2000 Fiscal Year Final Research Report Summary
Elucidation of Molecular Mechanism of Muscle Degenaration using Developmental Biology Technique and development of therapeutics
| Project/Area Number |
10557065
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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 | 展開研究 |
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| Research Field |
Neurology
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| Research Institution | National Institute of Neuroscience, NCNP |
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Principal Investigator |
TAKEDA Shin'ichi Department of Molecular Therapy, National Institute of Neuroscience, Therapy NCNP, 神経研究所・遺伝子疾患治療研究部, 部長 (90171644)
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| Co-Investigator(Kenkyū-buntansha) |
SUZUKI Yuko Department of Molecular Therapy, National Institute of Neuroscience, NCNP, Section chief, 神経研究所・遺伝子疾患治療研究部, 室長(研究職)
HANAOKA Kazunori KITAZATO UNIVERSITY, National Institute of Neuroscience, NCNP, Professor, 大学理学部・分子発生, 教授 (40189577)
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| Project Period (FY) |
1998 – 2000
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| Keywords | merosin-deficient congenital muscular dystrophy / merosin / laminin α2 chain / dy^<3K> / dy^<3K>mice / laminin M chain / apoptosis / αdystroglycan / integrin |
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| Research Abstract |
Laminin-2(merosin), composed of α2, β1 and γ1 chains, is a major comnponent of skeletal muscle basal lamina. Murarions of the laminin α2 chain gene cause merosin-deficient congenital muscular dystrophy(MD-CMD). To clarify the molecular pathology of
Laminin-2(merosin), composed of α2, β1 and γ1 chains, is a major comnponent of skeletal muscle basal lamina. Murarions of the laminin α2 chain gene cause merosin-deficient congenital muscular dystrophy(MD-CMD). To clarify the molecular pathology of MD-CMD, we generated lamininarufα2 chain knock out mouse(dy^<3K>), where the expression of laminin α2 chain is completely absent. The dy^<3K>revealed typical phenotype of muscular dystrophy, therefore the mouse is accepted as an ideal model of MD-CMD at date. We precisely ezamined morphological changes of the sleletal muscle of dy^<3K>/dy^<3K>mice. On postnatal day 9(P9) a few fibers showed necrotic changes, but on P10 manuy necrotic fibers were seen. In this stage, Evans Blue dye IgG influx into muscle fibers were found along necrotic changes of muscle fibers. Several fibers began to regenerate on P11, nad numerous regenerating fibers appeared on P13. In this stage, canpase-3 antivation and TUNEL-posotive myonuclei were found in manyu regeneratin fibers. Dephosphorylation of Bad, which triggers apoptotic signaling cascade, was also detected, suggesting that the absence of laminin α2 chain results in apoptosis of early regfenerating fibers through the interruption of survival signal from the extracellular matrix. Imcomplete or abortive regenarating process. The mouse also showed incomplete myelination in peripheral nervous system and maturational abnomality in the immunne system.
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