| Project/Area Number |
15590917
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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 |
Neurology
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| Research Institution | Kansai Medical University |
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Principal Investigator |
ITO Hidefumi Kansai Medical University, Faculty of Medicine, Associate Professor, 医学部, 助教授 (20250061)
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| Co-Investigator(Kenkyū-buntansha) |
KUSAKA Hirofumi Kansai Medical University, Faculty of Medicine, Professor, 医学部, 教授 (70250066)
NISHIZAWA Mikio Kansai Medical University, Faculty of Medicine, Assistant Professor, 医学部, 講師 (40192687)
ITO Seiji Kansai Medical University, Faculty of Medicine, Professor, 医学部, 教授 (80201325)
NAKANO Satoshi Kansai Medical University, Faculty of Medicine, Assistant Professor, 医学部, 講師 (30333206)
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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 |
¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 2004: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2003: ¥1,200,000 (Direct Cost: ¥1,200,000)
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| Keywords | ALS / transgenic mouse / ER stress / GRP78 / nucleocytoplasmic transport / importin / IBM-BMT / edaravone / SOD1 / iNOS / SREBP-2 / β-catenin / amyotrophic lateral sclerosis / MAP kinase / JNK pathway / karyopherin |
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| Research Abstract |
1.We found the immunohistochemical colocalization of endoplasmic reticulum (ER) chaperone, glucose regulated protein 78 (GRP78), with the mutant SOD1 within Lewy body-like hyaline inclusions (LBHIs) in the lumbar spinal cord from G93A transgenic mice. The immunoreactivity was distributed diffusely within LBHIs, and was positive even in those of their earliest emergence, suggesting that GRP78 would be related to LBHI formation.
2.We found the reduced immunoreactivity of nucleocytoplasmic transport-related proteins such as importin beta, importin alpha, histone H1, and beta-catenin, in the nucleus of the remaining anterior horn cells of the transgenic mice. Moreover, we demonstrated the abnormal accumulations of these proteins in the cytoplasm of these cells and in LBHIs. Our results suggest that dysfunction of the nucleocytoplasmic transport would be involved in the pathomechanisms of the transgenic mice.
3.We found the statistically significant suppressive effect of edaravone, one of the free radical scavengers, on the clinical disease progression of G93A SOD1 transgenic mice. Pathologically, the number of the remaining anterior horn cells was found to be proportional to the daily dose of edaravone. Furthermore, the 3-nitrotyrosine/tyrosine ratio, which reflects the extent of oxidative stress, in the spinal cord homogenates was lower in the edaravone-administered transgenic mice than those of controls.
4.We found that intra bone marrow-bone marrow transplantation (IBM-BMT) from wild type mice to G93A transgenic mice ameliorated their decline of motor function. Pathological investigation of the recipients revealed that transplanted cells migrated into the spinal cords and a subset of these cells expressed Iba-1, a marker of microglia.
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