| Project/Area Number |
15K06763
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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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| Research Field |
Nerve anatomy/Neuropathology
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| Research Institution | Kyorin University (2016-2018)
Tokyo Metropolitan Institute of Medical Science (2015) |
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Principal Investigator |
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| Project Period (FY) |
2015-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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| Keywords | 運動ニューロン / 筋萎縮性側索硬化症 / TDP-43 / FUS / 組換えウイルス / プロテアソーム / オートファジー / 熱ショック応答 / 凝集体 / HSF1 |
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| Outline of Final Research Achievements |
Formation of TDP-43- or FUS-positive cytoplasmic aggregates in neuronal and glial cells is one of the pathological hallmarks of amyotrophic lateral sclerosis (ALS). We have shown that inhibition of protein degradation pathways enhanced adenovirus-induced neuronal cytoplasmic aggregate formation of TDP-43 and FUS in vitro and in vivo. We also performed time-lapse imaging analysis of neuronal and glial cells infected with adenoviruses encoding TDP-43 under conditions of proteasome inhibition and demonstrated cytoplasmic aggregate formation, cell death, and cell to cell spreading of these aggregates. These TDP-43 aggregate formation was markedly suppressed by co-infection of an adenovirus expressing heat shock transcription factor 1 (HSF1), a master regulator of heat shock response. We then performed cDNA microarray analysis to identify candidate molecules locating downstream of HSF1 that counteract TDP-43 aggregate formation.
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| Academic Significance and Societal Importance of the Research Achievements |
ALSモデル動物として，これまで多数のTDP-43遺伝子改変マウス，ラットが報告されているが，ヒトALSの病態，特にTDP-43凝集体形成を忠実に反映したものは殆ど知られていない．我々は組換えウイルスを用いた独自の培養系および成体マウス・ラットTDP-43凝集体形成モデルを確立し，粗大なTDP-43凝集体が細胞死を惹起し細胞間を伝播することを培養タイムラプス解析で明らかにした．近年，熱ショック応答関連分子によるTDP-43凝集体形成抑制作用が報告されているが，いずれも明瞭な凝集体形成モデルではなく，他の未知の分子を含め臨床応用を考える上で我々の実験モデルによる詳細な検討が必要である．
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