| Project/Area Number |
20K07016
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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 47030:Pharmaceutical hygiene and biochemistry-related
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| Research Institution | Aichi Gakuin University (2023)
Nagoya City University (2020-2022) |
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Principal Investigator |
TSUIJI Hitomi 愛知学院大学, 薬学部, 教授 (40455358)
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| Project Period (FY) |
2020-04-01 – 2024-03-31
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| Project Status |
Completed (Fiscal Year 2023)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2023: ¥390,000 (Direct Cost: ¥300,000、Indirect Cost: ¥90,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
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| Keywords | ALS / TDP-43 / FUS / Ataxin-2 / 筋萎縮性側索硬化症 / RNA結合タンパク質 |
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| Outline of Research at the Start |
筋萎縮側索硬化症ALSは、運動ニューロンの進行的変性とRNA結合タンパク質TDP-43またはFUSの蓄積を伴う神経難病であり、その神経細胞死にはRNA代謝異常が深く寄与する。私はこれまでに、ALS患者運動ニューロンでsurvival of motor neuron (SMN)の発現減少とそれに伴うRNA代謝異常が起きていることを見出した。本研究では、ALS患者由来のiPS運動ニューロンでSMN発現減少が再現されるか、SMN発現量の増加が運動ニューロン変性死を抑制できるかを検証する。これらの成果により新規なALS発症機構の解明と根治療法につながる医薬品の開発に発展することが期待できる。
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| Outline of Final Research Achievements |
Mutations in the RNA-binding protein FUS are observed in approximately 5% of familial ALS patients. In this study, we focused on FUS and Ataxin-2, aiming to elucidate the mechanisms of motor neuron degeneration mediated by these proteins. We generated ALS model mice expressing mutant FUS. The mutant FUS transgenic mice exhibited ALS-like symptoms such as weight loss, decreased survival rate, and neurological abnormalities. By crossing these mice with FUS knockout mice or Ataxin-2 knockout mice, we generated mice with a reduced level of nuclear FUS protein or Ataxin-2 protein. We observed an improvement in neurological abnormalities, as indicated by clasping behavior, in mice with a reduced level of nuclear FUS protein. While motor function deteriorated, there was an improvement in weight and survival rate of mice with a reduced level of Ataxin-2. These findings suggest that reducing the levels of FUS or Ataxin-2 may ameliorate ALS pathology in mutant FUS transgenic mice.
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| Academic Significance and Societal Importance of the Research Achievements |
筋萎縮性側索硬化症ALSは根治療法がない神経難病である。本研究により、FUSやAtaxin-2タンパク質量を減少させることがALS病態を改善する可能性が示唆された。
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