| Project/Area Number |
14580745
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Neurochemistry/Neuropharmacology
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| Research Institution | Ehime University |
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Principal Investigator |
SHIGEMOTO Kazuhiro Ehime University, School of Medicine, Associate Professor, 医学部, 助教授 (40284400)
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| Co-Investigator(Kenkyū-buntansha) |
MARUYAM Naoki Tokyo Metropolitan Institute of Gerontology, Organ Disorder and Aging Research Group, Group leader, 分子病理部門, 研究部長 (00115940)
久保 幸穂 東京都老人総合研究所, 分子病理部門, 研究員 (00280769)
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| Project Period (FY) |
2002 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2003: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2002: ¥2,600,000 (Direct Cost: ¥2,600,000)
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| Keywords | MuSK / agrin / acetylcholine receptor / neuromuscular junction / myasthenia gravis / autoimmune disease / protein structure / Agrin |
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| Research Abstract |
We firstly identified anti-MuSK autoantibodies in generalized myasthenia gravis(MG) with detectable AChR autoantibodies(seropositive MG) and reported in Nurology(in press, 2004). Previously, Hoch et al. found a novel antigen, MuSK in MG without detectable AChR autoantibodies(seronegative MG) in 2001. Therefore we could provide a new scope for the functions of MuSK and the molecular pathogenesis of generalized MG caused by the MuSK autoaintibodies.
Next we could produce the MuSK autoantibodies by immunization of MuSK proteins in rabbits in which a MG-like muscular weakness had been induced. We then found clear-cut evidence that these MuSK antibodies specifically inhibited the AChR clustering response to all known stimuli including those of the agrin-independent pathways. Agrin induces AChR clustering by activation of MuSK, whereas agrin-independent stimuli did not. That is, the MuSK autoantibodies rigorously inhibited AChR clustering mediated by multiple pathways, an outcome that broadens general comprehension of MG's pathogenesis(submitted for publication in 2004).
Finally, we prepared a large amount of MuSK protein for the analysis of protein structure. We are now screening the optimal conditions for the crystallization to analyze the structure using a synchrotron(Spring-8) in Harima-riken. In addition, we are now analyzing MuSK-lacZ-knock-in mice to elucidate the MuSK functions in the organisms.
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