| Project/Area Number |
17H04195
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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 | 一般 |
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| Research Field |
Neurology
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| Research Institution | Nagoya University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
橋詰 淳 名古屋大学, 医学部附属病院, 病院助教 (00637689)
井口 洋平 名古屋大学, 医学部附属病院, 助教 (80790659)
佐橋 健太郎 名古屋大学, 医学部附属病院, 病院助教 (90710103)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥16,770,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥3,870,000)
Fiscal Year 2019: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2017: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000)
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| Keywords | 運動ニューロン疾患 / エクソサイトーシス / インスリン / DNAメチル化 / Src / TDP-43 / アンドロゲン受容体 / カルシウムチャンネル / エクソサイト-シス / 運動ニューロン / 神経変性疾患 / 神経活動 / DREADD / エクソソーム / 後根神経節 |
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| Outline of Final Research Achievements |
Nuclear depletion of TDP-43 is the histopathological hallmark of amyotrophic lateral sclerosis. In this research, we showed that loss of TDP-43 inhibited exocytosis by down-regulating CaV1.2 calcium channels, thereby reducing early-phase insulin secretion. Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease caused by a CAG repeat expansion in the androgen receptor (AR) gene. In this research, we showed that DNA methyltransferase 1 is highly expressed in the motor neurons of an SBMA mouse model, and in patients with SBMA. Treatment with RG108, a DNA methylation inhibitor, ameliorated the viability of SBMA model cells and s the motor function of SBMA mice. We also found that the level of phosphorylated Src was markedly increased in the spinal cords and skeletal muscles of SBMA mice prior to the onset, by utilizing a phosphoprotein assay. Intraperitoneal administration of a Src kinase inhibitor improved the behavioral and histopathological phenotypes of SBMA mice.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究は、ニューロンが細胞外分泌などを介して行っている他の細胞との情報・分子伝達の異常が運動ニューロン疾患における神経・筋システム変性の基盤であるとの仮説に基づき、従来にはない画期的な視点で運動ニューロン疾患の病態の本質を明らかにした。この成果は運動ニューロン疾患の進行メカニズムの解明と、それに基づく予後予測や治療法の開発に直結するだけでなく、認知症を含む他の多くの神経変性疾患や筋疾患などの病態メカニズム研究に応用が可能である。
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