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KAKEN_24591633seika.pdf
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Title |
Title |
メダカHRAS悪性黒色腫モデルを用いた薬剤スクリーニング系の構築
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メダカ HRAS アクセイ コクショクシュ モデル オ モチイタ ヤクザイ スクリーニングケイ ノ コウチク
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Medaka HRAS akusei kokushokushu moderu o mochiita yakuzai sukuriningukei no kochiku
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Establishment of transgenic HRAS medaka as a tumor model for in vivo drug screening
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松崎, ゆり子
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マツザキ, ユリコ
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Matsuzaki, Yuriko
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慶應義塾大学・医学部・助教
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Research team head
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科研費研究者番号 : 40255435
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佐谷, 秀行
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サヤ, ヒデユキ
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Saya, Hideyuki
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慶應義塾大学・医学部・教授
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Research team member
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科研費研究者番号 : 80264282
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2015
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科学研究費補助金研究成果報告書
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2014
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既に樹立したヒト癌遺伝子HRASの変異型導入メダカ系統を利用した新規抗癌化合物スクリーニングシステムの確立を目的とした。既存薬ライブラリーを用いた一次スクリーニングではゼブラフィッシュ胚の黒色素産生を減少させる35薬剤を取得し, 神経冠細胞系列遺伝子の発現低下を起こす7薬剤を候補とした。二次スクリーニングにおける薬剤投与試験の予備実験としていくつかのRASシグナル下流因子の阻害剤を水槽へ投与し, 変異型HRASメダカ個体への効果として生存期間の延長や腫瘍組織中の活性化タンパク質量の減少を確認できた。このシステムでHRAS高発現型腫瘍に効果のある薬剤をスクリーニングできると考えている。
We have previously reported a transgenic medaka strain expressing human HRAS mutant gene. Here, we further intend to establish a novel drug screening system using this medaka. In the first screen using our drug library, we obtained 35 drugs which could decrease pigmentation of zebrafish embryos. Seven out of 35 drugs were selected as candidate drugs because they had affected the downregulation of the gene for marker of embryonic neural crest progenitors. Before the second screening, we tried to validate the experimental system using the transgenic HRAS medaka. Inhibitors for downstream molecules of RAS signaling were administered to the HRAS medaka. Treatment with sorafenib, an inhibitor of Raf kinase, improved their survival, and Trametinib, an inhibitor of MEK, decreased the levels of phosphorylated ERK in the tumor tissue. The in vivo system presented here is promising to screen potential anticancer drugs.
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研究種目 : 基盤研究(C)
研究期間 : 2012~2014
課題番号 : 24591633
研究分野 : 腫瘍医学
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