| Project/Area Number |
15390273
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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 |
Neurology
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| Research Institution | Okayama University |
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Principal Investigator |
ABE Koji Okayama University, Graduate school of Medicine, Dentistry and Pharmaceutical Sciences, Professor, 大学院・医歯薬学総合研究科, 教授 (20212540)
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| Co-Investigator(Kenkyū-buntansha) |
SHOJI Mikio Hirosaki University, Neurology, Professor, 医学部附属脳神経血管病態研究施設, 教授 (60171021)
NAGAI Makiko Okayama University, University Hospital of Medicine and Dentistry, Assistant professor, 医学部歯学部附属病院, 助手 (80420488)
HAYASHI Takeshi Okayama University, University Hospital of Medicine and Dentistry, Assistant Professor, 医学部歯学部附属病院, 助手 (40314679)
永野 功 岡山大学, 医学部・歯学部附属病院, 講師 (80335603)
永田 哲也 岡山大学, 医学部・歯学部附属病院, 助手 (50362976)
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| Project Period (FY) |
2003 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥12,100,000 (Direct Cost: ¥12,100,000)
Fiscal Year 2005: ¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2004: ¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2003: ¥5,300,000 (Direct Cost: ¥5,300,000)
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| Keywords | Amyotrophic lateral sclerosis / SOD1 / transgenic mice / intrathecal administration / IGF-1 / neurotrophic factor / hypoxia / ALS |
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| Research Abstract |
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder affecting motor neurons selectively. There is currently no effective pharmacological treatment for ALS. In a transgenic mouse model of ALS, we found that the intrathecal administration of insulin-like growth factor (IGF)- 1 improved motor performance, delayed the onset of clinical disease, and extended survival in the G93A transgenic mice. Furthermore, it increased the expression of phosphorylated Akt and ERK in spinal motor neurons, and partially prevented motor neuron loss in these mice. Then, we performed a double-blind clinical trial to assess the effect of intrathecal administration of IGF-1 on disease progression in patients with ALS. The high-dose treatment slowed a decline of motor functions of the ALS patients in total Norris and limb Norris scales, but not in bulbar Norris or vital capacity. The intrathecal administration of IGF-1 had a modest but significant beneficial effect in ALS patients without any serious adverse effects.
Vascular endothelial growth factor (VEGF) is reported to play a neuroprotective role through a VEGF receptor, fetal liver kinase-1 (Flk-1) in vitro. We showed that VEGF is mainly expressed in motor neuron, however, VEGF was hardly induced after hypoxia in G93A transgenic mice. We demonstrated that hypoxia plus the inhibiting the expression of Flk-1 using antisense oligodeoxynucleotides induced motor neuron loss in rat spinal cord, in which the activation of Akt and ERK was markedly inhibited. These results suggest that VEGF exerts its protective effect on motor neurons against hypoxia-induced toxicity by the Flk-1 receptor through the PI3-K/Akt and the MEK/ERK signaling pathways.
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