細胞膜情報交換系の構造、機能解析と個体レベルでの役割

• 研究課題/領域番号: 09273105
• 研究種目: 特定領域研究(A)
• 配分区分: 補助金
• 研究機関: 京都大学
• 研究代表者: 市川 厚 京都大学, 薬学研究科, 教授 (10025695)
• 研究分担者: 門松 健治 名古屋大学, 医学部, 助教授 (80204519) ; 藤井 穂高 東京大学, 医学系研究科, 助手 (30302665) ; 佐藤 公道 京都大学, 薬学研究科, 教授 (80025709) ; 芳賀 達也 東京大学, 医学係研究科, 教授 (30011646) ; 牛首 文隆 旭川医科大学, 医学部, 教授 (50243035) ; 宮崎 忠昭 東京大学, 医学部, 助手 (60272431)
• 研究期間 (年度): 1998
• 研究課題ステータス: 完了 (1998年度)
• 配分額: 115,900千円 (直接経費: 115,900千円); 1998年度: 44,900千円 (直接経費: 44,900千円); 1997年度: 71,000千円 (直接経費: 71,000千円)
• キーワード: 情報伝達 / プロスタグランジン受容体 / オピオイド受容体 / G蛋白共役型受容体 / インターロイキン2受容体 / ミッドカイン / ペイシジン / 自己免疫性疾患 / ミドカイン / ベイシジン / 自己免疫生疾患

研究概要

以下のような研究成果を得た。
(1) 細胞膜受容体のリガンド結合ドメインと機能ドメインの解析:PGE受容体では、EP3のC末端鎖と第7膜貫通領域のそれぞれにG蛋白活性化ドメインを(市川)、また、IP/DPの細胞外領域と第1,3,4膜貫通領域のそれぞれに、PGの5員環構造と側鎖構造を認識するドメインを同定した(牛首)。PGの生体作用を検索するため、7種類のPG受容体の遺伝子欠損マウスを作製し、フェノタイプを解析中である(市川・牛首)。PGI合成酵素の遺伝子欠損マウスは強度の腎障害を起こすことを見出した(田辺)。
(2)orphanの細胞膜受容体に対するリガンドの解析:オピオイド受容体/nociceptin受容体の段階的な点変異キメラ受容体を用いたorphan受容体のリカンド探索系を(佐藤)、また、ムスカリン受容体m1-m5サブタイプの選択的なアゴニスト、及びアゴニスト作用を促進するアロステリックリガンドの評価系を確立した(芳賀)。
(3) インターロイキン2(IL-2)受容体の細胞増殖シグナル:Jak PTKsの下流でのシグナル伝達にStat経路とは別の.Pyk2経路を同定し、それらの情報伝達を介するリンパ球分化、及び増殖シグナルの経路を解明した(藤井・宮崎)。
(4) ミッドカイン・ベイシジンの生理機能:ミッドカインは細胞のトランスフォーム能、海馬歯状回の発達、新生内膜形成に、一方、ベイシジンは両性の生殖生理、特に妊娠の必須因子であることを発見した。また、ベイシジンには記憶学習、匂いに対する反応性等の機能的神経ネットワーク形成作用のあることが判明した(門松)。
(5) 自己免疫性脳脊髄炎の調節:本疾患のモデルマウスを用い、疾患の標的相ではNK細胞が、また、誘導相ではNKT細胞が関与していることを見出し、両細胞の働きを制御する薬物を合成した(田平)。

研究成果

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