Epigenetic regulation of drug metabolism via RNA editing and microRNA
| Project/Area Number |
15H04663
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Medical pharmacy
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| Research Institution | Kanazawa University |
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Principal Investigator |
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| Research Collaborator |
NAKANO Masataka
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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 |
¥17,030,000 (Direct Cost: ¥13,100,000、Indirect Cost: ¥3,930,000)
Fiscal Year 2017: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2016: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000)
Fiscal Year 2015: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
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| Keywords | 薬物応答性 / 個人差 / 転写後調節 / RNA編集 / マイクロRNA / 薬物代謝 / 薬物動態 |
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| Outline of Final Research Achievements |
We found that there is a large interindividual variability in ADAR1 expression in the human liver. We identified multiple A-to-I RNA editing sites in the 3'-UTR of AhR mRNA in the human liver. Knockdown of ADAR1 by siRNA in hepatoma cells resulted in the increase of AhR protein and CYP1A1 induction. This phenomenon was owing to the fact that miR-378-dependent down-regulation of AhR was abolished by ADAR1 knockdown. Next, we found multiple A-to-I RNA editing sites in the 3'-UTR of DHFR mRNA in the human breast tissue. The knockdown of ADAR1 by siRNA in breast cancer cells resulted in the decrease of DHFR protein. That was due to the creation of binding sites of miR-25 and miR-125-3p. The decreased level of DHFR protein increased the response to methotrexate, an DHFR inhibitor which is used for treatment of cancers. In summary, we could demonstrate that A-to-I RNA editing post-transcriptionally regulates pharmacokinetics and pharmacodynamics.
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Report
(4 results)
Research Products
(17 results)
