| Project/Area Number |
14580742
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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 | Osaka University |
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Principal Investigator |
FUNAKOSHI Hiroshi Osaka University, Graduate School of Medicine, Associate Professor, 医学系研究科, 助教授 (40273685)
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| Co-Investigator(Kenkyū-buntansha) |
NAKAMURA Toshikazu Osaka University, Graduate School of Medicine, Professor, 医学系研究科, 教授 (00049397)
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| Project Period (FY) |
2002 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥4,100,000 (Direct Cost: ¥4,100,000)
Fiscal Year 2003: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2002: ¥2,500,000 (Direct Cost: ¥2,500,000)
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| Keywords | Neurodegenerative disease / HGF / c-Met / Neurotrophic / Amyotrophic lateral sclerosis (ALS) / Neurons / Glia / Transgenic mice / 肝細胞増殖因子(HGF) / HGF-like protein(HLP) / Ron / ミクログリア / 神経栄養因子 |
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| Research Abstract |
We previously indeitified that HGF and its family member, HGF-like protein (HLP)/MSP are novel neurotrophic factors for variety of neurons, such as cerebral cortex, hippocampus, midbrain dopaminergic, sensory, motor and sympathetic neurons. In the current study, we further investigated the roles of HGF and HLP in the nervous system, especially in neurodegenerative diseases. In addition, by generation and analyses of LIMK-2 KO mice, we found that LIM-kinase 2 play an important role in neuronal degenerative process.
(1) Roles of HGF in amyotrophic lateral sclerosis (ALS): Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive loss of motoneurons and degeneration of motor axons. We showed that overexpression of hepatocyte growth factor (HGF) in the nervous system attenuates motoneuron death and axonal degeneration and prolongs the life span of transgenic mice overexpressing mutated SOD1. HGF prevented induction of caspase-1 in motoneurons an
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d retained the levels of the glial-specific glutamate transporter (EAAT2/GLT1) in reactive astrocytes. We propose that HGF may be the first example of an endogenous growth factor that can alleviate the symptoms of ALS by direct neurotrophic activities on motoneurons and indirect activities on glial cells, presumably favoring a reduction in glutamatergic neurotoxicity.
(2) Roles of HLP/MSP in the nervous system: We previously reported that HLP act as a novel neurotrophic factor for chicken sensory neurons. Here we identified that Ron/HLP receptor is expressed in primary microglia and HLP accelerates microglial activities in vitro. Taken together with notion that HLP is neurotrophic, HLP may be one of the critical factor involving not only the protecting process of the neurodegeneration but also the degeneration and regeneration processes of the nervous system.
(3) Roles of LIMKase-2 (LIMK2) in the nervous system: By generation and analyses if LIMK2 deficient mice, we found that limk2 variants were differently expressed in hippocampal neurons and play important roles in neurodegenerative process of hippocampal neurons. Less
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