| Project/Area Number |
10557232
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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 |
医薬分子機能学
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| Research Institution | The University of Tokyo |
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Principal Investigator |
KIRINO Yutaka The University of Tokyo, Graduate School of Pharmaceutical Sciences, Professor, 大学院・薬学系研究科, 教授 (10012668)
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| Co-Investigator(Kenkyū-buntansha) |
KAWAKAMI Yoshiyuki Eisai Co., Ltd., Tsukuba Research Laboratories, Senior Scientist, 筑波探索研究所, 主幹研究員
WATANABE Satoshi The University of Tokyo, Graduate School of Pharmaceutical Sciences, Assistant Professor, 大学院・薬学系研究科, 助手 (80302610)
KAWAHARA Shigenori The University of Tokyo, Graduate School of Pharmaceutical Sciences, Assistant Professor, 大学院・薬学系研究科, 助手 (10204752)
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| Project Period (FY) |
1998 – 1999
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| Project Status |
Completed (Fiscal Year 1999)
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| Budget Amount *help |
¥13,500,000 (Direct Cost: ¥13,500,000)
Fiscal Year 1999: ¥3,900,000 (Direct Cost: ¥3,900,000)
Fiscal Year 1998: ¥9,600,000 (Direct Cost: ¥9,600,000)
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| Keywords | Neuromuscular Junction / Autoimmune Disease / Electric Ray / Electric Organ / Synaptosome / Monoclonal Antibody / CaィイD12+ィエD1 Channel / ランバート・イートン症候群 |
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| Research Abstract |
1. Development of LES animal model by immunization with electric organ synaptosomes. Mice immunized with synaptosomes isolated from the electric organ of Japanese electric ray displayed a symptom typical for the Lambert, Eaton Myasthenic Syndrome (LES) : a decrease in the quantal content of transmitter release was observed at the neuromuscular junction (NMJ) in the diaphragm from the immunized mice.
2. Development of LES animal model by passive immunization. Mice were passively immunized by injection of the serum from the actively immunized rabbits with synaptosomes. Again a decrease in the quantal content was observed, indicating that LES animal model was successfully generated.
3. Effect of the serum/IgG from IES patients to P-type Ca channels of SCLC cultured cells. The presence of P-type Ca channels of small cell lung carcinoma (SCLC) cells, which are a potential candidate for the auto-immunogen implicated in the etiology of LES, was examined by Ca imaging technique. About 20% of the cytoplasmic Ca increase induced by high KィイD1+ィエD1 stimulation was estimated to be due to P-type Ca channels as evidenced by the inhibition with a P-type specific inhibitor Agatoxin IVA. Then, the effect of LES serum to cytoplasmic Ca rise was examined but no significant inhibition was detected.
4. Effect of an acetylcholine esterase (ACE) inhibitor to the synaptic transmission at NMJ. An ACE inhibitor donepezil chloride, which is a sole effective drug for Alzheimer's disease now on market, increased the quantal content at the diaphragm NMJ. Furthermore, it was synergetic with 4-aminopyridine that is now the major medicine for LES but has a severe side effect.
5. Attempt to visualize internalization of P-type Ca channels with LES antibody. The down-regulation of P-type Ca channels with LES auto-antibody may be due to the internalization, which we attempted to visualize, if any. However, it was not successful so far.
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