獲得性生体情報の構築・応答ならびにその異常と病態の研究

• 研究課題/領域番号: 12CE2006
• 研究種目: 特別推進研究(COE)
• 配分区分: 補助金
• 研究機関: 京都大学
• 研究代表者: 本庶 佑 京都大学, 医学研究科, 教授 (80090504)
• 研究分担者: 中西 重忠 京都大学, 生命科学研究科, 教授 (20089105) ; 湊 長博 京都大学, 生命科学研究科, 教授 (40137716) ; 北 徹 京都大学, 医学研究科, 教授 (60161460)
• 研究期間 (年度): 2000 – 2004
• 研究課題ステータス: 完了 (2004年度)
• 配分額: 2,280,000千円 (直接経費: 1,950,000千円、間接経費: 330,000千円); 2004年度: 468,000千円 (直接経費: 360,000千円、間接経費: 108,000千円); 2003年度: 468,000千円 (直接経費: 360,000千円、間接経費: 108,000千円); 2002年度: 494,000千円 (直接経費: 380,000千円、間接経費: 114,000千円); 2001年度: 470,000千円 (直接経費: 470,000千円); 2000年度: 380,000千円 (直接経費: 380,000千円)
• キーワード: クラススイッチ / 体細胞突然変異 / AID / PD-1 / PD-L / IMCT法 / LDL受容体 / グルタミン酸受容体 / SPA-1 / パーキンソン / 立体構造

研究概要

本庶グループは、AIDの突然変異体を用いてAIDのN末端が体細胞突然変異に、C末端がクラススイッチ組換えに必要な機能特異的ドメインであることを証明した。一方、DNA deamination学説において、中心的な役割をすると考えられているウラシルDNAグリコシラーゼ(UNG)がDNAの切断には関与せず、この酵素の役割は酵素活性を通じてではなく、そのタンパク質として関与することを明かにした。一方、PD-1の自己免疫制御についてはPD-1欠失が自己免疫性糖尿病の発症を著しく促進し、この実験系を用いてNODマウスの糖尿病感受性遺伝子座の解析が可能であることを示した。
湊グループは、SPA-1 KOマウスの新しい病態形質として、抗DNA抗体・抗核抗体の産生とそれによる典型的なループス腎炎の発症を確認した。これは異常な自己反応性B1細胞の出現とその抗原特異的免役応答によるもので、構成的Rap1シグナルによる転写共因子OcaBの過剰発現による免疫グロブリンL鎖の編集(レセプター・エディション)異常に起因することが示された。レセプター・エディションの異常による自己免疫病の発症は従来、自己抗体遺伝子トランスジェニック・モデルを用いて精力的に研究が進められてきたが、今回の結果により、通常の動物のシグナル遺伝子変異によるレセプター・エディションの異常が確かにヒトのループスに相当する自己免疫病態に至りうることが示された。
中西グループは、グルタミン酸受容体と共役するイオン・チャンネル及び新たな足場蛋白質(GIRK・K+チャンネル、ubiquitin ligase、tamalin等)を明らかにし、これらの複合体形成がグルタミン酸伝達の制御に重要な役割を果たしていることを示した。さらに小脳発達期の顆粒細胞の増殖、移動、分化、シナプス形成にカルシニュリン・シグナル系が重要な役割を果たし、BDNFとCa2+シグナルの協調的作用がグルタミン酸系シナプス成熟に必須であることを示した。また、大脳皮質の構築を制御するCaja1-Retzius(CR)細胞の特異的遺伝子を同定し、CR細胞が細胞増殖、分化、シナプス成熟に特異性を持って作用していることを示した。
北グループは、彼らが同定した酸化LDL受容体LOX-1の血清濃度が急性冠症候群で上昇しており血清LOX-1値は急性冠症侯群の予知因子となる可能性を示した。北らが同定した別の酸化LDL受容体SR-PSOX(CXCL16と同一)は感染性心内膜炎等で心臓の弁内皮細胞に強発現しCD8T細胞のVCAM-1への接着を促進し、IFNγの産生を増加さることを発見した。GFP発現マウスの骨髄移植マウスで実験的動脈硬化を解析し血管平滑筋様細胞も含めて浸潤した多くの細胞が骨髄由来であることを見出した。アダプター蛋白ShcAがインテグリンβ3のチロシンリン酸化依存的に結合し、血小板凝集に重要であることを証明した。

研究成果

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• [文献書誌] Latchman,Y.,(中略)Nishimura,H.,Honji,T.,Sharpe,A.and Freeman,G.: "PD-L2, a novel B7 homologue, is a second ligand for PD-1 and inhibits T cell activation."Nature Immunol.. (in press). (2001)
• [文献書誌] Muramatsu,M.,and Honjo,T.: "Complex layers of genetic alteration in generation of antibody diversity."Immunol.Today. 22. 66-68 (2001)
• [文献書誌] Nishimura,H.,Tanaka,Y.,Okazaki,T.,Nakatani,K.,Hara,M.,Matsumori,A.,Sasayama,S.,Hiai,H.,Minato,N.,and Honjo,T.: "Autoimmune dilated cardiomyopathy in PD-1 receptor deficient mice."Science. 291. 319-322 (2001)
• [文献書誌] Tanigaki,K.,Nogaki,F.,Takahashi,J.,Tashiro,K.,Kurooka,H.,Honjo,T.: "Notch1 and Notch3 instructively restrict bFGF-responsive multipotent neural progenitor cells to an astroglial fate."Neuron. 29. 45-55 (2001)
• [文献書誌] Watanabe,N.,Ikuta,K.,Fagarasan,S.,Yazumi,S.,Chiba,T.,and Honji,T.: "Migration and differentiation of autoreactive B-1 cells induced by activated γ/δ T cells in antierythrocyte immunoglobulin transgenic mice."J.Exp.Med.. 192. 1577-1586 (2000)
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• [文献書誌] Revy,P.,(中略) Kinoshita,K.,Honjo,T.,Fischer,A.,and Durandy,A.: "Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper-IgM syndrome (HIGM2)."Cell. 102. 565-575 (2000)
• [文献書誌] Muramatsu,M.,Kinoshita,K.,Fagarasan,S.,Yamada,S.,Shinkai,Y.,and Honjo,T.: "Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing eazyme."Cell. 102. 553-563 (2000)
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• [文献書誌] Kurooka,H.and Honjo,T.: "Functional interaction between the mouse Notch1 intracellular region and histone acetyltransferases PCAF and GCN5."J.Biol.Chem.. 275. 17211-17220 (2000)
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• [文献書誌] Nishimura,H.,Honjo,T.,and Minato,N.: "Facilitation of b selection and modification of positive selection in the thymus of PD-1 deficient mice."J.Exp.Med.. 191. 891-897 (2000)
• [文献書誌] Miyagawa,F.,Tanaka,Y.,Yamashita,S.and Minato,N.: "Essential requirement of antigen presentation by monocyte-lineage cells for the activation of primary human γδ T cells by aminobisphosphonate antigen."J.Immunol. in press. (2001)
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• [文献書誌] Suga,K.,Katagiri,K.,Harazaki,M.,Kinashi,T.,Hattori,M.and Minato,N.: "CD98 induces LFA-1-mediated cell adhesion in lymphoid cells via activation of."FEBS Letters.. 489. 249-253 (2001)
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• [文献書誌] Korematsu,S.,Tanaka,Y.,Hosoi,S.,Koyanagi,S.,Yokota,T.,Mikami,B.and Minato,N.: "C8/119S Mutation of Major Mite Allergen Derf-2 Leads to Degenerate Secondary Structure and Molecular Polymerization, and Induces Potent and Exclusive Th1 Cell Differentiation."J.Immunol.. 165. 2895-2902 (2000)
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• [文献書誌] Morimoto,M.,Kume,N.,Miyamoto,S.,Ueno,Y.,Kataoka,H.,Minami,M.,Hayashida,K.,Hashimoto,N.and Kita,T: "Lysophosphatidylcholine induces Egr-1 expression and activates the core promoter of PDGF-A chain in vascular endothelial cells."Arterioscler.Thromb.Vasc.Biol.. (in press). (2001)
• [文献書誌] Kataoka,H.,Kume,N.,Miyamoto,S.,Minami,M.,Morimoto,M.,Hayashida,K.,Hashimoto,N.and Kita.T.: "Oxidized low density lipoprtoein (Ox-LDL) modulates Bax/Bcl-2 through lectin-like Ox-LDL receptor-1 in vascular smooth muscle cells."Arterioscler.Thromb.Vasc.Biol.. (in press). (2001)
• [文献書誌] Ashida,N.,Arai,H.,Yamasaki,M.and Kita,T.: "Distinct signaling pathways for MCP-1-dependent integrin activation and chemotaxis."J.Biol.Chem.. (in press). (2001)
• [文献書誌] Yamasaki,M.,Arai,H.,Ashida,N.,Ishii,K.and Kita,T.: "Monocyte chemoattractant protein-1 causes differential proline-rich tyrosin kinase 2-mediated signaling in THP-1 cells."Biochemical J.. (in press). (2001)
• [文献書誌] Nakatani,J.,Mizuseki,K.,Tsuda,H.,Nakanishi,S.and Sasai,Y.: "Xenopus Xenf : An early endodermal nuclear factor that is regulated in a pathway distinct from Sox17 and Mix-related gene pathways."Mech.Dev.. 91. 81-89 (2000)
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• [文献書誌] Takao,M.,Morigiwa,K.,Sasaki,H.,Miyoshi,T.,Shima,T.,Nakanishi,S.,Nagai,K.and Fukuda,Y.: "Impaired behavioral Suppression by light in the mGluR6-deficient mice."Neuroscience. 97. 779-787 (2000)
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• [文献書誌] Matsui,M.,Mizuseki,K.,Nakatani,J.,Nakanishi,S.and Sasai,Y.: "Xenopus Kielin : A dorsalizing factor containing multiple chordin-type repeats secreted from the embryonic midline."Proc.Natl.Acad.Sci.USA. 97. 5291-5296 (2000)
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• [文献書誌] Tomita,K.,Moriyoshi,K.,Nakanishi,S.,Guillmot,F.and Kageyama,R.: "Mammalian achaete-scute and atonal homologs regulate neuronal versus glial fate determination in the central nervous system."EMBO J.19:5460-5472. 19. 5460-5472 (2000)
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• [文献書誌] Tsuji,Y.,Shidama,Y.,Takeshita,T.,Kajimura,N.,Nomura,S.,Sekiyama,N.,Otomo,J.,Usukura,J.,Nakanishi,S.and Jingami,H.: "Cryptic dimer interface and domain organization of the extracellular region of metabotropic glutamate receptor subtype 1."J.Biol.Chem.. 275. 28144-28151 (2000)
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• [文献書誌] Imamura,Y.,Inokawa,H.,Ito,A.,Kadotani,H.,Toyama,K.,Noda,M.,Nakanishi,S.and Hirano,T.: "Roles of GABAergic inhibition and NMDA receptor subunits in the spatio-temporal integration in the cerebellar cortex of mice."Neurosci.Res.. 38. 289-301 (2000)
• [文献書誌] Kawasaki,H.,Mizuseki,K.,Nishikawa,S.,Kaneko,S.,Kuwana,Y.,Nakanishi,S.,Nishikawa,SI.and Sasai,Y.: "Induction of midbrain dopaminergic neurons from ES cells by stromal cell-drived inducing activity."Neuron 28:31-40. 28. 31-40 (2000)
• [文献書誌] Yoshida,K.,Watanabe,D.,Ishikane,H.,Tachibana,M.,Pastan,I.and Nakanishi,S.: "A key role of starburst amacrine cells in originating retinal directional selectivity and optokinetic eye movement"Neuron. (in press). (2001)