The treatment strategy for HIBCH deficiency targeting mitochondrial dysfunction
| Project/Area Number |
15K09610
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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 |
Pediatrics
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| Research Institution | Institute for Developmental Research, Aichi Human Service Center |
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Principal Investigator |
Yamada Kenichiro 愛知県心身障害者コロニー発達障害研究所, 遺伝学部, 主任研究員 (30291173)
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| Project Period (FY) |
2015-04-01 – 2018-03-31
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| Project Status |
Completed (Fiscal Year 2017)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | HIBCH欠損症 / ミトコンドリア / バリン代謝 / グルタチオン |
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| Outline of Final Research Achievements |
In HIBCH deficiency, methacrylyl-CoA, an intermediate product of valine metabolism, accumulates in mitochondria of multiple tissues. Methacrylyl-CoA reacts with thiol compounds (e.g., cysteamine, cysteine and reduced glutathione (GSH)) and essential cysteine residues of mitochondrial enzymes, including multiple respiratory chain enzymes and pyruvate dehydrogenase complex, and reduces their activities. This leads to cell damage, especially in the basal ganglia, by dramatically decreasing the cellular reduction state and reducing ATP production. In this study, we analyzed patient’s lymphoblasts, and found that the survival rate of patient’s lymphoblasts decreased during culture with a low glucose medium. Using this condition, we evaluated the therapeutic effect (maintaining of the survival rate) of candidate drugs for HIBCH deficiency. We found that one candidate drug that increases intracellular GSH levels restored the survival rate of patient lymphoblasts.
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Report
(4 results)
Research Products
(23 results)
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[Journal Article] The effect of rapamycin, NVP-BEZ235, aspirin, and metformin on PI3K/AKT/mTOR signaling pathway of PIK3CA-related overgrowth spectrum (PROS).2017
Author(s)
Suzuki Y, Enokido Y, Yamada K, Inaba M, Kuwata K, Hanada N, Morishita T, Mizuno S, Wakamatsu N.
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Journal Title
Oncotarget
Volume: 8(28)
Issue: 28
Pages: 45470-45483
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Clinical, biochemical and metabolic characterisation of a mild form of human short-chain enoyl-CoA hydratase deficiency: significance of increased N-acetyl-S-(2-carboxypropyl)cysteine excretion2015
Author(s)
Yamada K, Aiba K, Kitaura Y, Kondo Y, Nomura N, Nakamura Y, Fukushi D, Murayama K, Shimomura Y, Pitt J, Yamaguchi S, Yokochi K, Wakamatsu N
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Journal Title
Journal of Medical Genetics
Volume: 52
Issue: 10
Pages: 691-698
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Presentation] Leigh disease and the valine pathway.2015
Author(s)
Pitt J, Peters H, Yaplito-Lee J, Boneh A, Ferdinandusse S, Ruiter J, Wanders RJA, Kok F, Boy R, Korman SH, Fitzsimons PE, Crushell E, Hughes J, Yamaguchi S, Goto Y, Wakamatsu N, Yamada K, Yokochi K, Chen BC, Ngu LH
Organizer
Annual Symposium 2015, Society for the Study of Inborn Errors of Metabolism
Place of Presentation
Lyon, France
Year and Date
2015-09-04
Related Report
Int'l Joint Research
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[Presentation] Clinical and biochemical characterization of patients with HIBCH deficiency.2015
Author(s)
Wakamatsu N, Yamada K, Naiki M, Hoshino S, Kitaura Y, Kondo Y, Nomura N, Kimura R, Fukushi D, Yamada Y, Shimozawa N, Yamaguchi S, Shimomura Y, Miura K
Organizer
第56回日本神経学会学術大会
Place of Presentation
新潟
Year and Date
2015-05-20
Related Report
