| Project/Area Number |
17K08361
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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 |
Drug development chemistry
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| Research Institution | Tohoku University |
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Principal Investigator |
Hirano Ikuo 東北大学, 医学系研究科, 助教 (00708117)
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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 |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | Erythropoietin / GATA / Mitoxantrone / ESA / drug screening / erythropoietin / ハイスループットスクリーニング / GATA1 / 化合物スクリーニング / Anemia |
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| Outline of Final Research Achievements |
Anemia of renal disease is mainly due to deficient erythropoietin (EPO) that produced from the kidney. Recombinant human EPO treatment is the first choice of treatment of the renal anemia, but rhEPOs are very expensive and need intravenous administration. Our purpose of this study was finding the seeds of new erythropoiesis-stimulating agents that was inexpensive and oral administrative. We established reporter cell lines using mouse kidney collecting duct derived cell line (mIMCD). We done high throughput screening with the drug libraries, and identified several compounds as seeds of new ESA. One of them, Compound-A showed inducing activity of EPO gene expression in vitro (mIMCD, A549 and TFK-1) and in vivo (mouse lung). It is reported that Epo gene expression is negatively regulated in some epithelial cells by transcription factor GATA. The Compound-A maybe affects GATA factor binding to GATA motif located on Epo promoter region and induce ectopic expression of Epo gene.
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| Academic Significance and Societal Importance of the Research Achievements |
慢性腎臓病などの腎障害では、腎EPO産生が障害されることで生じる腎性貧血が問題となっている。現在はEPO製剤を用いた治療が主に行われているが、薬価が高く血中への投与が必須であるため、経口投与が可能な造血誘導剤の開発が進められている。EPO遺伝子のレギュレーターである低酸素誘導性因子HIFの誘導剤が臨床試験が行われているが、すでに腎EPO産生細胞が高度に障害された状態ではこれらの薬剤の効果は限定的であると考えられる。本研究で同定されたミトキサントロンは本来EPO産生能を持たない細胞におけるEpo遺伝子の転写誘導効果が認められており、将来的に重度に腎臓が障害された患者にも効果が期待できる。
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