| Project/Area Number |
16K20153
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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 |
Urology
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| Research Institution | Nagoya City University |
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Principal Investigator |
UNNO rei 名古屋市立大学, 大学院医学研究科, 研究員 (40755683)
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| Research Collaborator |
YASUI takahiro
TOZAWA keiichi
OKADA atsushi
ANDO ryosuke
HAMAMOTO shuzo
TAGUCHI kazumi
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | 尿路結石 / オートファジー / 炎症 / 酸化ストレス / mTOR / 腎結石 / LC3 / p62 / オステオポンチン |
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| Outline of Final Research Achievements |
We found that autophagic activity was significantly decreased in mouse RTCs exposed to calcium oxalate (CaOx) monohydrate crystals and in the kidneys of GFPLC3B transgenic mice with CaOx nephrocalcinosis induced by glyoxylate. An impairment of autophagy was also observed in the mucosa with plaques of CaOx kidney stone formers. We determined that the decrease in autophagy was caused by an upregulation of MTOR, which consequently resulted in the suppression of the upstream autophagy regulator TFEB. Furthermore, we showed that an MTOR inhibitor could recover a decrease in autophagy and alleviate crystal-cell interactions and the formation of crystals associated with increased inflammatory responses. Taken together, we conclude that autophagy compromised by MTOR deregulation is a fundamental feature in the pathology of kidney stone formation, and propose that chemical inhibition of MTOR could be a prospective strategy for disease suppression.
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| Academic Significance and Societal Importance of the Research Achievements |
尿路結石は、全世界で有病率10%に達し、形成機序の解明と再発予防法の確立は急務である。今回、傷害を受けた細胞が自己を防御するために誘導するオートファジーに着目したところろ、尿路結石形成過程においてオートファジーが有意に低下することを見出した。さらに、オートファジー亢進による結石抑制効果を見出した。今回のオートファジーを介した新規尿路結石の治療は、無機物質の管理や、物理的な排石促進剤などの従来の結石治療とは全く違った着想である。生体内における恒常的な機能の活性化であり、自己修復能の亢進による結石治療という観点は世界初の試みであり、創造的である。
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