| Project/Area Number |
17390391
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Cerebral neurosurgery
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| Research Institution | Gunma University |
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Principal Investigator |
ISHIUCHI Shogo Gunma University, School of Medicine, assistant Professor (10312878)
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| Co-Investigator(Kenkyū-buntansha) |
OZAWA Seiji Gunma University, 理事 (40049044)
SAITO Nobuhito The University of Tokyo, Hospital, Professor (60262002)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥15,900,000 (Direct Cost: ¥15,900,000)
Fiscal Year 2006: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2005: ¥14,200,000 (Direct Cost: ¥14,200,000)
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| Keywords | glioblastoma / invasive growth / signal transduction / glutamate / AMPA antagonists |
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| Research Abstract |
Evidence has accumulated that glioblastoma cells release and exploit glutamate for proliferation and migration by autocrine or paracrine loops.
Ca^<2+>-permeable-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-type glutamate receptors are important role for the invasive growth of human glioblastomas. Here we show that Ca^<2+> signaling mediated by AMPA receptors regulates the growth and motility of glioblastoma cells via activation of Akt. Ca^<2+> supplied through Ca^<2+>-permeable AMPA receptors phosphorylated Akt at Ser-473, thereby facilitating proliferation and mobility. A dominant negative form of Akt inhibited proliferation and migration accelerated by overexpression of Ca^<2+>-permeable AMPA receptors. In contrast, introduction of a constitutively active form of Akt rescued tumor cells from apoptosis induced by the conversion of Ca^<2+>-permeable AMPA receptors to Ca^<2+>-impermeable receptors by the delivery of GluR2 cDNA.
Therefore, Akt functions as a downstream effector for Ca^<2+>-signaling mediated by AMPA receptors in glioblastoma cells. Glutamate released by glioma cells is involved in Akt activity through Ca^<2+>-permeable AMPA receptors and the activation of Glutamate-AMPA-Akt pathway contributes to the high degree of anaplasia and invasive growth of human glioblastoma. Thus this novel pathway might give alternative therapeutic target.
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