Development of novel therapy for heart failure targeting the crosstalk between amino acid and nucleotide metabolism
Project/Area Number |
20K08452
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Review Section |
Basic Section 53020:Cardiology-related
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Research Institution | Sapporo Medical University |
Principal Investigator |
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Co-Investigator(Kenkyū-buntansha) |
久野 篤史 札幌医科大学, 医学部, 教授 (30468079)
矢野 俊之 札幌医科大学, 医学部, 講師 (40444913)
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Project Period (FY) |
2020-04-01 – 2023-03-31
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Project Status |
Completed (Fiscal Year 2022)
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Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2021: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
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Keywords | 心不全 / 糖尿病 / 心筋代謝 / 核酸 / アミノ酸 / AMP deaminase / 分岐鎖アミノ酸 / BCKDH / 代謝 |
Outline of Research at the Start |
近年、心不全とアミノ酸代謝異常の関連が報告されている。申請者らは、核酸分解の律速酵素であるAMP deaminase(AMPD)3が糖尿病心筋で増加し、ATP欠乏から心不全発症に寄与することを報告した。AMPD3は骨格筋においてアミノ酸代謝を制御している。本研究では心筋におけるアミノ酸代謝の分子機構と、その制御異常の心不全病態形成における役割を、特に核酸代謝との連関に注目して解明する。
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Outline of Final Research Achievements |
We discovered that BCKDH, a rate-limiting enzyme in branched-chain amino acid metabolism, localizes not only to mitochondria but also outside mitochondria in cardiomyocytes and that AMPD3, a rate-limiting enzyme in the purine nucleotide cycle, regulates its activity. Furthermore, we found that the imbalanced expression of BCKDH and AMPD3 occurs in diabetic myocardium, which may contribute to impaired energy metabolism in diabetic hearts.
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Academic Significance and Societal Importance of the Research Achievements |
心不全の病態形成において、BCAA代謝不全の関与が近年示唆されているが、その分子機序は明らかでない。本研究で見出した心筋細胞におけるBCAA代謝の新たな制御機構は、BCAA代謝を標的とした心不全の新規治療法の開発に寄与する可能性がある。高齢化社会を背景に心不全は増加の一途をたどり、治療法の限られた予後不良な疾患である。心不全の発症や重症化を予防する治療法の開発を目指した研究は、社会的意義も大きい。
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Report
(4 results)
Research Products
(25 results)
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[Journal Article] Adenosine monophosphate deaminase in the endoplasmic reticulum-mitochondria interface promotes mitochondrial Ca2+ overload in type 2 diabetes rat hearts2023
Author(s)
Osanami A, Sato T, Toda Y, Shimizu M, Kuno A, Kouzu H, Yano T, Ohwada W, Ogawa T, Miura T, Tanno M.
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Journal Title
J Diabetes Investig
Volume: 14
Issue: 4
Pages: 560-569
DOI
Related Report
Peer Reviewed / Open Access
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[Presentation] Downregulation of BCKDH activity and uncoupling from AMP deaminase underlie substrate inflexibility in type 2 diabetic hearts2023
Author(s)
Ogawa T, Kouzu H, Osanami A, Shimizu M, Toda Y, Ohwada W, Sato T, Yano T, Kuno A, Tanno M, Miura T, Furuhashi M
Organizer
第87回日本循環器学会学術集会
Related Report
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[Presentation] 糖尿病合併心不全における血漿分枝鎖アミノ酸の規定因子と予後予測能の検討2022
Author(s)
神津 英至, 片野 唆敏, 大堀 克彦, 長岡 凌平, 沼澤 瞭, 小山 雅之, 永野 伸卓, 藤戸 健史, 大和田 渉, 佐藤 達也, 矢野 俊之
Organizer
第65回日本糖尿病学会年次学術集会
Related Report
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[Presentation] Novel Role of Cardiac AMP Deaminase in Extramitochondrial BCAA Metabolism: A Potential Therapeutic Target for Lipotoxicity in Diabetic Hearts2022
Author(s)
Ogawa T, Kouzu H, Osanami A, Tatekoshi Y, Kuno A, Fujita Y, Ino S, Shimizu M, Toda Y, Ohwada W, Sato T, Yano T, Miura T, Tanno M.
Organizer
第86回 日本循環器学会 学術集会
Related Report
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[Presentation] Plasma 3-methylhistidine Predicts the Impact of Renin-angiotensin System Inhibition on Skeletal Muscle Preservation in Heart Failure Patients2022
Author(s)
Kouzu H, Katano S, Ohori K, Nagaoka R, Numazawa R, Koyama M, Nagano N, Fujito T, Ohwada W, Nishikawa R, Yano T
Organizer
第86回 日本循環器学会 学術集会
Related Report
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[Presentation] Intracellular localization of AMP deaminase and its novel role in BCAA and lipid metabolism in diabetic cardiomyopathy.2021
Author(s)
Ogawa T, Kouzu H, Osanami A, Tatekoshi Y, Oshima H, Mizuno M, Kuno A, Fujita Y, Ino S, Shimizu M, Ohwada W, Sato T, Yano T, Tanno M, Miura T.
Organizer
ESC congress(国際学会)
Related Report
Int'l Joint Research
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[Presentation] Novel role of AMP deaminase in cardiac branched-chain amino acid metabolism: A potential therapeutic target for diabetic cardiomyopathy.2021
Author(s)
Ogawa T, Kouzu H, Osanami A, Tatekoshi Y, Mizuno M, Kuno A, Fujita Y, Ino S, Shimizu M, Ohwada W, Sato T, Yano T, Miura T, Tanno M.
Organizer
第25回 日本心不全学会 学術集会
Related Report
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[Presentation] Novel regulation of cardiac branched-chain amino acid metabolism through AMP deaminase: A possible therapeutic target for diabetic cardiomyopathy2021
Author(s)
Ogawa T, Kouzu H, Osanami A, Tatekoshi Y, Mizuno M, Kuno A, Sugawara H, Fujita Y, Ino S, Ohwada W, Sato T, Yano T, Moniwa N, Tanno M, Miura T.
Organizer
第85回 日本循環器学会年次学術集会
Related Report
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[Presentation] Plasma valine-to-glycine ratio is a novel prognostic maker for adverse events in patients with heart failure.2020
Author(s)
Kouzu H, Katano S, Yano T, Ohori K, Honma S, Shimomura K, Inoue T, Takamura Y, Takahashi R, Nishikawa R, Nagano N, Koyama M, Fujito T, Hashimoto A, Miura T.
Organizer
第84回 日本循環器学会年次学術集会
Related Report
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[Presentation] Novel regulation of cardiac branched-chain amino acid metabolism through AMP deaminase: A possible therapeutic target for diabetic cardiomyopathy.2020
Author(s)
Ogawa T, Kouzu H, Tatekoshi Y, Osanami A, Oshima H, Mizuno M, Kuno A, Igaki Y, Sugawara H, Fujita Y, Sato T, Yano T, Tanno M, Miki T, Miura T.
Organizer
ESC congress
Related Report
Int'l Joint Research
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[Presentation] Prognostic role of plasma amino acid profile in patients with chronic heart failure.2020
Author(s)
Kouzu H, Katano S, Yano T, Ohori K, Honma S, Shimomura K, Inoue T, Takamura Y, Takahashi R, Nishikawa R, Nagano N, Koyama M, Fujito T, Hashimoto A, Miura T.
Organizer
第 24 回 日本心不全学会学術集会
Related Report
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