| Project/Area Number |
15500253
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Neurochemistry/Neuropharmacology
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| Research Institution | Jichi Medical School School of Medicine (2004)
The University of Tokyo (2003) |
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Principal Investigator |
GOTOH Takaya Jichi Medical School, School of Medicine, Lecturer, 医学部, 講師 (80284355)
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| Co-Investigator(Kenkyū-buntansha) |
HATTORI Seisuke Tokyo University, Institute of Medical Science, Professor, 医科学研究所, 客員教授 (50143508)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2004: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2003: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Keywords | Ras / NMDA receptor / Neuronal Cell / Calcium Channel / Knock out Mouse / ヌクレオチド交換因子 |
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| Research Abstract |
Previous study showed Ras is key molecule and important player for learning and memory in the brain. However, the signaling pathway of Ras signals is still unclear. We analyzed the calcium and Ras signal pathway that works in the neuron. Last 2 years, we have focused and investigated potential dependent type calcium ion channel using reconstruction ion channel system on the neuronal cell membrane. And we have already reported Ras activator RasGRF1/2 works under calcium signals. Thus, we also analyze RasGRF1/2 function under the reconstruction system. During this study, the research group of the US and France reported the research result which RasGRF1 joins to the NR2B subunit of the Calcium coupled NMDA glutamate receptor (Neuron Vol.40,775-784). Based of these reports, we established the RasGRFs knock-out mouse for studying RasGRF1/2 function in the neuron. We analyzed the tissue slice and primary cell culture from the KO mouse brain and studied protein expression difference of signal molecules. RasGRF1 and RasGRF2 deficient mouse survive respectively. We additionally established RasGRF1/2 double deficient mouse for this study. The double deficient mouse also survived and the neurological development looked normal. Studies on lacking mice revealed that both RasGRF1and RasGRF2 couple NMDA receptors to the activation of the Ras/Erk signaling cascade and to the maintenance of CREB transcription factor activity in cortical neurons of adult mice. Consistent with this function for RasGRFs and the known neuroprotective effect of CREB activity, ischemia-induced CREB activation is reduced in the brains of adult RasGRFs knockout mice and neuronal damage is enhanced. We also found that NMDAs signal through SOS rather than RasGRF in cortical neurons of neonatal. These result imply that Ras-GRFs endow NMDARs with functions unique to mature neurons.
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