Novel therapeutic strategy against hyperammonemia based on intervention in regulatory mechanism of bodily protein anabolism and catabolism
| 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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Report
(6 results)
Research Products
(7 results)
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[Presentation] A novel therapeutic strategy for hyperammonemia that targets glutaminolysis2021
Author(s)
Kaori Fukui, Tomoyuki Takahashi, Hitomi Matsunari, Ayuko Uchikura, Masahito Watanabe, Hiroshi Nagashima, Naotada Ishihara, Tatsuyuki Kakuma, Yoriko Watanabe, Yushiro Yamashita, Makoto Yoshino
Organizer
5th International Symposium on UREA CYCLE DISORDERS
Related Report
Int'l Joint Research
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