| Project/Area Number |
15K10908
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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 |
Ophthalmology
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| Research Institution | St. Marianna University School of Medicine |
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Principal Investigator |
KITAOKA YASUSHI 聖マリアンナ医科大学, 医学部, 准教授 (10367352)
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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 |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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| Keywords | 視神経 / 緑内障 / 神経保護 / タクロリムス / NFATc / astrocyte / interleukin-1 / ROCK / sirtuin / autophagy / TNF / p62 / LC3 / オートファジー / 軸索変性 / NFAT / Beclin1 / チオレドキシン / 老化 / ＴＮＦ |
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| Outline of Final Research Achievements |
The study has been performed to investigate what molecules are involved in tumor necrosis factor (TNF)-mediated axonal degeneration. We found an upregulation of interleukin-1 beta in optic nerve after TNF injection and taht exogenous thioredoxin prevented this upregulation. Thioredoxin exerted substantial axonal protection. Next, we tested whether ROCK inhibitor alters autophagic status in optic nerve. Ripasudil, a ROCK inhibitor, upregulated autophagic status and exerted axonal protection. We also found an increase in autophagosomes inside axons. Lastly, we examined nuclear factor of activated T cells (NFATc), a downstream effector of CaN signaling. A significant increase in NFATc1 protein level was observed in optic nerve 7 days after TNF injection. This increase was negated by simultaneous administration of tacrolimus. The increased immunoreactivity was colocalized with glial fibrillary acidic protein. Treatment of tacrolimus significantly ameliorated the TNF-mediated axonal loss.
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| Academic Significance and Societal Importance of the Research Achievements |
緑内障とTNFの密接な関係は国内外で報告されている。まずinterleukin-1βが視神経変性に関与していることを示した。また眼圧下降作用により緑内障点眼として現在使用されているripasudilの新しい作用としてオートファジーを活性化することを見出した。また難治性アレルギー結膜炎で臨床で使用されているタクロリムス点眼が、緑内障などの視神経変性疾患に適応拡大できる可能性を示した。さらにNFATc1という新しい標的分子が治療の開発に役立つ可能性も示した。
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