造血細胞のシグナル伝達

• 研究課題/領域番号: 10181101
• 研究種目: 特定領域研究(A)
• 配分区分: 補助金
• 審査区分: 生物系
• 研究機関: 東京大学
• 研究代表者: 宮島 篤 東京大学, 分子細胞生物学研究所, 教授 (50135232)
• 研究分担者: 吉村 昭彦 九州大学, 生体防御医学研究所, 教授 (90182815) ; 田賀 哲也 熊本大学, 発生医学研究センター, 教授 (40192629) ; 福永 理己郎 大阪大学, 医学部, 助教授 (40189965) ; 金倉 譲 大阪大学, 医学部, 教授 (20177489) ; 横田 崇 金沢大学, 医学系研究科, 教授 (50134622) ; 小松 則夫 自治医科大学, 講師 (50186798)
• 研究期間 (年度): 1998 – 2001
• 研究課題ステータス: 完了 (2001年度)
• 配分額: 207,200千円 (直接経費: 207,200千円); 2001年度: 53,800千円 (直接経費: 53,800千円); 2000年度: 52,600千円 (直接経費: 52,600千円); 1999年度: 50,400千円 (直接経費: 50,400千円); 1998年度: 50,400千円 (直接経費: 50,400千円)
• キーワード: 造血因子 / サイトカイン / シグナル伝達 / 受容体 / キナーゼ / 転写因子 / 細胞増殖 / 細胞分化

研究概要

造血細胞の増殖分化に関わるシグナルリングについての本年度の主要な成果は以下のようである。
AGM領域で発生した造血幹細胞胎生肝臓での増幅をin vitroで再現し、長期の造血再構築能が発生段階が進むにつれて低下することを示した(宮島)。gp130欠損マウスマウスのAGM培養では、血球の出現がほぼ完全に抑制され、AGM内の背側大動脈に発現する分子としてendomucin-1を同定し、この分子が細胞接着阻害作用をもつことを見いだした(田賀)。c-Kitを介する細胞遊走シグナルやCa2+influxには、Y567/srcファミリーキナーゼ/p38MAPK経路とY719/PI3kinase経路の二経路が重要であることを明らかにした(金倉)。c-Kitに結合する新規分子Spredをクローニングし,細胞膜に局在し活性化されたRas, Rafと複合体を形成することで、チロシンキナーゼからのRas/MAKキナーゼ経路を選択的に阻害することを明らかにした(吉村)。Stat1とStat3の造血における機能を解析するために、抑制型Stat3トランスジェニックマウス、さらにStat1のKOマウスとの交配により、抑制型Stat3/Stat1 KOマウスを作製し、Stat3は巨核球系前駆細胞の増幅に、Stat1は赤芽球系前駆細胞の増幅に重要であることを示した(小松)。骨髄球特異的転写因子MZF-2に結合する核内因子を探索し,SWI2/SNF2型クロマチン再構成因子であるmDomino/p400を同定し,骨髄球分化に関わる遺伝子発現には,MZF-2とmDominoの相互作用によるクロマチン再構成が関与することを示唆した(福永)。新規Znフィンガータンパク質SalIのノックアウトマウスでは左右の腎臓が完全に欠失していた。胎生11.5日に尿管芽が間葉に進入して後腎の発生は開始するが、ノックアウトマウスではこの段階で発生が障害されており、この遺伝子は後腎発生のもっとも初期に必須であることが判明した。この遺伝子は腎臓未分化細胞である後腎間葉のみならず、神経幹細胞、ES細胞でも発現しており、共通の機構が幹細胞において働いている可能性が示唆された(横田)。

研究成果

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