| Project/Area Number |
14570202
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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 |
Experimental pathology
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| Research Institution | Tokyo Women's Medical University |
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Principal Investigator |
SHIBATA Noriyuki Tokyo Wom.Med.Univ, Dept.of Pathol., Associate Prof., 医学部, 助教授 (90226176)
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| Co-Investigator(Kenkyū-buntansha) |
KATO Yoichiro Tokyo Wom.Med.Univ, Dept.of Pathol., Assistant, 医学部, 助手 (40233829)
KOBAYASH Makio Tokyo Wom.Med.Univ, Dept.of Pathol., Professor, 医学部, 教授 (80060086)
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| Project Period (FY) |
2002 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 2005: ¥400,000 (Direct Cost: ¥400,000)
Fiscal Year 2004: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 2003: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 2002: ¥1,100,000 (Direct Cost: ¥1,100,000)
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| Keywords | amyotrophic lateral sclerosis / superoxide dismutase / transgenic mice / oxidative stress / carbonyl stress / inflammation / glia / neuron / スーパーオキシドジスムターゼ / 炎症反応 / グリア反応 / 酸化的ストレス / プロスタグランジン / 15d-PGJ_2 / PPARγ / 蛋白糖酸化 / 脂質過酸化 / グルタミン酸トランスポーター |
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| Research Abstract |
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive amyotrophy and motor weakness. Recent investigations documented the involvement of oxidative stress and inflammatory reaction in ALS. In general, increased oxidative stress in aerobic life produces reactive aldehydes (carbonyls) during lipid peroxidation and protein glycoxidation, leading to activation of inflammatory cell signaling. The aim of this study was to determine whether carbonyl stress connecting oxidative stress with inflammation may occur actually in mice expressing a transgene for G93A mutant superoxide dismutase-1 (SOD1)-as a transgenic mouse model for ALS. Immunohistocehmical analysis on the spinal cord of G93A mice revealed that the determinants of protein-bound aldehydes derived from lipid peroxidation such as crotonaldehyde-lysine adduct (CRA-Lys) and protein glycoxidation such as N^E-(carboxymethyl)lysine, and pyrraline were localized in the cytoplasm of motor neurons and reactive glia, and that the density of immunoreactive glia increased in an age-dependent manner. CRA-Lys immunoreactivity was also detected in vacuolated motor neurons, spheroids, and cordlike swollen axons. The binding of the proinflammatory cytokines represented by tumor necrosis factor-α and Fas ligand to their respective receptors recruits Fas-associated death domain (FADD) toward the inner surface of the receptors. The cytosolic factor cFLIP transduces FADD-induced, caspase 8-mediated apoptosis signal to NF-κB-mediated inflammation. Reverse-transcription polymerase chain reaction (RT-PCR) and immunoblot analyses disclosed the upregulated expression of FADD mRNA and cFLIP protein, respectively. Our results suggest that in G93A mice, carbonyl stress gives rise to motor neuron death via glial inflammatory response.
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