| 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)
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| 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.
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