| Project/Area Number |
17K09582
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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 |
Cardiovascular medicine
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| Research Institution | Kyushu University |
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Principal Investigator |
Ide Tomomi 九州大学, 医学研究院, 准教授 (90380625)
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| Co-Investigator(Kenkyū-buntansha) |
池田 昌隆 九州大学, 医学研究院, 学術研究員 (10567382)
山田 健一 九州大学, 薬学研究院, 教授 (60346806)
筒井 裕之 九州大学, 医学研究院, 教授 (70264017)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | 心筋症 / 心不全 / 薬剤性心筋症 / 抗がん剤 / ミトコンドリア / フェロトーシス / 脂質ラジカル / 脂質過酸化 / 脂質 / ラジカル |
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| Outline of Final Research Achievements |
Doxorubicin (DOX) induces cardiotoxicity and has a poor prognosis, but its molecular mechanism has not been elucidated. In this study, DIC revealed that expression of GPx4 was suppressed at both the mRNA and protein level in mitochondria and was caused by lipid radical and lipid peroxide accumulation. These cardiac disorders were ameliorated in GPx4 overexpressing mice and exacerbated in GPx4 heterozygous mice, upstream of which was associated with a decrease in GPX4, which is also a regulator of ferrotosis.
We also showed that DOX induces excessive lipid peroxidation via mitochondrial DOX-Fe2 + complex and causes mitochondrial-dependent ferrocytosis, which is a major cause of DOX cardiotoxicity.
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| Academic Significance and Societal Importance of the Research Achievements |
増え続ける癌患者に対してドキソルビシンは以前有効な薬剤の1つとして広く用いられているが、その副作用である心毒性の機序は明らかではなかった。今回、DOX心筋症が、ミトコンドリアにおけるフェロトーシスであることを明らかにし、今後DOX誘発性心筋症の新たな治療ターゲットとなりうることを示すことができた。脂質ラジカル可視化剤によるスクリーニングに展開する予定である。
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