| Project/Area Number |
26893025
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| Research Category |
Grant-in-Aid for Research Activity Start-up
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| Allocation Type | Single-year Grants |
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| Research Field |
Cardiovascular medicine
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| Research Institution | Yamagata University |
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Principal Investigator |
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| Project Period (FY) |
2014-08-29 – 2016-03-31
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| Project Status |
Completed (Fiscal Year 2015)
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| Budget Amount *help |
¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2014: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | 酸化ストレス / ユビキチン / ITCH / 翻訳後修飾 / ユビキチン転移酵素 / 心筋梗塞 / ROS / Apoptosis / Myocardial infarction |
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| Outline of Final Research Achievements |
The HECT-Type ubiquitin E3 ligase ITCH is an enzyme that plays a pivotal role in posttranslational modification by ubiquitin proteasomal protein degradation. Thioredoxin-interacting protein (TXNIP) is a negative regulator of thioredoxin system. We focused on the functional role of ubiquitin E3 ligase ITCH and its interaction with TXNIP to elucidate the mechanism of cardiotoxicity induced by ROS. Protein interaction between TXNIP and ITCH was confirmed by immunoprecipitation assays. Overexpression of ITCH increased proteasomal TXNIP degradation and inhibited ROS generation, p38 MAPK, p53, and subsequent intrinsic pathway apoptosis in ROS-induced cardiotoxicity. We generated ITCH transgenic mouse. In ITCH-Tg mice, cardiac dysfunction and remodeling were restored compared with wild-type littermates after Dox injection and myocardial infarction surgery. ITCH targets TXNIP for ubiquitin-proteasome degradation and ameliorates ROS-induced cardiotoxicity through the thioredoxin system.
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