| Project/Area Number |
09470156
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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 | Teikyo University |
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Principal Investigator |
SHIMIZU Teruo TEIKYO UNIVERSITY, DEPARTMENT OF NEUROLOGY, PROFESSOR, 医学部, 教授 (00107666)
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| Co-Investigator(Kenkyū-buntansha) |
OHI Hiroaki SHOWA UNIVERSITY, SCHOOL OF PHARMACRUTICAL SCIENCE, LECTURER, 薬学部, 講師 (60194065)
SUNADA Yoshihide KAWASAKI MEDICAL SCHOOL, DEPARTMENT OF NEUROLOGY, PROFESSOR, 医学部, 教授 (00240713)
MATSUMURA Kiichiro TEIKYO UNIVERSITY, DEPARTMENT OF NEUROLOGY, ASSOCIATE PROFESSOR, 医学部, 助教授 (50260922)
荒田 悟 昭和大学, 薬学部, 講師 (20159502)
斉藤 史明 帝京大学, 医学部, 助手 (40286993)
武田 伸一 国立精神神経センター神経研究所, 遺伝子工学研究部, 室長 (90171644)
鍋島 陽一 国立精神神経センター神経研究所, 遺伝子工学研究部, 部長 (60108024)
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| Project Period (FY) |
1997 – 1999
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| Project Status |
Completed (Fiscal Year 1999)
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| Budget Amount *help |
¥13,100,000 (Direct Cost: ¥13,100,000)
Fiscal Year 1999: ¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 1998: ¥4,800,000 (Direct Cost: ¥4,800,000)
Fiscal Year 1997: ¥5,500,000 (Direct Cost: ¥5,500,000)
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| Keywords | muscular dystrophy / caveolin-3 / dystrophin / signal transduction / transgenic mouse / molecular engineering / 筋ジストロフィー / ジストロフィン結合蛋白 / カベオリン / 遺伝子ターゲティング / ノックアウトマウス |
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| Research Abstract |
Caveolin-3 is the muscle-specific isoform of the caveolin protein family, which is a major component of caveolae, small membrane invaginations found in most cell types. Caveolins play important roles in the formation of caveola membranes, acting as scaffolding proteins to organize and concentrate lipid-modified signaling molecules, and modulate a signaling pathway. For instance, caveolin-3 interacts with neuronal nitric-oxide synthase (nNOS) and inhibits its catalytic activity. Via the syntrophin-nNOS linkage, caveolin-3 also interacts with the dystroglycan complex, which is a major player of muscle cell adhesion to laminin. Recently, specific mutations in the caveolin-3 gene, including the Pro104Leu missense mutation, have been shown to cause an autosomal dominant limb-girdle muscular dystrophy (LGMD1C), which is characterized by the deficiency of caveolin-3 in the sarcolemma. However, the molecular mechanism by which these mutations cause the deficiency of caveolin-3 and muscle cell degeneration remains elusive. Here we generated transgenic mice expressing the Pro104Leu mutant caveolin-3. They showed severe myopathy accompanied by the deficiency of caveolin-3 in the sarcolemma, indicating a dominant negative effect of mutant caveolin-3. Interestingly, we found a great increase of nNOS activity in their skeletal muscle, which, we propose, may play a role in muscle fiber degeneration in caveolin-3.
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