Regulation of cancer and aging by FoxO and investigation of compounds for regulation of FoxO
| Project/Area Number |
15H04682
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Environmental physiology(including physical medicine and nutritional physiology)
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| Research Institution | Nagasaki University |
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Principal Investigator |
SHIMOKAWA Isao 長崎大学, 医歯薬学総合研究科(医学系), 教授 (70187475)
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| Co-Investigator(Kenkyū-buntansha) |
森 亮一 長崎大学, 医歯薬学総合研究科(医学系), 准教授 (30509310)
朴 盛浚 長崎大学, 医歯薬学総合研究科(医学系), 助教 (60635853)
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| Research Collaborator |
KOMATSU Toshimitsu
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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 |
¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000)
Fiscal Year 2018: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
Fiscal Year 2017: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
Fiscal Year 2016: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2015: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000)
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| Keywords | 老化 / カロリー制限 / FoxO転写因子 / 癌 / フォークヘッド転写因子 / カロリー制限模倣剤 / 発達・成長・老化 / ミトコンドリア |
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| Outline of Final Research Achievements |
To elucidate the differential roles of FoxO1 and 3 in inhibition of cancer and extension of lifespan by calorie restriction (CR), we focused on mitochondria functions and metabolism in Foxo1+/- and Foxo3+/- mice. Oxygen consumption rates in the state 3 of mitochondria isolated from liver tissues were greater in Foxo3+/- CR mice than in WT CR mice at 24 months of age (mo). The mitochondrial membrane potential was also elevated in Foxo3+/- CR mice. A hepatic metabolome revealed that some metabolites in the glycolysis were significantly affected in Foxo3+/- CR mice. These findings suggest necessity of FoxO3 for inhibition by CR of aging-related declines in mitochondrial functions and metabolism. A carcinogen-induced hepatocellular carcinoma model suggests that FoxO3 is required for development of the tumor. Conditional knock-out of Foxo3 gene in the white adipose tissue and in the brain indicated that these tissues are not essential for the life-extending effect of CR.
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| Academic Significance and Societal Importance of the Research Achievements |
ヒトのFOXO3遺伝子多形と長寿の関連性が複数の集団で指摘されていた。CRによる寿命延伸に関わるFoxO3関連メカニズムを解明することは、ヒトの健康寿命の延伸メカニズムに迫ることができる点で、学術的、社会的意義は大きい。今後、アイソフォーム特異的活性化化合物を探索できれば、老化関連疾患の制御を目指す創薬に発展できる。
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Report
(5 results)
Research Products
(21 results)
