| Project/Area Number |
18K07503
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 52020:Neurology-related
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| Research Institution | Yokohama City University |
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Principal Investigator |
DOI Hiroshi 横浜市立大学, 医学部, 准教授 (10326035)
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| Co-Investigator(Kenkyū-buntansha) |
竹内 英之 横浜市立大学, 医学部, 准教授 (30362213)
田中 章景 横浜市立大学, 医学研究科, 教授 (30378012)
國井 美紗子 横浜市立大学, 医学部, 助教 (80725200)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | spinocerebellar ataxia / mouse model / calcium channel / 脊髄小脳失調症 / 脊髄小脳変性症 / マウスモデル |
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| Outline of Final Research Achievements |
Mouse model (Cacna1g_R1723H_KI) with the R1723H variant in Cacna1g corresponding to the R1715H variant of CACNA1G, which is responsible for spinocerebellar ataxia type 42 (SCA42), were developed by genome editing using CRISPR / Cas9. Behavioral analysis confirmed that both heterozygous and homozygous knock-in mice showed ataxia on the rotarod and footprint tests. Pathologically, degeneration of Purkinje cells (PCs) was observed at week 50 in both heterozygous and homozygous knock-in mice. Electrophysiological analysis of the PC revealed a positive shift in the current-voltage curve and a reduced frequency of rebound firing in homozygous knock-in mice. Therefore, we conclude that the SCA42 model has been established. Furthermore, oral administration of T-type VGCC modifier showed improvement in ataxia and PC neurodegeneration in heterozygous knock-in mice.
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| Academic Significance and Societal Importance of the Research Achievements |
SCA分野においては、現時点で有効な疾患修飾治療が存在しない。SCA42自体は希少疾患であるが、本研究ではSCA42の症状を再現するモデルの開発に成功し、チャネル機能修飾治療により失調症状、神経変性が抑制されることを示唆する所見が得た。この結果は、SCAの新たな疾患修飾治療の可能性を示したものと考えられる。
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