2001 Fiscal Year Final Research Report Summary
Aberrant intracellular signaling in the pathogenesis of muscular dystrophy
| Project/Area Number |
11470152
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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 | KAWASAKI MEDICAL SCHOOL |
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Principal Investigator |
SUNADA Yoshihide Kawasaki Medical School, Neurology, MD, 医学部, 教授 (00240713)
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| Co-Investigator(Kenkyū-buntansha) |
OHI Hiroaki Showa University, Pharmaceutical Science, PhD, 薬学部, 講師 (60194065)
OHSAWA Yutaka Kawasaki Medical School, Neurology, Professor, 医学部, 講師 (80246511)
MURAKAMI Tatsufumi Kawasaki Medical School, Neurology, Professor, 医学部, 助教授 (30330591)
MATSUMURA Kiichiro Teikyo University, Neurology, Professor, 医学部, 助教授 (50260922)
ARATA Satoru Showa University, Biotechnology, PhD, 薬学部, 講師 (20159502)
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| Project Period (FY) |
1999 – 2001
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| Keywords | muscular dystrophy / signal transduction / transgenic mouse / model animal / caveolin |
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| Research Abstract |
Caveolin is the principal component of caveolae microdomain in the plasma membrane and plays importantroles in modulating signal transduction. Recent studies demonstrated that mutations in the caveolin-3 gene, the muscle-specific caveolin isoform, cause several types of myopathy including limb-girdle muscular dystrophy (LGMD 1C). To understand the molecular mechanisms underlying muscle degeneration in caveolin-3 deficiency, we have been working on generation and characterization of the mutant (P104L) caveolin-3 transgenic (Tg) mice. Tg mice developed myopathic symptoms and skeletal muscle pathology showed myopathic changes with decreased density of caveolae in the plasma membrane. Surprisingly numerous rimmed vacuoles were observed. Overexpression of the mutant caveolin-3 mRNA resulted in deficiency of the caveolin-3 protein, which implicates a dominant negative effect of the mutation. We demonstrated a significant increase of nNOS activity fhat may be involved in the pathogenesis. Gene expression profile analysis using DNA array technology revealed eight up-regulated genes including c-Jun, ubiquitin conjugate E2p, G-protein-coupled receptor 25, laminin (32, defender against apoptotic cell death (dad-1), etc. and four down-regulated genes including glucocorticoid receptor form A and TNF receptor 1.More interestingly, one of the up-regulated genes, dad-1 has the anti-apoptotic activity against apoptosis related to ER stress. These results suggest that caveolin-3 deficiency caused by a dominant negative effect leads to alteration in apoptotic signaling pathways and results in muscle degeneration.
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