| Project/Area Number |
17K16285
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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 |
Pediatrics
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| Research Institution | Kurume University |
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Principal Investigator |
FUKUI KAORI 久留米大学, 医学部, 助教 (50771193)
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| Project Period (FY) |
2017-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
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| Keywords | 高アンモニア血症 / グルタミノリシス / α-ケトグルタル酸 / ジメチルα-ケトグルタル酸 / 尿素サイクル異常症 / α-ケトクグルタル酸 / 尿素サイクル酵素欠損症 / mTORC1 / オートファジー / グルタミン酸脱水酵素１ / グルタミン分解 |
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| Outline of Final Research Achievements |
Patients with urea cycle disorders intermittently develop episodes of decompensation with hyperammonemia. Because such an episode is often associated with starvation, we attempted to elucidate the mechanism of such starvation-associated hyperammonemia. Using a cell culture system, we found that glucose starvation increases ammonia production, and that it is associated with enhanced glutaminolysis. These results led us to focus on α-ketoglutarate (AKG), a glutamate dehydrogenase inhibitor and a major anaplerotic metabolite. We found that dimethyl αketoglutarate (DKG), a cell-permeable AKG analog, mitigates ammonia production primarily by reducing glutaminolytic flux. We also verified that DKG reduces ammonia also in in vivo animal models. Thus, AKG itself or cell-permeable forms of AKG are feasible candidates for a novel hyperammonemia treatment.
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| Academic Significance and Societal Importance of the Research Achievements |
高アンモニア血症の治療法は現在、産生されたアンモニアを除去することが主体となっている。いっぽう我々は飢餓と高アンモニア血症の関係に注目し、アンモニア産生の抑制に重点をおいて研究を行った。その結果、飢餓により亢進したグルタミノリシスを抑制し、かつTCAサイクルへの基質補充を行うことで、高アンモニア血症を是正できることを示した。これは高アンモニア血症の新奇、かつ現実的な治療戦略となりうる。
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