Molecular mechanism of autophagy inhibition and cytotoxicity by silver nanoparticles
| Project/Area Number |
17K15856
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Hygiene and public health
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| Research Institution | Tokyo Women's Medical University |
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Principal Investigator |
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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 |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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| Keywords | 銀ナノ粒子 / オートファジー / リソソーム / 肺がん細胞 / 初代培養細胞 / 肺気道上皮細胞 / 肺胞上皮細胞 / ヒト肺胞上皮細胞 / ヒト肺気道上皮細胞 / TFEB / pH / V-ATPase / LC3B-II / p62/SQSTM1 / ナノ材料 / 社会医学 / 環境分析 / 細胞・組織 / 薬学 |
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| Outline of Final Research Achievements |
Although silver nanoparticles (AgNPs) are widely expected in nano medicine, the mechanism by which AgNPs cause pulmonary damage is unclear. In cells exposed to citrate-coated 60-nm AgNPs, confocal laser microscopic examination showed a decrease in the LysoTracker fluorescence signal and an increase in that of Cyto-ID, indicating lysosomal pH alkalization and autophagosome formation, respectively. The proteins p62 and microtubule-associated protein light chain 3B-II (LC3B-II) are both degraded by autophagy, and their levels increased depending on AgNP dose. Furthermore, AgNP-induced increase in LC3B-II was not enhanced by treatment with the autophagic inhibitor bafilomycin A1. TFEB mRNA levels, and protein levels in cytosolic and nuclear fractions, were suppressed by exposure to AgNPs, suggesting transcriptional inhibition of TFEB expression. The present study suggests that AgNP-induced lysosomal dysfunction plays a principal role in the autophagic flux defect.
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| Academic Significance and Societal Importance of the Research Achievements |
肺を構成するあらゆる細胞種において、銀ナノ粒子の応答は共通に保存されていたことから、確かな学術的証明を得た。一方で、銀ナノ粒子の毒性はTFEBの遺伝子発現調節のみでは解決できない新しい学術的問いを見出すこととなった。このことは、銀ナノ粒子の科学的エビデンスに基づいた創薬開発が、より一層波及すると期待される。また、他の金属ナノ粒子の創薬開発にも応用できるので、将来的に抗がん剤や抗病原微生物薬などの治療を受ける患者が恩恵を受けるのみならず、開発製造に関わる研究者や技術者へのナノ粒子曝露に対する健康リスクを確保することにもつながり、衛生学分野において学術的なインパクトが期待される。
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Report
(4 results)
Research Products
(9 results)
