Elucidation of Keap1/Nrf2-mediated control system of bone metabolism and application to in silico drug discovery
| Project/Area Number |
16K11480
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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 |
Functional basic dentistry
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| Research Institution | Nagasaki University |
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Principal Investigator |
SAKAI Eiko 長崎大学, 医歯薬学総合研究科(歯学系), 助教 (10176612)
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| Co-Investigator(Kenkyū-buntansha) |
筑波 隆幸 長崎大学, 医歯薬学総合研究科(歯学系), 教授 (30264055)
西下 一久 長崎大学, 医歯薬学総合研究科(歯学系), 助教 (20237697)
岡元 邦彰 長崎大学, 医歯薬学総合研究科(歯学系), 准教授 (10311846)
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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 |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2016: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
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| Keywords | 破骨細胞 / Keap1 / Nrf2 / 創薬 / osteoclast / NFATc1 / Osteoclast / MafB / IRF-8 / PGC-1beta / ミトコンドリア / 歯学 / 薬理学 / ストレス / 老化 / トランスレーショナルリサーチ |
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| Outline of Final Research Achievements |
We revealed that Nrf2 activation, which reduces oxidative stress, not only suppresses osteoclast differentiation, but also inhibits osteoblast differentiation. However, contrary to expectation, no remarkable abnormality of the skeleton was observed.Furthermore, we constructed Keap1/Nrf2 double knockout mice to determine whether the cause of marked suppression of osteoclast differentiation in Keap1 deficiency is due to constitutive activation of Nrf2.
As a result, it was revealed that the constitutive activation of Nrf2 raises the expression of MafB, a NFATc1 inhibitor molecule, and negatively regulates osteoclast differentiation.On the other hand, among 1360 kinds of synthetic compounds and marine microorganism-derived components, those having an osteoclast differentiation inhibitory effect at very low concentrations, or those activating Nrf2 were found.Administration of candidate compounds to pathological model mice and analysis of pathological conditions were conducted.
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| Academic Significance and Societal Importance of the Research Achievements |
酸化ストレスを減らすことは体にとって良いイメージがあるが、本研究によって、Nrf2の恒常的な活性化は、破骨細胞や骨芽細胞の分化を阻害し、必ずしも骨にとって有益なことばかりではないことが明らかになった。しかしNrf2をマイルドに活性化する化合物は、骨芽細胞分化を促進することも見出した。高齢化社会を迎え、日本の総人口の10％ 弱が骨粗鬆症といわれている。骨粗鬆症の第１選択薬であるビスフォスフォネート製剤に顎骨壊死の副作用が報告されてから、より安全な薬の開発が望まれている。本研究は新薬開発を目指した基礎的研究である。
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Report
(4 results)
Research Products
(16 results)
