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KAKEN_17K09940seika.pdf
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Title |
Title |
ハイリスク造血器腫瘍の髄外病変に着目した新規ターゲットの探索と創薬研究
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ハイリスク ゾウケツキ シュヨウ ノ ズイガイ ビョウヘン ニ チャクモクシタ シンキ ターゲット ノ タンサク ト ソウヤク ケンキュウ
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Hairisuku zōketsuki shuyō no zuigai byōhen ni chakumokushita shinki tāgetto no tansaku to sōyaku kenkyū
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Molecular analysis and drug discovery targeting extramedullary disease in high-risk multiple myeloma
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服部, 豊
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ハットリ, ユタカ
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Hattori, Yutaka
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慶應義塾大学・薬学部 (芝共立) ・教授
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Research team head
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科研費研究者番号 : 20189575
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木内, 文之
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キウチ, フミユキ
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Romanization |
Kiuchi, Fumiyuki
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慶應義塾大学・薬学部 (芝共立) ・教授
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Research team member
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科研費研究者番号 : 60161402
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山田, 健人
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ヤマダ, タケト
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Yamada, Taketo
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埼玉医科大学・医学部・教授
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Research team member
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科研費研究者番号 : 60230463
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柳川, 弘志
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ヤナガワ, ヒロシ
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Yanagawa, Hiroshi
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慶應義塾大学・薬学部・教授
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Collaborator
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科研費研究者番号 : 40327672
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須藤, 豊
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ストウ, ユタカ
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Sutō, Yutaka
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高崎健康福祉大学・有機合成化学・准教授
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2020
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科学研究費補助金研究成果報告書
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2019
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本研究ではリプログラミング遺伝子Oct4が多発性骨髄腫細胞に過剰発現することを見出し、その強制発現細胞を樹立して下流シグナルの変化を検索した。Oct4強制発現細胞では間葉系遺伝子発現が増強しEMT様現象を誘導すること、MRP1トランスポーターが過剰発現し薬剤耐性化に関わることがわかった。
新規フタルイミド体TC11の最適化体PEG-TC11を開発し、in vivoにおける薬物動態と抗骨髄腫作用を確認した。PEG-TCは、サリドマイド類の標的分子cereblonには結合せず、α-tubulin、nucleophosmin -1に結合しp53非依存的にG2/M arrestを引き起こした。
In this project, we found overexpression of Oct4 gene in multiple myeloma (MM) cells and also established Oct4-overexpresed MM cell lines. In the overexpressed cells, expression of mesenchymal genes such as Snail was increased, and the EMT-like morphological change was observed. Expression of MRP1 transporter proteins was also increased, and Oct-4-overexpressed cells obtained the resistance to various anti-MM drugs.
We have also developed a novel phthalimide, TC11, and its optimized form, PEG-TC11. PEG-TC11 revealed strong growth inhibitory effects to MM cells in mice xenograft model. Even though TC11 and PEG-TC11 have structural similarity to thalidomide, they did not associated with the thalidomide-binding protein, cereblon, but with α-tubulin and nucleophosmin-1. By binding to α-tubulin and nucleophosmin-1, PEG-TC11 induced G2/M arrest without involvement of p53 and caused apoptosis of high-risk MM cells with p53 deletion.
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研究種目 : 基盤研究 (C) (一般)
研究期間 : 2017~2019
課題番号 : 17K09940
研究分野 : 血液内科学
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Mar 5, 2021 | | インデックス を変更 |
Nov 15, 2022 | | Creator Name,Creator Kana,Creator Romanization,Creator Affiliation,Creator Affiliation (Translated),Creator Role,Creator Link,Creator 著者ID,Abstract 内容,Note 注記 を変更 |
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