| Project/Area Number |
19K16911
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 51030:Pathophysiologic neuroscience-related
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| Research Institution | Nagoya University |
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Principal Investigator |
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| Project Period (FY) |
2019-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | 神経軸索再生 / MAPK経路 / 線虫 / axon regeneration / C. elegans / MAPK / CDK14 / Wnt / CDC-42 / EPHX-1 / JNK MAPK / TNS-1 / MXL-1 / TDPT-1 / SVH-2 / ETS-4 / JNK |
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| Outline of Research at the Start |
The proposed research attempts to clarify on a molecular level how injured neurons can regenerate their axons by using the well-established model for axon regeneration, the nematode Caenorhabditis elegans.
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| Outline of Final Research Achievements |
Understanding how neurons regenerate their damaged axons is an important research topic, expected to make a major contribution to finding efficient therapy for conditions such as spinal cord injury. We used the small worm C. elegans as a model organism to analyze the function and regulation of the MAPK pathway, shown previously to have a major role in regulation of axon regeneration in both humans and worms. We found that the transcription factor ETS-4, an important upstream activator of the MAPK pathway, is inhibited under normal conditions by SUMOylation by TDPT-1. Upon axon injury, another transcription factor, MXL-1, binds to TDPT-1, thereby protecting ETS-4 and allowing it to induce activation of the MAPK pathway to promote axon regeneration. Further analysis showed that MDL-1 usually prevents the binding of MXL-1 to TDPT-1, but the F-box protein SDZ-33 initiates the proteasomal degradation of MDL-1 upon axon injury to promote MAPK activity and axon regeneration.
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| Academic Significance and Societal Importance of the Research Achievements |
神経細胞の軸索が事故などで切断されると、感覚や運動障害の原因となる。これまでの研究から、神経細胞は切断された軸索を再生する潜在的な能力を持っており、その制御機構は線虫から人まで保存されていることが示唆されている。しかし、特に中枢神経の神経細胞は、普段この再生能力を発揮できないため、脊髄損傷の治療は極めて難しいとされている。神経軸索再生の分子メカニズムの解明は、脊髄損傷の治療方法の開発に繋がることが期待されている。
これまでに神経軸索再生においてMAPK経路は重要な働きを担うことが分かっていたが、その制御機構について不明な点が多く残されている。本研究は、MAPK経路の上流制御機構の一つを同定した。
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