| Project/Area Number |
18K19748
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| Research Category |
Grant-in-Aid for Challenging Research (Exploratory)
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| Allocation Type | Multi-year Fund |
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| Review Section |
Medium-sized Section 59:Sports sciences, physical education, health sciences, and related fields
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| Research Institution | Kyushu University |
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Principal Investigator |
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| Project Period (FY) |
2018-06-29 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
Fiscal Year 2020: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2019: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
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| Keywords | セリン / 小児疾患 / Neu-Laxova症候群 / ミトコンドリア / エネルギー代謝 / アミノ酸代謝疾患 / 遺伝性代謝疾患 / PHGDH / インスリン/IGF / 遺伝性アミノ酸合成不全 / 電子伝達系 / 細胞死 / アミノ酸合成不全 / 神経変性 |
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| Outline of Final Research Achievements |
The purpose of this project is to elucidate the upstream mechanism of cell death induced by genetic serine deficiency at the molecular level focusing on mitochondrial alteration and metabolic dysregulation, especially energy failure. We observed that serine restriction caused extensive and marked quantitative changes in intracellular energy-producing metabolites, decreased mitochondrial function and quantity, and abnormal intracellular signaling related to glucose metabolism in normal fibroblasts. These findings indicate that Phgdh-dependent serine synthesis has an essential physiological function as a hub for overall cellular metabolism. By clarifying the linkage and interrelationship of changes at molecules and organella caused by serine deficiency, it will be possible to understand the pathobiological linkage between various diseases conditions and serine deficiency, which will contribute to the development of preventive and therapeutic treatment.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究の遂行により、細胞内でのセリン合成が、外部環境に影響を受けずにミトコンドリア機能を維持し、エネルギー代謝の恒常性を保つ代謝的ハブとしての不可欠な代謝生理機能を持つことを明らかにした。近年肝機能異常、アルツハイマー病や網膜変性疾患等の多様な疾患とセリンの減少や合成能低下との相関が指摘されている。今回細胞レベルで見いだしたセリン欠乏により惹起される各階層（分子、細胞内小器官、細胞形態）での変化について、相互関係と機序の詳細を今後明らかにすることで、多様な疾患とセリン合成不全の病態生理学的な連関が分子レベルで理解可能となり、それらの疾患予防や治療法の開発に資する知見の拡充が期待される。
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