血液細胞の分化と機能発現の制御機構の解明

• Project/Area Number: 08265204
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas (A)
• Allocation Type: Single-year Grants
• Research Institution: University of Tsukuba
• Principal Investigator: 山本 雅之 筑波大学, 基礎医学系, 教授 (50166823)
• Co-Investigator(Kenkyū-buntansha): 高橋 智 筑波大学, 基礎医学系, 講師 (50271896) ; 峯岸 直子 東北大学, 医学部, 助手 (40271895)
• Project Period (FY): 1999
• Project Status: Completed (Fiscal Year 1999)
• Budget Amount: ¥39,800,000 (Direct Cost: ¥39,800,000); Fiscal Year 1999: ¥10,000,000 (Direct Cost: ¥10,000,000); Fiscal Year 1998: ¥10,000,000 (Direct Cost: ¥10,000,000); Fiscal Year 1997: ¥10,000,000 (Direct Cost: ¥10,000,000); Fiscal Year 1996: ¥9,800,000 (Direct Cost: ¥9,800,000)
• Keywords: 転写因子 / GATA-1 / GATA-2 / トランスジェニックマウス / ジーンターゲディング / 赤血球 / 巨核球 / 細胞分化 / NF-E2 / 造血幹細胞 / 遺伝子部分破壊マウス / 赤血球分化 / ノックアウトマウス / 転写制御 / Nrf2 / グルタチオンS-トランスフェラーゼ / ヘムオキシゲナーゼ / CNCファミリー

Research Abstract

a)GATA因子群の転写制御:GATA転写因子群の発現に対して行われている転写調節様式をトランスジェニックマウス系を用いて個体レベルで検討した.GATA-1,GATA-2のそれぞれの細胞系列(赤血球・巨核球・マスト細胞・好酸球)での発現に必要なシスエレメントの同定を行い,GATA-1の赤血球と巨核球における発現には,個別の制御領域が必要であることを明らかにした.
b)個体レベルでの転写因子蛋白質のドメイン解析:我々はGATA-1遺伝子の発現制御領域の解析を通じて,すでに赤血球系におけるGATA-1の発現に必要十分な制御領域を同定している.この制御領域を用いて,GATA-1蛋白質の各ドメインの機能を個体レベルで解析した.その結果,培養細胞レベルの解析で同定された転写活性化ドメインは,生体内における赤血球分化において必要ないことが明らかとなった.
c)個体レベルでのGATA因子群の機能解析:GATA転写因子群は良く保存されたDNA結合領域を有しており,それぞれの転写因子にどのような機能の違いが存在するかは,未だに明らかになっていない.そこで,上述のGATA-1発現制御領域を用いて,それぞれのGATA因子を同じ場所・タイミングでGATA-1欠損個体に発現させ,それによって引き起こされる表現型の違いを解析することにより,GATA因子間に存在する機能の類似性と特異性を明らかにすることを試みた.その結果,GATA-1欠損個体はGATA-2でも,GATA-3でもレスキューされることが明らかになった.一方,それらのレスキュー個体では,GATA-1でレスキューされた個体と比較して明らかな貧血があり,GATA-1とGATA-2,3とには明らかな機能的な違いも存在することが示唆された.

Research Products

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