303:153-156, (2001)
[2]Nakajima et al. ; EMBO J, 15:3651-58 (1996) Less

Report

(3 results)
  • 2005 Annual Research Report   Final Research Report Summary
  • 2004 Annual Research Report
  • Research Products

    (15 results)

All 2005 2004 Other

All Journal Article (15 results)

  • [Journal Article] suppression of Stat3 promotes neurogenesis in cultured neural stem cells.2005

    • Author(s)
      Gu F, Hata R, Ma YJ, Tanaka J, Mitsuda N, Kumo Y, Hanakawa Y, Hashimoto K, Nakajima K, Sakanaka M
    • Journal Title

      J Neurosci Res. 86

      Pages: 163-171

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Neural stem cells suppress the hearing threshold shift caused by cochlear ischemia.2005

    • Author(s)
      Hakuba N, Hata R, Morizane I, Feng G, Shimizu Y, Fujita K, Yoshida T, Sakanaka M, Gyo K
    • Journal Title

      Neuroreport 16

      Pages: 1545-1549

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Annual Research Report 2005 Final Research Report Summary
  • [Journal Article] Identification of hippocampus-related candidate genes for Alzheimer's disease.2005

    • Author(s)
      Taguchi K, Yamagata HD, Zhong W, Kamino K, Akatsu H, Hata R, Yamamoto T, Kosaka K, Takeo M, Kondo I, Miki T
    • Journal Title

      Ann Neurol 57

      Pages: 585-588

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Neural stem cells suppress the hearing threshold shift caused by cochlear ischemia.2005

    • Author(s)
      Hakuba N, Hata R, Morizane I, Feng G, Shimizu Y, Fujita K, Yoshida T, Sakanaka M, Gyo K.
    • Journal Title

      Neuroreport 16

      Pages: 1545-1549

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Suppression of Stat3 promotes neurogenesis in cultured neural stem cells.2005

    • Author(s)
      Gu F, Hata R, Ma YJ, Tanaka J, Mitsuda N, Kumon Y, Hanakawa Y, Hashimoto K, Nakajima K, Sakanaka M.
    • Journal Title

      Neurosci Res. 86

      Pages: 163-171

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Identification of hippocampus-related candidate genes for Alzheimer's disease.2005

    • Author(s)
      Taguchi K, Yamagata HD, Zhong W, Kamino K, Akatsu H, Hata R, Yamamoto T, Kosaka K, Takeda M, Kondo I, Miki T.
    • Journal Title

      Ann Neurol. 57

      Pages: 585-588

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Suppression of Stat3 promotes neurogenesis in cultured neural star cells.2005

    • Author(s)
      Gu F, Hata R, Ma YJ, Tanaka J, Mitsuda N, Kumon Y, Hanakawa Y, Hashimoto K, Nakajima K, Sakanaka M.
    • Journal Title

      J Neurosci Res. 86

      Pages: 163-171

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Identification of hippocampus-related candidate genes for Alzheimer's disease.2005

    • Author(s)
      Taguchi K, Yamagata HD, Zhong W, Kamino K, Akatsu H, Hata R, Yamamoto T, Kosaka K, Takeda M, Kondo I, Miki T.
    • Journal Title

      Ann Neurol 57

      Pages: 585-588

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Possible inhibition of focal cerebral ischemia by angiotensin II type 2 receptor stimulation2004

    • Author(s)
      Iwai, M, Liu H.W., Chen R., Ide A., Okamoto S., Hata R., Sakanaka M., Shiuchi T., Horiuchi M
    • Journal Title

      Circulation 110

      Pages: 843-8

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Protective effect of vitamin E against focal brain ischemia and neuronal death through induction of target genes of hypoxia-inducible factor-12004

    • Author(s)
      Zhang, B., Tanaka J., Yang L., Sakanaka M., Hata R., Maeda N., Mitsuda N.
    • Journal Title

      Neuroscience 126

      Pages: 433-40

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Protective effect of vitamin E against focal brain ischemia and neuronal death through induction of target genes of hypoxia-inducible factor-12004

    • Author(s)
      Zhang, B., Tanaka J., Yang L., Sakanaka M., Hata R., bMaeda N., Mitsuda N.
    • Journal Title

      Neuroscience 126

      Pages: 433-440

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Possible inhibition of focal cerebral ischemia by angiotensin 11 type 2 receptor stimulation2004

    • Author(s)
      Iwai, M., Liu H.W., Chen R., Ide A., Okamoto S., Hata R., Sakanaka M., Shiuchi T., Horiuchi M.
    • Journal Title

      Circulation 110

      Pages: 843-848

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Possible inhibition of focal cerebral ischemia by angiotensin II type 2 receptor stimulation2004

    • Author(s)
      Iwai, M., Liu H.W., Chen R., Ide A., Okamoto S., Hata R., Sakanaka M., Shiuchi T., Horiuchi M
    • Journal Title

      Circulation 110

      Pages: 843-848

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Protective effect of vitamin E against focal brain ischemia and neuronal death through induction of target genes of hypoxia-inducible factor-12004

    • Author(s)
      Zhang, B., Tanaka J., Yang L., Sakanaka M., Hata R., Maeda N., Mitsuda N
    • Journal Title

      Neuroscience 126

      Pages: 433-440

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Prevention of ischemic neuronal death by intravenous infusion of a ginseng saponin, ginsenoside Rb(1), that upregulates Bcl-x(L) expression.

    • Author(s)
      Zhang B, Hata R, Zhu P, Sato K, Wen TC, Yan L, Fujita H, Mitsuda N, Tanaka J, Samukawa K, Maeda N, Sakanaka M
    • Journal Title

      J Cereb Blood Flow Metab (In press)

    • Related Report
      2005 Annual Research Report

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Published: 2004-04-01   Modified: 2016-04-21  

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