| Project/Area Number |
07457154
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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 | Kanazawa University |
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Principal Investigator |
TAKAMORI Masaharu Kanazawa University, Faculty of Medicine Professor, 医学部・神経内科学講座, 教授 (60039815)
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| Co-Investigator(Kenkyū-buntansha) |
SAKAJIRI Kenichi Kanazawa University, Faculty of Medicine, Instructor, 医学部・付属病院・神経内科, 助手 (00283127)
YOSHIKAWA Hiroaki Kanazawa University, Faculty of Medicine, Instructor, 医学部・付属病院・神経内科, 助手 (10272981)
KOMAI Kiyonobu Kanazawa University, Faculty of Medicine, Instructor, 医学部・付属病院・神経内科, 助手 (90283126)
NITTA Eishun Kanazawa University, Faculty of Medicine, Assistant Professor, 医学部・神経内科学講座, 講師 (50251947)
坂戸 俊一 金沢大学, 医学部・附属病院・神経内科, 講師 (10142275)
井出 芳彦 金沢大学, 医学部・神経内科学講座, 助教授 (10100835)
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| Project Period (FY) |
1995 – 1997
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| Project Status |
Completed (Fiscal Year 1997)
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| Budget Amount *help |
¥6,800,000 (Direct Cost: ¥6,800,000)
Fiscal Year 1997: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 1996: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 1995: ¥3,500,000 (Direct Cost: ¥3,500,000)
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| Keywords | Lambert-Eaton myasthenic syndrome / Myasthenia gravis / Calcium channel / Acetylcholine / Ryanodine receptor / synaptotagmin / Autoimmunity / 抗原抗体反応 / 動物モデル / カルシウム・チャネル / シナプス小胞 |
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| Research Abstract |
(1) Lambert-Eaton myasthenic syndrome (LEMS) LEMS,often ssociated with small cell lung carcinoma (SCLC), impairs the quantal release of acetylcholine (ACh) by antibodies against voltage-gated calcium channel (VGCC) in the motor nerve terminal. We focused attention on the P/Q-type VGCC,against which a majority of LEMS patients carry the specific antibody. This type of VGCC expresses in the motor nerve terminal and also in SCLC.In search of antigenic sites in the P/Q-type VGCC molecular structure, we synthesized peptides corresponding to the extracellular region (S5-S6 linker) of each of the four domains that form the alpha1A subunit of VGCC and tested their antigenicity. In LEMS patients' sera, some were positive for anti-domain II,and the other were positive for anti-domain IV.Lewis rats immunized with domain II and III peptides, each being conjugated with KLH,showed such characteristic LEMS features as presence of antibodies to P/Q-type VGCC and reduced ACh quantal release. In additio
… More
n, the possible role of synaptotagmin, a Ca^<++> sensor for exocytosis of synaptic vesicles taking place prior to ACh release, in the pathogenesis of LEMS was studied. The peptide corresponging to the extracellular region of synaptotagmin was found antigenic for the induction of an animal model of LEMS.A proportion of human LEMS antibodies reacted with the recombinant synaptotagmin in immunoblot.
(2) Myasthenia gravis (MG) In MG in which muscle anti-ACh receptor antibodies play a crucial role, we focused attention on an additional impairment of excitation-contraction coupling in muscle, attributable to a defect caused by antibodies against ryanodine receptor (RyR). Many of MG patients with thymomas contained anti-RyR antibodies in serum ; these sera inhibited the calcium-induced release of calcium in response to caffeine in human muscle cell line. The Buffalo/Mna rat with spontaneous benign thymoma was shown as an animal model of impaired subcellular machineries in MG muscle as evidenced by RyR expressed in thymic epithelial cells, anti-RyR antibodies in serum and reduced contractile forces without abnormality in synaptic transmission and muscle membrane properties. Less
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