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Genome-wide expression analysis of ischemic neuronal injury based on functional genomics and proteomics

Research Project

Project/Area Number 13307042
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Cerebral neurosurgery
Research InstitutionThe University of Tokyo

Principal Investigator

KIRINO Takaaki  The University of Tokyo, Faculty of Medicine, Professor, 医学部附属病院, 教授 (90126045)

Co-Investigator(Kenkyū-buntansha) HAMAKUBO Takao  The University of Tokyo, Research Center for Advanced Science and Technology, Professor, 先端科学技術研究センター・分子生物医学部門, 教授 (90198789)
ABURATANI Hiroyuki  The University of Tokyo, Research Center for Advanced Science and Technology, Professor, 先端科学技術研究センター・ゲノムサイエンス部門, 教授 (10202657)
KAWAHARA Nobutaka  The University of Tokyo, Faculty of Medicine, Associate Professor, 医学部附属病院, 助教授 (60214673)
浜窪 隆雄  東京大学, 先端科学技術研究センター, 教授 (90198797)
豊田 富勝  厚生年金病院, 医長(研究職) (00251257)
Project Period (FY) 2001 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥51,870,000 (Direct Cost: ¥39,900,000、Indirect Cost: ¥11,970,000)
Fiscal Year 2003: ¥12,870,000 (Direct Cost: ¥9,900,000、Indirect Cost: ¥2,970,000)
Fiscal Year 2002: ¥16,120,000 (Direct Cost: ¥12,400,000、Indirect Cost: ¥3,720,000)
Fiscal Year 2001: ¥22,880,000 (Direct Cost: ¥17,600,000、Indirect Cost: ¥5,280,000)
KeywordsCerebral ischemia / Hippocampus / Delayed neuronal death / Ischemic Tolerance / mRNA Expression Analysis / Stress Protein / MAP kinase / Apoptosis / 遺伝子発現情報解析 / プロテオミクス
Research Abstract

Transient cerebral ischemia causes selective and delayed neuronal death in the vulnerable hippocampal CA1 region. Various studies have provided evidence that cerebral ischemia induces transcriptional activation of a variety of genes, particularly those related to stress response, cell death or survival, suggesting a close relationship with neuronal ischemic vulnerability. Recent advances in DNA microarray technology have provided tools to analyze the expression of thousands of genes in a single hybridization experiment. Employing these techonogies, genome-wide gene expression analysis of the hippocampal CA1 region was conducted in a rat global ischemia model for delayed neuronal death and induced ischemic tolerance using an oligonucleotide-based DNA microarray containing 8,799 probes.
The results showed that expression levels of 246 transcripts were increased and 213 were decreased following ischemia, corresponding to 5.1% of the represented probe sets. These changes were divided into seven expression clusters using hierarchical cluster analysis, each with distinct conditions and time-specific patterns. Ischemic tolerance was associated with transient up-regulation of transcription factors (c-Fos, JunB Egr-1,-2,-4, NGFI-B), Hsp70 and MAP kinase cascaderelated genes (MKP-1), which are implicated cell survival. Delayed neuronal death exhibited complex long-lasting changes of expression, such as up-regulation of proapoptotic genes (GADD 153, Smad2, Dral, Caspase-2 and -3) and downregulation of genes implicated in survival signaling (MKK2, and PI4 kinase, DAG/PKC signaling pathways), suggesting an imbalance between death and survival signals.
Our study provides a differential gene expression profile between delayed neuronal death and induced ischemic tolerance in a genomewide analysis, and contributes to further understanding of the complex molecular pathophysiology in cerebral ischemia.

Report

(4 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • Research Products

    (17 results)

All Other

All Publications (17 results)

  • [Publications] Yonekura I, Kawahara N, Nakatomi H, Furuya K, Kirino T: "A model of global cerebral ischemia in C57 BL/6 mice"J Cereb Blood Flow Metab. 24(2). 151-158 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kawahara N, Wang Y, Mukasa A, Furuya K, Shimizu T, Hamakubo T, et al.: "Genome-wide gene expression analysis for induced ischemic tolerance and delayed neuronal death following transient global ischemia in rats"J Cereb Blood Flow Metab. 24(2). 212-223 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Furuya K, Kawahara N, Kawai K, Toyoda T, Maeda I, Kirino T: "Proximal occlusion of the middle cerebral artery in C57Black6 mice : relationship of patency of the posterior communicating artery, infarct evolution, and animal survival"J Neurosurg. 100. 97-105 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kirino T: "Ischemic Tolerance"J Cereb Blood Flow Metab. 22(11). 1283-1296 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Nakatomi H, Kuriu T, Okabe S, Yamamoto S, Hatano O, Kawahara N, Tamura A, Kirino T, Nakafuku M: "Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors"Cell. 110. 429-441 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Asai A, Tanahashi N, Qiu JH, Saito N, Chi S, Kawahara N, Tanaka K, Kirino T: "Selective proteasomal dysfunction in the hippocampal CA1 region after transient forebrain ischemia"J Cereb Blood Flow Metab. 22(6). 705-710 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kawahara N, Kawai K, Toyoda T, Nakatomi H, Furuya K, Kirino T: "Cardiac arrest cerebral ischemia model in mice failed to cause delayed neuronal death in the hippocampus"Neurosci Lett. 322. 91-94 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Yonekura I, Kawahara N, Nakatomi H, Furuya K, Kirino T: "A model of global cerebral ischemia in C57 BL/6 mice."J Cereb Blood Flow Metab. 24. 151-158 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kawahara N, Wang Y, Mukasa A, Furuya K, Shimizu T, Hamakubo T, Aburatani H, Kodama T, Kirino T: "Genome-wide gene expression analysis for induced ischemic tolerance and delayed neuronal death following transient global ischemia in rats."J Cereb Blood Flow Metab. 24. 212-223 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Furuya K, Kawahara N, Kawai K, Toyoda T, Maeda I, Kirino T: "Proximal occlusion of the middle cerebral artery in C57Black6 mice : relationship of patency of the posterior communicating artery, infarct evolution, and animal survival"J Neurosurg. 100. 97-1055 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kirino T: "Ischenic Tolerance"J Cereb Blood Flow Metal. 22. 1283-1296 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Nakatomi H, Kuriu T, Okabe S, Yamamoto S, Hatano O, Kawahara N, Tamura A, Kirino T, Nakafuku M: "Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors"Cell. 110. 429-441 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Asai A, Tanahashi N, Qiu JH, Saito N, Chi S, Kawahara N, Tanaka K, Kirino T: "Selective proteasomal dysfunction in the hippocampal CA1 region after transient forebrain ischemia"J Cereb Blood Flow Metab. 22. 705-710 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kawahara N, Kawai K, Toyoda T, Nakatomi H, Furuya K, Kirino T: "Cardiac arrest cerebral ischemia model in mice failed to cause delayed neuronal death in the hippocampus"Neurosci Lett.. 322. 91-94 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Yonekura I, Kawahara N, Nakatomi H, Furuya K, Kirino T: "A model of global cerebral ischemia in C57 BL/6 mice"J Cereb Blood Flow Metab. 24(2). 151-158 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kawahara N, Wang Y, Mukasa A, et al.: "Genome-wide gene expression analysis for induced ischemic tolerance and delayed neuronal death following transient global ischemia in rat"J Cereb Blood Flow Metab. 24(2). 212-223 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Furuya K, Kawahara N, Kawai K, Toyoda T, Maeda I, Kirino T: "Proximal occlusion of the middle cerebral artery in C57Black6 mice : relationship of patency of the posterior communicating artery, infarct evolution, and animal survival"J Neurosurg. 100. 97-105 (2004)

    • Related Report
      2003 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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