1. Tanaka Y, Hamano S, Gotoh K, Murata Y, Kunisaki Y, Nishikimi A, Takii R, Kawaguchi M, Inayoshi A, Masuko S, Himeno K, Sasazuki T, Fukui Y. T helper

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(1)㨎㧕❑ゲ⎇ⓥ㧔߹ߚߪᮮゲ⎇ⓥ㧕߳ߩ⽸₂ߦ❬߇ࠆ⎇ⓥᚑᨐ ℂൻቇ⎇ⓥᚲ ᨋ㦮వ↢߅ࠃ߮ᘮᔕᄢቇ ᩉᎹవ↢ߣߩ౒ห⎇ⓥߣߒߡ‫&ޔ‬1%-ળวಽሶߩ ✂⟜⊛⸃ᨆࠍⴕ޿‫ߩߘޔ‬ᚑᨐߪ㗅ᰴ)02ࡊ࡜࠶࠻ࡎ࡯ࡓ߳ߣ౏㐿ߐࠇࠆ੍ቯߢ޽ࠆ‫߁ࠃߩߎޕ‬ ߦᧄ⎇ⓥߪ‫ޔ‬ᯏ⢻⊒⃻ߦ⥋ࠆ&1%-ࠪࠣ࠽࡞ࡀ࠶࠻ࡢ࡯ࠢߩ⸃᣿ߦะߌ⌕ታߦᚑᨐࠍ޽ߍߡ߅ ࠅ‫ߩߘޔ‬ᚑᨐߪᣂⷙ఺∉ᛥ೙೷㐿⊒ߩߚ߼ߩಽሶၮ⋚ࠍឭଏߔࠆ߽ߩߣᦼᓙߐࠇࠆ‫ޕ‬ ࠥࡁࡓࡀ࠶࠻ࡢ࡯ࠢࡊࡠࠫࠚࠢ࠻ߩᦨ⚳⋡ᮡߪ‫⚦ޔ‬⢩ߩ㜞ᰴᯏ⢻೙ᓮߦ߅ߌࠆ♖✺ߥࡀ࠶ ࠻ࡢ࡯ࠢࡑ࠶ࡊߩ૞ᚑߣߘߩකቇ࡮↢‛ቇ߳ߩᔕ↪ߣ૏⟎ߠߌࠄࠇࠆߎߣ߆ࠄ‫⎇ᧄޔ‬ⓥߪ޽ ࠆᗧ๧ߎࠇࠍవขࠅߒߚᒻߢታᣉߐࠇߚ߽ߩߣ⸒߃ࠆ‫ޕ‬ ‫ޣ‬ᒰ⹥⎇ⓥߦ㑐ߒߡᵴ↪ߒߚ⎇ⓥ࠺࡯࠲࡮࡝࠰࡯ࠬ‫ޤ‬ 40#K࡟࠻ࡠࡌࠢ࠲࡯߅ࠃ߮E&0#ߩଏਈࠍฃߌߚ߇‫ࠍࠇߎޔ‬ᵴ↪ߒߚ⺰ᢥ࠺࡯࠲ߪ߹ߛߥ ޿‫ޕ‬ ‫ޣ‬ਥߥ⎇ⓥ⺰ᢥߣߘߩ᭎ⷐ‫ޤ‬ . 1.. Tanaka Y, Hamano S, Gotoh K, Murata Y, Kunisaki Y, Nishikimi A, Takii R, Kawaguchi M, Inayoshi A, Masuko S, Himeno K, Sasazuki T, Fukui Y. T helper type 2 differentiation and intracellular trafficking of the interleukin 4 receptor-D subunit controlled by the Rac activator DOCK2. Nature Immunol. 8: 1067-1075, 2007. ᛫ේೝỗߦ઻޿‫ޔ‬6⚦⢩ߪ6J‫ޔ‬6Jߣ޿߁⇣ߥࠆࠨࠗ࠻ࠞࠗࡦㆮવሶࠍ⊒⃻ߔࠆ6⚦⢩ࠨࡉ࠮ ࠶࠻ߦಽൻߔࠆ‫ޔߦߢ߹ࠇߎޕ‬6⚦⢩ฃኈ૕ 6%4 ࠍ੺ߒߚࠪࠣ࠽࡞ߣ+.ฃኈ૕ߩࠪࠣ࠽࡞ߣ ߩ㑆ߦ૗ࠄ߆ߩࠢࡠࠬ࠻࡯ࠢ߇ሽ࿷ߔࠆߣ⠨߃ࠄࠇߡ߈ߚ߇‫ߩߘޔ‬ಽሶታ૕ߪਇ᣿ߢ޽ߞߚ‫ޕ‬ ᚒ‫&ޔߪޘ‬1%-ᰳ៊%& 6⚦⢩߇᛫ේೝỗߦ઻޿ᄢ㊂ߩ+.ࠍಽᴲߒ‫ޔ‬6JRTQPGߩ$#.$Eࡑ࠙ࠬ ߦ߅޿ߡࠕ࡟࡞ࠡ࡯∔ᖚࠍ⥄ὼ⊒∝ߔࠆߎߣࠍ⷗޿ߛߒߚ‫&ޕ‬1%-ᰳ៊%& 6⚦⢩ߦ߅޿ߡߪ‫ޔ‬ ᛫ේೝỗߦ઻߁+.ฃኈ૕ߩ࠳࠙ࡦ࡟ࠡࡘ࡟࡯࡚ࠪࡦ߇㓚ኂߐࠇߡ߅ࠅ‫⚿ߩߘޔ‬ᨐ+.ฃኈ૕ ࠍ੺ߒߚࠪࠣ࠽࡞߇੣ㅴ‫ޔ‬ㆫᑧൻߒߡ޿ߚ‫⸃ࠍࡓ࠭࠾ࠞࡔߩߎޕ‬᣿ߔߴߊ⹦⚦ߥ⸃ᨆࠍⴕ޿‫ޔ‬ 6%4ߩਅᵹߢ⺃ዉߐࠇࠆ&1%-4CEࠪࠣ࠽࡞વ㆐♽߇‫ޔ‬ᓸዊ▤േᘒࠍ੺ߒߡ+.ฃኈ૕ߩ⚦⢩ౝ ャㅍߣ࠲ࡦࡄࠢ⾰ಽ⸃ࠍࠦࡦ࠻ࡠ࡯࡞ߒ‫ߩࡦࠗࠞ࠻ࠗࠨߦ⊛⚳ᦨޔ‬ㆮવሶ⊒⃻ࠍ೙ᓮߔࠆߣ޿ ߁ᭂ߼ߡ♖✺ߥࡔࠞ࠾࠭ࡓ߇ሽ࿷ߔࠆߎߣࠍ᣿ࠄ߆ߦߒߚ‫ߩߎޕ‬ᚑᨐߪ‫ᦺޔ‬ᣣᣂ⡞‫ޔ‬ᣣᧄ⚻ᷣ ᣂ⡞‫ޔ‬Ფᣣᣂ⡞╬ᄙߊߩᣂ⡞ߢขࠅ਄ߍࠄࠇࠆߣ౒ߦ‫ޔ‬0*-ో࿖ ╬ߢ࠹࡟ࡆႎ㆏߽ߥߐࠇߚ‫ޕ‬. 2.. Gotoh K, Tanaka Y, Nishikimi A, Inayoshi A, Enjoji M, Takayanagi R, Sasazuki T, Fukui Y. Differential requirement for DOCK2 in migration of plasmacytoid dendritic cells versus myeloid dendritic cells. Blood 111: 2973-2976, 2008. ᮸⁁⚦⢩ߪᗵᨴߦ઻޿ㅦ߿߆ߦ⒖േߒ‫ޔ‬ේᓸ↢‛ࠍ⽽㘩ߒ‫ޔ‬6 ⚦⢩ߦ᛫ේࠍឭ␜ߔࠆ৻ᣇ‫ޔ‬ 6QNNNKMG ฃኈ૕ࠍ੺ߒߡ∛ේᓸ↢‛ࠍ⹺⼂ߒ‫ࠍࡦࠗࠞ࠻ࠗࠨޔ‬ಽᴲߔࠆߎߣߢ₪ᓧ఺∉ᔕ╵ࠍ ೙ᓮߒߡ޿ࠆ‫ޕ‬᮸⁁⚦⢩ߪߘߩᒻᘒ߿ᯏ⢻㧘⚦⢩⴫㕙ࡑ࡯ࠞ࡯ߩ㆑޿߆ࠄ㛽㜑♽᮸⁁⚦⢩㧔O&%㧕 ߣᒻ⾰⚦⢩᭽᮸⁁⚦⢩ R&% ߦᄢ೎ߐࠇࠆ‫ޕ‬R&% ߪ࠙ࠗ࡞ࠬᗵᨴߦ઻޿ᄢ㊂ߩ + ဳࠗࡦ࠲࡯ࡈࠚ ࡠࡦࠍ↥↢ߔࠆߎߣ߆ࠄᵈ⋡ࠍ㓸߼ߡ޿ࠆ⚦⢩ߢ޽ࠆ߇‫ߩߘޔ‬ㆆ⿛೙ᓮᯏ᭴ߪਇ᣿ߢ޽ߞߚ‫ޕ‬ ⑳㆐ߪ &1%- ᰳ៊ࡑ࠙ࠬߦ߅޿ߡ R&% ߩಽൻ࡮ᚑᾫߪᱜᏱߢ޽ࠆߦ߽㑐ࠊࠄߕ‫ޔ‬㧞ᰴ࡝ࡦࡄ⚵ ❱ߦ߅޿ߡ R&% ߇⪺ᷫߔࠆߎߣࠍ⷗޿಴ߒߚ‫&ޕ‬1%- ᰳ៊ R&% ߢߪ 4CE ᵴᕈൻ߇⪺ߒߊ㓚ኂߐࠇ ߡ߅ࠅ‫⚿ߩߘޔ‬ᨐ޿ߕࠇߩࠤࡕࠞࠗࡦߦኻߒߡ߽߶ߣࠎߤㆆ⿛ᔕ╵ࠍ␜ߐߥ߆ߞߚ‫ߦࠇߎޕ‬ኻ ߒߡ‫&ޔ‬1%M ᰳ៊ߪ O&% ߦ߅ߌࠆ 4CE ᵴᕈൻ߿ㆆ⿛ᔕ╵ߦߪ߶ߣࠎߤᓇ㗀ࠍਈ߃ߥ߆ߞߚ‫ޕ‬એ਄ ࠃࠅ‫ޔ‬O&% ߣ R&% ߩㆆ⿛ߦ߅޿ߡ⇣ߥࠆಽሶ߇ 4CE ᵴᕈൻࠍᜂߞߡ޿ࠆߎߣࠍ᣿ࠄ߆ߦߒߚ‫ޕ‬.

(2) 3.. Kunisaki Y, Nishikimi A, Tanaka Y, Takii R, Noda M, Inayoshi A, Watanabe K, Sanematsu F, Sasazuki T, Sasaki T, Fukui Y. DOCK2 is a Rac activator that regulates motility and polarity during neutrophil chemotaxis. J. Cell Biol., 174: 647-652, 2006. ᅢਛ⃿ߪᭂ߼ߡㆇേᕈߩ㜞޿‫↢ޔ‬૕㒐ᓮࠪࠬ࠹ࡓߩᦨ೨✢ߢᯏ⢻ߔࠆ⊕ⴊ⃿ߢ޽ࠆ‫߹ࠇߎޕ‬ ߢࡁ࠶ࠢࠕ࠙࠻ࡑ࠙ࠬࠍ↪޿ߚ⸃ᨆࠃࠅ‫ޔ‬ᅢਛ⃿ߩㆆ⿛߿ᵴᕈ㉄⚛↥↢ߦ߅޿ߡ‫ޔ‬4CE߇㊀ⷐߥ ᓎഀࠍṶߓࠆߎߣ߇᣿ࠄ߆ߦߐࠇߡ޿ࠆ߇‫ޔ‬4CEᵴᕈൻߦ㑐ࠊࠆಽሶߪਇ᣿ߢ޽ߞߚ‫ޕ‬ᚒ‫ޔߪޘ‬ &1%- ࡁ࠶ࠢࠕ࠙࠻ࡑ࠙ࠬߦ߅޿ߡᅢਛ⃿ߩㆆ⿛߿ᵴᕈ㉄⚛↥↢߇⪺ߒߊ㓚ኂߐࠇߡ޿ࠆߎߣ ࠍ⷗޿ߛߒߚ‫&ޕ‬1%- ᰳ៊ᅢਛ⃿ߢߪ㧘H/.2ೝỗߦࠃࠆ4CEᵴᕈൻ߇㓚ኂߐࠇߡ߅ࠅ‫⚿ߩߘޔ‬ᨐ NGCFKPIGFIGߦ߅ߌࠆ(ࠕࠢ࠴ࡦ෸߮2+2 ߩ㓸Ⓧ߇ᶖᄬߒߡ޿ߚ‫&ޔߦࠄߐޕ‬1%- ߩ⚦⢩ౝേᘒ ࠍ↢ℂ⊛ߥ᧦ઙਅߢนⷞൻߔࠆߚ߼‫&ޔ‬1%- ㆮવሶߩᦨ⚳ࠛࠠ࠰ࡦ⋥ਅߦ)(2ࠍᝌ౉ߒߚࡁ࠶ࠢ ࠗࡦࡑ࠙ࠬࠍ૞⵾ߒ‫&ߡ޿↪ࠍࠬ࠙ࡑߩߎޔ‬1%- ߇2+2 ߣળวߒ‫ޔ‬2+-ଐሽ⊛ߦ⚦⢩⤑ߦ⒖ⴕߔ ࠆߎߣࠍ᣿ࠄ߆ߦߒߚ‫⥝ޕ‬๧ᷓ޿ߎߣߦ‫&ޔ‬1%- ߦࠃࠆ4CEᵴᕈൻߪᜬ⛯ߒߚ2+2 ߩ㓸Ⓧ߿#MVߩ ࡝ࡦ㉄ൻߦߪ㊀ⷐߢ޽ߞߚ߇‫ޔ‬2+2 ߩ↥↢ߘߩ߽ߩߦߪోߊᓇ㗀ߒߥ߆ߞߚ‫ޕ‬એ਄ࠃࠅ‫&ޔ‬1%- ߪᅢਛ⃿ߩㆆ⿛ߦ߅޿ߡ‫ޔ‬4CEߣ2+2 㑆ߩᱜߩࡈࠖ࡯࠼ࡃ࠶ࠢ࡞࡯ࡊߢᯏ⢻ߔࠆ4CEᵴᕈൻಽሶߢ ޽ࠆ߇‫ࠢ࠶ࡃ࠼࡯ࠖࡈߩߘޔ‬ᯏ᭴ߪ2+-ߩ⸅ᇦᵴᕈࠍ੺ߒߚ߽ߩߢߪߥ޿ߎߣࠍ᣿ࠄ߆ߦߒߚ‫ޕ‬ ߎߩ⺰ᢥߪ‫ޔ‬,%$ߩ+P6JKU+UUWG ࡂࠗ࡜ࠗ࠻ᰣ ߢ߽ߣࠅ޽ߍࠄࠇߚ‫ޕ‬. . ‫⸵․ޣ‬಴㗿ᢙߩታ❣‫ޤ‬ ᧄ⎇ⓥߩᚑᨐߣߒߡߩ಴㗿ߪߥ޿߇‫&ޔ‬1%-ߦ㑐ߒߡߪ‫⃿ࡄࡦ࡝ޟ‬ㆆ⿛೙ᓮᯏ⢻ᰳᄬࡕ࠺࡞ 㕖ࡅ࠻േ‛‫⃿ࡄࡦ࡝ޟޠ‬ㆆ⿛ߦਇนᰳߥ&1%-ߩᯏ⢻࠼ࡔࠗࡦ෸߮ળวಽሶ‫ߡߒߣޠ‬࿖ౝ㧛࿖ ᄖߩ․⸵↳⺧ࠍⴕߞߡ߅ࠅ‫৻ߜ߁ޔ‬ㇱߪࠕࡔ࡝ࠞ߅ࠃ߮ᣣᧄߢᣢߦ⹺นᷣߺߢ޽ࠆ‫ޕ‬.

(3) ࠥࡁࡓࡀ࠶࠻ࡢ࡯ࠢࡊࡠࠫࠚࠢ࠻ߩ ⺖㗴ߩႎ๔. ࡊࡠࠣ࡜ࡓฬ ⺖㗴ߩಽ㘃⺖㗴 ฬ 㧔๺⧷૬⸥㧕. 㧔㧝㧕ࠥࡁࡓᯏ⢻ᖱႎߩ⸃ᨆ 㧔㧞㧕ࡅ࠻ࠥࡁࡓࡀ࠶࠻ࡢ࡯ࠢ ࡊ࡜࠶࠻ࡈࠜ࡯ࡓߩ᭴▽ 㧔㧟㧕ᰴ਎ઍࠥࡁࡓ⸃ᨆᛛⴚߩ㐿⊒ 㧔㧠㧕୘೎↢๮ᯏ⢻ߩ⸃ᨆ 㧔㧡㧕േ⊛ࡀ࠶࠻ࡢ࡯ࠢ⸃ᨆᛛⴚ㐿⊒ 㧔㧝㧕ਛᩭᯏ㑐㧔㧞㧕ᜰቯ⺖㗴㧔㧟㧕౏൐⺖㗴 Ⱞ⊕ߩนⷞൻߣᯏ⢻⊛ⶄว૕⸃ᨆߢ⸃ߊࠥࡁࡓ቟ቯᕈࡀ࠶࠻ࡢ࡯ࠢ 㧔Visual and Functional Proteome Analysis of Genome Integrity Network in Human Cell㧕. ઍ⴫⎇ⓥ⠪ฬ ቟੗ ᣿ 㧔࿖┙ᄢቇᴺੱ᧲ർᄢቇ࡮ᢎ᝼㧕㧔ᚲዻᯏ㑐࡮⡯ฬ㧕㧝㧤ᐕᐲ 㧝㧥ᐕᐲ 㧞㧜ᐕᐲ ᐕᐲ೎⎇ⓥ⾌㧔ජ౞㧕. . . . ว ⸘ . ⎇ⓥ⠪ฬ ᚲዻᯏ㑐࡮ㇱዪ࡮⡯ ኾ㐷ಽ㊁ ⎇ ઍ⴫ᯏ㑐 ‫ ڏ‬቟੗ ᣿ ᧲ർᄢቇ࡮ട㦂කቇ⎇ⓥᚲ࡮ᢎ᝼ ಽሶ↢‛ቇ 㜞የ 㓷 ᧲ർᄢቇ࡮ട㦂කቇ⎇ⓥᚲ࡮⻠Ꮷ ಽሶ↢‛ቇ ⓥ ⚵ ਛ᎑ ᢅ ᧲ർᄢቇ࡮ട㦂කቇ⎇ⓥᚲ࡮ഥᢎ ⚦⢩↢‛ቇ ❱ ಽᜂᯏ㑐 ‫ڏ‬㧔ઍ⴫⎇ⓥ⠪㧕 ࿑ 㧔ಽᜂ⎇ⓥ⠪㧕 ‫⎇ޣ‬ⓥ⋡⊛‫ޤ‬ ࠥࡁࡓߩ቟ቯᕈࠍ଻⸽ߔࠆᯏ᭴ߪ↢‛ቇߣකቇߩಽ㊁ߢ౒ㅢߔࠆᦨ߽㊀ⷐߥ⺖㗴ߩ৻ߟ ߢ޽ࠆ‫∔ࡓࡁࠥޕ‬ᖚߣ⒓ߐࠇࠆ≸ߣㆮવ∛ߩߘ߽ߘ߽ߩේ࿃ߪࠥࡁࡓߩਇ቟ቯᕈߢ޽ࠅ‫ޔ‬ ⠧ൻ߿␹⚻∔ᖚߩේ࿃ߦ߽ߥࠆߎߣ߇␜ߐࠇߡ޿ࠆ‫∔ࡓࡁࠥߥ߁ࠃߩߎޕ‬ᖚࠍ㒐ߋࡅ࠻ࠥ ࡁࡓߩ቟ቯᕈࠍ଻⸽ߔࠆᯏ᭴ߪ‫ߢ߹ࠇߎޔ‬㜞⊒≸ㆮવ∛ߩේ࿃ㆮવሶࠍਛᔃߦ⸃ᨆߐࠇߡ ߈ߚ߇‫ޔ‬ታ㓙ߩ⚦⢩ౝߢߩᯏ᭴ࠍℂ⸃ߔࠆ߹ߢߦ⥋ߞߡ߅ࠄߕ‫ޔ‬ᄙߊߩ⊒≸ේ࿃ㆮવሶ߿ ᣧ⠧∝‫ޔ‬⠧ൻ‫∔⚻␹ޔ‬ᖚߩේ࿃ㆮવሶ߇߹ߛ⷗ߟ߆ߞߡ޿ߥ޿ߣ⠨߃ࠄࠇࠆ‫⎇ߩߎޕ‬ⓥߪ‫ޔ‬ ᚒ‫ߩ⥄⁛ߩޘ‬ᛛⴚߢ޽ࠆ⚦⢩ౝߢߩࠥࡁࡓ៊்ᔕ╵ߩนⷞൻ⸃ᨆߣ‫⃻ߩ்៊ޔ‬႐ߢ௛ߊⰮ ⊕ߩⶄว૕ߩ᳿ቯߣߘߩᯏ⢻⸃ᨆࠍⲢวߒߡ‫ޔ‬ᣢ⍮࡮ᧂ⍮Ⱞ⊕߇᭴ᚑߔࠆⶄว૕ߩหቯߣ ᯏ⢻ߩ⸃᣿ࠍⴕ޿‫⚦࠻ࡅޔ‬⢩ౝߢߩࠥࡁࡓ቟ቯᕈߦ㑐ࠊࠆⶄว૕ߩ✂⟜⊛หቯߣᯏ⢻ᖱႎ ߩࡀ࠶࠻ࡢ࡯ࠢࠍ⸃᣿ߔࠆߩ߇⋡⊛ߢ޽ࠆ‫ޕ‬ ‫⺖ޣ‬㗴ߩ᭎ⷐ‫ޤ‬ ࠥࡁࡓ៊்ߩୃᓳ߿ࠪࠣ࠽࡞વ㆐ߥߤߩࠥࡁࡓ቟ቯᕈࠍ᳿ቯߔࠆⰮ⊕ߩᯏ⢻ᰳ៊ߪ≸߿ ⠧ൻ޽ࠆ޿ߪㆮવ∛ࠍ߽ߚࠄߔ߇‫߇⊕Ⱞߩࠄࠇߎޔ‬ታ㓙ߩ⚦⢩ౝߢߤߩࠃ߁ߦ௛޿ߡ޿ࠆ ߆ߦߟ޿ߡߪ߹ߛᄙߊߩߎߣ߇ಽߞߡ޿ߥ޿‫ޕ‬ᚒ‫ᦨߪޘ‬ㄭ‫ޔ‬㗼ᓸ㏜ߩ࡟ࡦ࠭ࠍㅢߒߡ⚦⢩ ᩭߦዪᚲ⊛ߦ࡟࡯ࠩ࡯శࠍᾖ኿ߒߡ⒳‫ࠍ்៊ߩޘ‬૞ᚑߒ‫ߦ்៊ޔ‬ᔕ╵ߒߡ㓸Ⓧߒ⸃㔌ߔࠆ Ⱞ⊕ࠍนⷞൻߒߡ⸃ᨆߔࠆ⎇ⓥᣇᴺࠍ㐿⊒ߒߚ‫ߩߎޕ‬ᣇᴺߢ‫⚦ޔ‬⢩ౝߢߤߩⰮ⊕߇૗ߦଐ ሽߒߡߤߩࠃ߁ߥ៊்ߦ㓸Ⓧߔࠆ߆ࠍ᣿ࠄ߆ߦ಴᧪ࠆ‫ߦ்៊߇⾰⊕Ⱞޔߚ߹ޕ‬ᔕ╵ߒߡᒻ ᚑߔࠆⶄว૕ࠍ⾰㊂ಽᨆᯏߢหቯߒ‫ޔ‬หᤨߦߘߩⶄว૕ߩᵴᕈࠍ⸃ᨆߔࠆᛛⴚࠍ⏕┙ߒߚ‫ޕ‬ ߎߩ↳⺧⺖㗴ߪ‫ߩࠄࠇߎޔ‬ᣇᴺࠍ⚵ߺวࠊߖߡ‫ࡓࡁࠥޔ‬቟ቯᕈߦ㑐ࠊࠆ㊀ⷐߥࡅ࠻Ⱞ⊕ⶄ ว૕ߩ᭴ᚑߣᯏ⢻ࠍ᣿ࠄ߆ߦߔࠆ‫ߡߒ߁ߎޔߦࠄߐޕ‬ᓧࠄࠇࠆᣂⷙⰮ⊕⾰߿ⶄว૕ߩᯏ⢻ ⊛ߥࡀ࠶࠻ࡢ࡯ࠢᖱႎࠍ≸‫ޔ‬⠧ൻ‫ޔ‬ㆮવ∛ߥߤߩࠥࡁࡓ∔ᖚߩ⸻ᢿߣᴦ≮ߦᓎ┙ߡࠆ‫ޕ‬.

(4) ‫ޣ‬ᐔᚑ㧞㧜ᐕ㧤᦬ᧃ߹ߢߩ⎇ⓥᚑᨐ‫ޤ‬ ߎߩ⎇ⓥߪ‫ޔ‬ᚒ‫߇ޘ‬㐿⊒ߒߚ‫⚦࠻ࡅࠆࠃߦ࡯ࠩ࡯࡟ޔ‬⢩ᩭߩዪᚲᾖ኿ߢ㓸ⓍߔࠆⰮ⊕ࠍน ⷞൻߒߡ⸃ᨆߔࠆታ㛎ᣇᴺߣ‫⃻ߩ்៊ޔ‬႐ߢᒻᚑߐࠇࠆⰮ⊕ⶄว૕ࠍ⾰㊂ಽᨆߢหቯߔࠆᣇ ᴺࠍ⚵ߺวࠊߖߡ‫⚦ޔ‬⢩ౝߢታ㓙ߦࠥࡁࡓ቟ቯᕈߦᯏ⢻ߔࠆⰮ⊕ࡀ࠶࠻ࡢ࡯ࠢࠍ᣿ࠄ߆ߦߔ ࠆ߽ߩߢ‫ࡓࡁࠥޔ‬቟ቯᕈࡀ࠶࠻ࡢ࡯ࠢߣォ౮ߣߩ㑐ㅪߦ߽ᵈ⋡ߒߡ⎇ⓥࠍዷ㐿ߒߡ޿ࠆ‫ߎޕ‬ ࠇ߹ߢߦ‫ⶄޔ‬ᢙߩ㊀ⷐߥᣂⷙߩⰮ⊕⾰ߣߘߩⶄว૕ߩหቯࠍ฽߻⎇ⓥᚑᨐ߇޽ࠅ‫)ޔ‬02ߩ CEMPQYNGFIGࠍᜬߟ⺰ᢥࠍ㧡ႎ㧔'/$1,/QN%GNN20#5߇ߘࠇߙࠇ㧝ႎ‫ޔ‬0WENGKE#EKFU4GU ߇㧞ႎ㧕ࠍᣢߦ⊒⴫ߒ‫⃻ޔ‬࿷‫ޔ‬KPRTGUUߩ⺰ᢥ߇㧞ႎ㧔,%GNN5EK'/$1,㧕‫ޔ‬ᛩⓂਛߩ⺰ ᢥ߇㧞ႎ‫ޔ‬ᛩⓂḰ஻ਛߩ⺰ᢥ߇㧞ႎ޽ࠆ‫੹ޕ‬ᓟߐࠄߦ‫ࠅࠃޔ‬ᄙߊߩ⦟޿⺰ᢥࠍ⊒⴫ߒߡ޿ߊ‫ޕ‬ ‫ޣ‬㧳㧺㧼ߣߩ㑐ㅪ࡮㧳㧺㧼߳ߩ⽸₂‫ޤ‬ 㨍㧕ォ౮࡮೙ᓮߩ⸃᣿ߦ㑐ㅪߔࠆ⎇ⓥᚑᨐ )02 ߪォ౮೙ᓮߩࡀ࠶࠻ࡢ࡯ࠢࡊࡠࠫࠚࠢ࠻ߢ޽ࠆ߇‫⎇ߩߎޔ‬ⓥߪᧄ᧪‫߿≸ޔ‬⠧ൻ೙ᓮߦ 㑐ࠊࠆࠥࡁࡓ቟ቯᕈߦ௛ߊⰮ⊕⾰㑆ߩࡀ࠶࠻ࡢ࡯ࠢߩ⸃᣿ࠍ⋡ᜰߒߡ޿ࠆ‫ߒ߆ߒޕ‬หᤨߦ‫ޔ‬ ォ౮೙ᓮߣࠥࡁࡓ቟ቯᕈߩᯏ᭴ߦ౒ㅢߒߡ௛ߊⰮ⊕⾰߿ߘࠇࠄߩォ౮ߩᯏ᭴ߦߟ޿ߡ⸃ᨆ ࠍㅴ߼ߡ޿ࠆ‫ޕ‬ 㨎㧕❑ゲ⎇ⓥ㧔߹ߚߪᮮゲ⎇ⓥ㧕߳ߩ⽸₂ߦ❬߇ࠆ⎇ⓥᚑᨐ ࠥࡁࡓ቟ቯᕈߦ㑐ࠊࠆ㉂⚛ᵴᕈࠍᜬߞߚࡅ࠻ᣂⷙⰮ⊕⾰㧔2#.(߿#2'0:㧕ߣߘߩⶄว૕ࠍ᳿ ቯߒ‫ߩࠄࠇߘޔ‬ᯏ⢻ࠍ᣿ࠄ߆ߦߒߚ㧔#2'0:ߪᣂⷙ#2ࠛࡦ࠼࠿ࠢ࡟ࠕ࡯࠯ߢ⺰ᢥḰ஻ਛ㧕‫ߎޕ‬ ࠇࠄߪᦨ߽㗫❥ߦ↢ߓࠆ&0#න㎮ಾᢿߩᣂⷙߩୃᓳ♽ࠍ␜ߔ߽ߩߢ‫∔ߩ♽⚻␹߿≸ޔ‬ᖚ೙ᓮߦ ㊀ⷐߢ޽ࠆߣ⠨߃ࠄࠇࠆ‫ޕ‬ ‫ޣ‬ᒰ⹥⎇ⓥߦ㑐ߒߡᵴ↪ߒߚ⎇ⓥ࠺࡯࠲࡮࡝࠰࡯ࠬ‫ޤ‬ E&0#࡝࠰࡯ࠬ‫ޕ‬UK40#࡝࠰࡯ࠬ‫ޕ‬᛫૕૞ᚑ‫ޕ‬.

(5) ‫ޣ‬ਥߥ⎇ⓥ⺰ᢥߣߘߩ᭎ⷐ‫ޤ‬ 1. Hong Z, Jiang J, Lan L, Nakajima S, Kanno S, Koseki H, Yasui A. A polycomb group protein, PHF1, is involved in the response to DNA double-strand breaks in human cell. Nucleic Acids Res. 36, 2939-47, 2008. ࡟࡯ࠩ࡯ᾖ኿ߦ㓸Ⓧߔࠆࡅ࠻ࡐ࡝ࠦ࡯ࡓⰮ⊕2*( ࠍ⊒⷗ߒ‫ޔ‬-7 ଐሽ⊛ߦੑ㊀㎮ಾᢿୃᓳ 㧔0*',㧕ߦ㑐ࠊࠅ‫ޔ‬: ✢ᛶ᛫ᕈߦ⽸₂ߒߡ޿ࠆ੐ࠍ⊒⷗‫ޕ‬2*( ߪߐࠄߦ R ߿ 4#& ߥߤߣ ⚿วߒߡ‫ࡓࡁࠥޔ‬቟ቯᕈࡀ࠶࠻ࡢ࡯ࠢߦ㑐ࠊߞߡ޿ࠆ㧔ฎ㑐వ↢ߣߩ౒ห⎇ⓥ㧕‫ޕ‬+2 ߣ⾰㊂ ಽᨆߢ᳿ቯߒߚ 2*( ߩ 22+ ࠍ࠺࡯࠲ࡌ࡯ࠬߦ⊓㍳‫ޕ‬ 2. Kanno, S, Kuzuoka, H, Sasao, S, Hong, Z, Lan, L, Nakajima, S, and Yasui A. A novel human AP endonuclease with conserved zinc-finger-like motifs involved in DNA strand break responses, EMBO J. 26, 2094-2103, 2007. ࡝ࡦ㉄ൻࡍࡊ࠴࠼ߦ⚿วߔࠆ (*# ࠼ࡔࠗࡦࠍᜬߟᣂⷙߩⰮ⊕ 2#.( ࠍ⊒⷗‫ޕ‬Ⴎၮߩή޿ㇱ૏ ࠍಾࠆ #2 ࠛࡦ࠼࠿ࠢ࡟ࠕ࡯࠯ߣ ̉̉ࠛࠠ࠰࠿ࠢ࡟ࠕ࡯࠯ߩᵴᕈ߇޽ࠅ‫ޔ‬න㎮ಾᢿㇱ૏ߦ ࠡࡖ࠶ࡊࠍ૞ࠅ⚿วߒߡ޿ࠆ 2#42 ߩࡐ࡝ #&2 ࡝ࡏࠪ࡞ᵴᕈࠍᵴᕈൻߔࠆ‫ޕ‬+2 ߣ⾰㊂ಽᨆߢ ᳿ቯߒߚ 2#.( ߩ 22+ ߪ㊀ⷐߥ &0# ੑ㊀㎮߅ࠃ߮න㎮ಾᢿߩୃᓳⰮ⊕ߣ⋧੕૞↪ࠍ⊒⷗ߒ‫࠺ޔ‬ ࡯࠲ࡌ࡯ࠬߦ⊓㍳‫ޕ‬ 3. Hashiguchi, K. Matsumoto, Y, and Yasui, A. Recruitment of DNA repair synthesis machinery to sites of DNA damage/repair in living human cells. Nucleic Acids Res. 35, 2913-2923, 2007. 2%0# ߣ 4(% ߪࠢ࡜ࡦࡊ෸߮ࠢ࡜ࡦࡊࡠ࡯࠳࡯ߣ๭߫ࠇࠆ &0# ⶄ⵾ߩㅴⴕᓎߢ޽ࠆ߇‫&ޔ‬0# ୃᓳߢߤߩࠃ߁ߦ៊்ㇱ૏ߦ߿ߞߡ᧪ࠆ߆ࠍ᣿ࠄ߆ߦߒߚ‫ޕ‬ᯏ⢻⊛࠼ࡔࠗࡦࠍหቯߒߚ‫⚿ޕ‬ ⺰ߪ‫ޔ‬2%0# ߣ 4(% ߇⋧੕ߦଐሽߒߡ៊்ㇱ૏ߦ㓸Ⓧߔࠆ‫ޕ‬ 4. Kamath-Loeb AS, Lan L, Nakajima S, Yasui A, Loeb LA. Werner syndrome protein interacts functionally with translesion DNA polymerases.Proc. Natl. Acad. Sci. USA, 104., 10394-10399, 2007. ⦟ߊ⍮ࠄࠇߡ޿ࠆ࠙ࠛ࡞࠽࡯ᣧ⠧∝ߩේ࿃Ⱞ⊕ߢ޽ࠆ 940 ߇៊்ߩਸ਼ࠅ⿧߃ &0# ⶄ⵾ߦ㑐 ࠊࠆࡐ࡝ࡔ࡜࡯࠯ J ߣ⋧੕૞↪ࠍߒߡ‫⚡ޔ‬ᄖ✢៊்ߥߤߩലᨐ⊛ߥਸ਼ࠅ⿧߃㧔VTCPUNGUKQP U[PVJGUKU㧕ߦ㑐ࠊࠅวߞߡ޿ࠆߎߣࠍ⸽᣿‫ޕ‬ 5. Prasad R, Liu Y, Deterding LJ, Poltoratsky VP, Kedar PS, Horton JK, Kanno S, Asagoshi K, Hou EW, Khodyreva SN, Lavrik OI, Tomer KB, Yasui A, Wilson SH. HMGB1 is a cofactor in mammalian base excision repair. Mol Cell, 27, 829-841, 2007. ᵴᕈ㉄⚛ߦࠃࠆႮၮ៊்ࠍ૞ࠆᣂߒ޿ᣇᴺࠍ㐿⊒ߒߡ㕖ࡅࠬ࠻ࡦࠢࡠࡑ࠴ࡦⰮ⊕ߩ */)$ ߇៊்ߦ㓸Ⓧߔࠆߎߣࠍนⷞൻߒߡ⸽᣿ߒߚ‫ޕ‬ ‫⸵․ޣ‬಴㗿ᢙߩታ❣‫ޤ‬ ߥߒ‫ޕ‬ .

(6) . ࠥࡁࡓࡀ࠶࠻ࡢ࡯ࠢࡊࡠࠫࠚࠢ࠻ߩ ⺖㗴ߩႎ๔. ࡊࡠࠣ࡜ࡓฬ. 㧔㧝㧕ࠥࡁࡓᯏ⢻ᖱႎߩ⸃ᨆ 㧔㧞㧕ࡅ࠻ࠥࡁࡓࡀ࠶࠻ࡢ࡯ࠢ ࡊ࡜࠶࠻ࡈࠜ࡯ࡓߩ᭴▽ 㧔㧟㧕ᰴ਎ઍࠥࡁࡓ⸃ᨆᛛⴚߩ㐿⊒ 㧔㧠㧕୘೎↢๮ᯏ⢻ߩ⸃ᨆ 㧔㧡㧕േ⊛ࡀ࠶࠻ࡢ࡯ࠢ⸃ᨆᛛⴚ㐿⊒. ⺖㗴ߩಽ㘃. 㧔㧝㧕ਛᩭᯏ㑐㧔㧞㧕ᜰቯ⺖㗴㧔㧟㧕౏൐⺖㗴. ⺖㗴 ฬ 㧔๺⧷૬⸥㧕. ੃߇ࠎ⚦⢩ߩ⮎೷ᛶ᛫ᕈߦ㑐ߔࠆࡀ࠶࠻ࡢ࡯ࠢߩേᘒ⸃ᨆ. 㧔Dynamic Analysis of Drug Resistance-related Networks in Breast Cancer Cells㧕. ઍ⴫⎇ⓥ⠪ฬ ർ㊁ ብ᣿ 㧔ᚲዻᯏ㑐࡮⡯ฬ㧕㧔․ቯ㕖༡೑ᵴേᴺੱࠪࠬ࠹ࡓ࡮ࡃࠗࠝࡠࠫ࡯⎇ⓥᯏ᭴࡮ળ㐳㧕㧝㧥ᐕᐲ 㧞㧜ᐕᐲ ว ⸘ ᐕᐲ೎⎇ⓥ⾌ 49,000 45,000 94,000 㧔ජ౞㧕 ⎇ⓥ⠪ฬ ᚲዻᯏ㑐࡮ㇱዪ࡮⡯ ኾ㐷ಽ㊁ ઍ⴫ᯏ㑐 ․ቯ㕖༡೑ᵴേᴺੱࠪࠬ࠹ࡓ࡮ࡃࠗ ‫ڏ‬ർ㊁ ብ᣿ ࠪࠬ࠹ࡓ↢‛ቇ ࠝࡠࠫ࡯⎇ⓥᯏ᭴࡮ળ㐳 ᧻ጟ ↱Ꮧሶ หᯏ᭴࡮⎇ⓥຬ ࠦࡦࡇࡘ࡯࠲ࠨࠗࠛࡦࠬ ᧻ේ ๺ሶ หᯏ᭴࡮ᛛⴚຬ ಽሶ↢‛ቇ Natalia Polouliakh หᯏ᭴࡮ቴຬ⎇ⓥຬ Bioinformatics Samik Ghosh หᯏ᭴࡮⎇ⓥຬ ࠦࡦࡇࡘ࡯࠲ࠨࠗࠛࡦࠬ ⮮ᧄ ዏᧂ หᯏ᭴࡮ᛛⴚຬ ಽሶ↢‛ቇ ㋈ᧁ 㗼 หᯏ᭴࡮ቇ↢⎇ⓥ⵬૒ຬ ಽሶ↢‛ቇ ಽᜂᯏ㑐 ࿖┙ᄢቇᴺੱ᧲੩ᄢቇක⑼ቇ⎇ⓥ ࡊࡠ࠹ࠝࡒࠢࠬ ‫ڏ‬የጊ ᄢ᣿ ᚲ ∔ᖚࡊࡠ࠹ࠝࡒࠢࠬ࡜ࡏ࡜࠻ ࡃࠗࠝࠗࡦࡈࠜࡑ࠹ࠖࠢࠬ ࡝࡯࡮․છഥᢎ หක⑼ቇ⎇ⓥᚲࠪࠬ࠹ࡓ↢๮ක⑼ ≸↢‛ቇ ᓟ⮮ ౖሶ ቇᛛⴚ㐿⊒౒ห⎇ⓥ࡙࠾࠶࠻࡮ ⚦⢩↢‛ቇ ⎇ ․છಎᢎ᝼ ⓥ หක⑼ቇ⎇ⓥᚲ ∔ᖚࡊࡠ࠹ࠝࡒ ⒌ ⵨ሶ ࡊࡠ࠹ࠝࡒࠢࠬ ⚵ ࠢࠬ࡜ࡏ࡜࠻࡝࡯࡮ᛛⴚኾ㐷⡯ຬ ❱ ቶᯅ ㆏ሶ หක⑼ቇ⎇ⓥᚲࠪࠬ࠹ࡓ↢๮ක⑼ ≸↢‛ቇ ࿑ ቇᛛⴚ㐿⊒౒ห⎇ⓥ࡙࠾࠶࠻࡮↥ቇ ⚦⢩↢‛ቇ ቭㅪ៤⎇ⓥຬ ‫ڏ‬੗਄ ⡡ ቇᩞᴺੱၯ₹ක⑼ᄢቇ කቇㇱ࡮ㇱ ࠥࡁࡓකቇ࡮ౝಽᴲቇ 㐷㐳 ᳰ↰ ๺ඳ หቇㇱ࡮ഥᢎ ಽሶ↢‛ቇ ↢ൻቇ ‫⇗ڏ‬ጊ ⋿㉿ሶ ⁛┙ⴕ᡽ᴺੱℂൻቇ⎇ⓥᚲ ၮᐙ⎇ⓥᚲ వ┵⸘▚⑼ቇ⎇ⓥ㗔ၞ ࠪࠬ࠹ࡓࡃࠗࠝࡠࠫ࡯ ࠪࠬ࠹ࡓ⸘▚↢‛ቇ⎇ⓥࠣ࡞࡯ࡊ ⚦⢩ࠪࠬ࠹ࡓࡕ࠺࡞ൻ⎇ⓥ࠴࡯ࡓ࡮ ࠴࡯ࡓ࡝࡯࠳࡯ 㐳᎑ ೰ผ ห࠴࡯ࡓ࡮⎇ⓥຬ ࡃࠗࠝࠗࡦࡈࠜࡑ࠹ࠖࠢࠬ 㤥ᧁ 㓁ሶ ห࠴࡯ࡓ࡮⎇ⓥຬ ࠥࡁࡓ⑼ቇ.

(7) ‫⎇ޣ‬ⓥ⋡⊛‫ޤ‬ ࠲ࡕࠠࠪࡈࠚࡦᗵฃᕈ࡮㕖ᗵฃᕈ੃߇ࠎ⚦⢩ࠍ↪޿ߡ‫㉄ࡦ࡝ޔ‬ൻࡊࡠ࠹ࠝ࡯ࡓ࡮ㆮવሶ⊒ ⃻⸃ᨆࠍⴕ޿‫ࡦࠥࡠ࠻ࠬࠛޔ‬ฃኈ૕ߩ⣕೙ᓮߣEGFRࠪࠣ࠽࡞વ㆐♽ߦ㑐ਈߔࠆࡀ࠶࠻ࡢ࡯ࠢ ⷐ⚛ߩหቯߣߘߩേᘒߩ⸃ᨆࠍⴕ߁‫࡞࠽ࠣࠪࠎ߇੃ޕ‬વ㆐ࡀ࠶࠻ࡢ࡯ࠢߩMAPൻ߿ᢙℂࡕ࠺ ࡞᭴▽‫ߩࠢ࡯ࡢ࠻࠶ࡀޔ‬៨േ⸃ᨆࠍㅢߓߡ⮎೷ᛶ᛫ᕈࡔࠞ࠾࠭ࡓߩ⸃᣿ߣ୥⵬ߣߥࠆ⮎೷ᮡ ⊛⚻〝ߩหቯࠍ⋡ᜰߔߣߣ߽ߦ‫࠻࠶ࠥ࡯࠲࠴࡞ࡑߦ․ޔ‬ഃ⮎ߩน⢻ᕈࠍᬌ⸛ߔࠆ‫ޕ‬ ‫⺖ޣ‬㗴ߩ᭎ⷐ‫ޤ‬ ౕ૕⊛ߦ‫ޔ‬2ᐕ㑆ߢએਅߩ੐ᨩࠍ೔㆐น⢻ߦߔࠆ‫ޕ‬Ԙ ੃߇ࠎߦ㑐ߔࠆࠪࠣ࠽࡞વ㆐♽ࡀ࠶ ࠻ࡢ࡯ࠢMAPߩ૞ᚑ‫ޕ‬ԙ TAMᗵฃᕈ࡮㕖ᗵฃᕈMCF-7⚦⢩ߦߟ޿ߡߩࠛࠬ࠻ࡠࠥࡦᛩਈᤨ‫ޔ‬ EGFᷝടᤨߩ⁁ᘒߢߩᤨ♽೉࡮ቯ㊂⊛࡝ࡦ㉄ൻࡊࡠ࠹ࠝ࡯ࡓߩ♖ኒᤨ♽೉᷹ቯߦࠃࠆࠪࠣ࠽ ࡞વ㆐♽ߩ࠳ࠗ࠽ࡒ᷹ࠢࠬቯ‫ޕ‬Ԛ ห᭽ߩ᧦ઙਅߢߩㆮવሶ⊒⃻⸃ᨆߦࠃࠆࠪࠣ࠽࡞ᮡ⊛ㆮવ ሶߣォ౮࿃ሶࡀ࠶࠻ࡢ࡯ࠢߩหቯߣߘߩ࠳ࠗ࠽ࡒ᷹ࠢࠬቯ‫ޕ‬ԛ ԙߣԚߩ࠺࡯࠲ࠍ߽ߣߦߒߚ േ⊛ࡀ࠶࠻ࡢ࡯ࠢផቯ߅ࠃ߮਄⸥MAPࠍ೑↪ߒߚ೙ᓮࡀ࠶࠻ࡢ࡯ࠢߩ੍᷹ߣᢙℂࡕ࠺࡞ߩ᭴ ▽‫ޕ‬Ԝ ៨േ⸃ᨆߦࠃࠆࡀ࠶࠻ࡢ࡯ࠢ⸃ᨆߣࠦࡦࡆ࠽࠻࡝ࠕ࡞࡮࠮࡜ࡇ࡯ߩᮡ⊛⚻〝ߩหቯ‫ޕ‬ ԝ ߇ࠎ⚦⢩ߣᱜᏱ⚦⢩ߩ࠳ࠗ࠽ࡒࠢࠬߣࡠࡃࠬ࠻ࡀࠬߩᏅಽߩᢙℂ⸃ᨆ‫ޕ‬Ԟ ߐࠄߦ‫ࠇߎޔ‬ ࠄߩ⸃ᨆࡊࡠ࠮ࠬࠍ᣿⏕ߦቯ⟵ߒ‫ޔ‬น⢻ߥ㒢ࠅࠪࠬ࠹ࡓൻߔࠆߎߣߢ‫ࠢ࡯ࡢ࠻࠶ࡀࡓࡁࠥޔ‬ ߩ⸃ᨆࡄࠗࡊ࡜ࠗࡦߩ᭴▽ࠍ⋡ᜰߔ‫ޕ‬ ‫ޣ‬ᐔᚑ㧞㧜ᐕ㧤᦬ᧃ߹ߢߩ⎇ⓥᚑᨐ‫ޤ‬ 㨍㧕േ⊛ᢙℂࡕ࠺࡞ߩ᭴▽ߦ㑐ߒߡ EGFR ߩಽሶ⋧੕૞↪ MAP ࠍ᜛ᒛߒ‫ޔ‬ER ߥߤࠍ฽߼ߚ⋧੕૞↪ࡀ࠶࠻ࡢ࡯ࠢࠍ᭴▽ߒ ߚ‫⃻ޕ‬࿷ߪ‫ ߩߘޔ‬Version0.5 ࠍ૞ᚑ‫੹ޔ‬ᓟߐࠄߦᒝൻߔࠆ੍ቯߢ޽ࠆ‫ޕ‬ ࡅࠕ࡝ࡦࠣߦ߅޿ߡߪ‫ ߩߎޔ‬MAP ߩ᭴▽߇น⢻ߢ޽ࠆ߆߇৻ߟߩࡐࠗࡦ࠻ߦߥߞߡ޿ߚ‫ޕ‬ ታ㓙ߦ‫ޔ‬EGFR ߣ ER ߥߤࠍ⚿߱⋧੕૞↪ࠍᢥ₂ᖱႎߥߤ߆ࠄหቯߒ‫⟜✂ޔ‬ᕈߩ㜞޿ MAP ߇ቢᚑߒߟߟ޽ࠆ‫ ߩߎޕ‬MAP ߩ૞ᚑㆊ⒟ߢ‫ޔ‬EGFR ߣ ER ߇ⶄว૕ࠍ૞ߞߡ޿ࠆߣ޿߁ႎ ๔ࠍߔࠆ⺰ᢥ߇‫ޔ‬ᢙㅢ⊒⷗ߐࠇߚ‫ߥ⊛⥸৻ޔߪࠇߎޕ‬ℂ⸃ߣߪ⇣ߥࠆ߇‫ⶄޔ‬ᢙߩ⎇ⓥቶ߆ࠄ ߩႎ๔ߢ޽ࠅ‫ߩߎޔ‬ਛりߦ㑐ߒߡࡊࡠࠫࠚࠢ࠻ࡔࡦࡃ࡯ో૕ߢี๧ߔࠆߎߣߣߥߞߚ‫ޔߚ߹ޕ‬ ᒰೋߪ‫ޔ‬EGFR ߣ ER ߩߺࠍ฽߼ࠆ੍ቯߢ޽ߞߚ߇‫ ߩ߆ߟߊ޿ޔ‬GPCR ࠪࠣ࠽࡞♽ࠍ߽฽ ߼ࠆᔅⷐ߇޽ࠆߎߣ߇್᣿ߒ‫ࠍࠄࠇߘޔ‬฽߼ߚ MAP ߣߥߞߚ‫ޕ‬MAP ߩⷙᮨߪ‫ޔ‬ಽሶ⒳ᢙ 449‫⋧ޔ‬੕૞↪ᢙ 282 ߣߥࠅ‫ᦨޔ‬ᄢⷙᮨߩ MAP ߢ޽ࠆ‫ޕ‬ 㨎㧕ࡃࠗࠝࠗࡦࡈࠜࡑ࠹ࠖࠢࠬ‫ޔ‬ᢙℂ⑼ቇ⊛⸃ᨆߦߟ޿ߡ MAP ߩ૞ᚑㆊ⒟ߦ߅޿ߡ‫⸃࠲࡯ࡕࡠࡊޔ‬ᨆ߿⊒⃻⸃ᨆࠍⴕ޿‫⋧ޔ‬੕૞↪ߩ⏕߆ߐߩ৻ߟ ߩற⸽ߣߒߚ‫ޕ‬ ৻ᣇ‫ߩ࠻ࠢࠚࠫࡠࡊࠢ࡯ࡢ࠻࠶ࡀࡓࡁࠥޔ‬ᖱႎၮ⋚ࠨࠗ࠼㧔ㆮવ⎇▤ロ㧕ߩ᧲੩ᄢቇߩㄞ ੗⎇ߣኒߦㅪ៤ߒ‫ޔ‬ᢥ₂ᖱႎࡑࠗ࠾ࡦࠣ࠷࡯࡞ PathTEXT ࠍㅪേߐߖ‫ޔ‬㧹㧭P 㐿⊒ߦ೑↪ ߔࠆࡊ࡜࠶࠻ࡈࠜ࡯ࡓࠍ᭴▽ߒߟߟ޽ࠆ‫ߩߎޕ‬ㅪേߢ‫ޔ‬MAP ߩㇱ૏ࠍⷞⷡ⊛ߦ⏕⹺࡮ᜰቯ ߒߥ߇ࠄ‫ޔ‬㑐ㅪㇱ૏ߩᢥ₂ᖱႎࠍㄦㅦߦ߆ߟ⊛⏕ߦ⍮⊛ត⚝ߔࠆߎߣ߇น⢻ߣߥࠅ‫ޔ‬MAP 㐿⊒ߩ૞ᬺല₸ߩะ਄߇⷗ㄟ߹ࠇࠆ‫ޕ‬ ߹ߚ‫ޔ‬ታ㛎࠺࡯࠲ߩ⸃ᨆߪ‫ޔ‬ฦ‫ߩޘ‬ታ㛎࠴࡯ࡓ߇╙৻Ბ㓏ߩ⸃ᨆࠍⴕߞߚ‫⛔࠲࡯࠺ޕ‬วᓟ ߦߐࠄߦో૕ߩ⸃ᨆࠍⴕ߁੍ቯߢ޽ࠆ‫ޕ‬.

(8) 㨏㧕ࡕ࠺࡞ࠍ᭴▽ߔࠆߚ߼ߩ⚦⢩ౝಽሶേᘒ⸃ᨆ‫↥↢࠲࡯࠺ޔ‬ ታ㛎࡮࠺࡯࠲↥಴ߦ㑐ߒߡߪ‫ޔ‬ℂ⎇⇗ጊ࠴࡯ࡓ‫᧲ޔ‬ᄢየጊ࠴࡯ࡓ‫ޔ‬ၯ₹කᄢ੗਄࠴࡯ࡓ߇ ᜂᒰߒߡ޿ࠆ‫ޕ‬ၮᧄ⊛ߦ㗅⺞ߢ޽ࠆ‫ޔߦ․ޕ‬ᵈ⸥ߐࠇࠆ੐㗄ߣߒߡߪ‫ࡦࠚࡈࠪࠠࡕ࠲ޔ‬㕖ᗵ ฃᕈMCFг7⚦⢩ᩣߩ᮸┙ߦᚑഞߒߚߎߣ߇޽ࠆ‫ߩࠣࡦ࡝ࠕࡅޔߪࠇߎޕ‬㓙ߦ ᔨߐࠇߚ੐ 㗄ߢ޽ߞߚߩߢ‫ޔ‬ᄢ߈ߥ೨ㅴߢ޽ࠆ‫ޕ‬᮸┙ߒߚ࠲ࡕࠠࠪࡈࠚࡦ㕖ᗵฃᕈᩣ6♽⛔ࠍ⸃ᨆߒߚ ߣߎࠈ‫ࡦࠚࡈࠪࠠࡕ࠲ޔ‬ሽ࿷ਅߦ߅޿ߡ߽‫ࡦࠥࡠ࠻ࠬࠛޔ‬ሽ࿷ਅߦ߅޿ߡ߽‫⚦ޔ‬⢩Ⴧᱺㅦᐲ ߇੣ㅴߒߡ޿ࠆߎߣ߇᣿ࠄ߆ߦߥߞߚ‫ࡦࠚࡈࠪࠠࡕ࠲ߩࠄࠇߎޔߚ߹ޕ‬㕖ᗵฃᕈᩣߦ߅޿ߡ ߪESR1/ERD࠲ࡦࡄࠢ⾰ߩ⊒⃻߇੣ㅴߒߡ޿ࠆ௑ะ߇ⷰኤߐࠇߚ‫ޔߚ߹ޕ‬᮸┙ߒߚ࠲ࡕࠠࠪ ࡈࠚࡦ㕖ᗵฃᕈᩣߪ৻ߟࠍ㒰޿ߡᭂ߼ߡૃㅢߞߚㆮવሶ⊒⃻ߩࡄ࠲࡯ࡦࠍ᦭ߒߡ߅ࠅ‫ޔ‬㕖Ᏹ ߦ቟ቯߒߡ޿ࠆ‫ߩߎޕ‬ᩣࠍ೑↪ߒߡ‫ࡦࠚࡈࠪࠠࡕ࠲ޔ‬ᛶ᛫ᕈߦ㑐ߔࠆ⎇ⓥ߇น⢻ߣߥߞߚ‫ޕ‬ ߹ߚ‫ࡦࠥࡠ࠻ࠬࠛޔ‬ᨗᷢ⠴ᕈMCF-7⚦⢩ᩣ߽᮸┙ߢ߈ߡ߅ࠅ‫ࡦࠥࡠ࠻ࠬࠛޔ‬㕖ଐሽᕈߩ੃≸ Ⴧᱺࡕ࠺࡞ࠍ᭴▽ߒߡ޿ࠆ‫ޕ‬ ⃻ᤨὐߦ߅޿ߡߪ‫ޔ‬MCFг7 ⚦⢩ࠍ૶ߞߡ‫ޔ‬ㆮવሶ⊒⃻࠺࡯࠲‫㉄ࡦ࡝⾰ߊ߬ࠎߚޔ‬ൻߩᤨ ♽೉࠺࡯࠲߇ขᓧߐࠇ‫⛔࠲࡯࠺ޔ‬วࠍ㐿ᆎߔࠆ⋡ಣ߇┙ߞߚ‫ޕ‬ =⚦⢩ࠨࡦࡊ࡞ߩ⺞ᢛ? ࠲ࡕࠠࠪࡈࠚࡦᗵฃᕈ/%( ㊁↢ᩣ ߦߟ޿ߡ‫㉄ࡦ࡝ޔ‬ൻࡊࡠ࠹ࠝ࡯ࡓ⸃ᨆ↪߅ࠃ߮ࡑࠗ ࠢࡠࠕ࡟ࠗ⸃ᨆ↪ߩࠨࡦࡊ࡞⺞ᢛࠍⴕߞߚ‫㉄ࡦ࡝ޔߦ․ޕ‬ൻࡊࡠ࠹ࠝ࡯ࡓ↪ߩࠨࡦࡊ࡞ߦߟ ޿ߡߪ‫⾰ࠢࡄࡦ࠲ޔ‬ᬌ಴⢻ࠍ਄ߍࠆࠃ߁ၭ㙃⚦⢩ߩ᧦ઙ߿ࠨࡦࡊ࡞⺞ᢛߩᲑ㓏ߢߩ᧦ઙᬌ⸛ ࠍⴕߞߚ‫㉄ࡦ࡝ࡦࠪࡠ࠴ޕ‬ൻ⸃ᨆ↪ࠨࡦࡊ࡞ߦߟ޿ߡߪฦᤨ㑆ὐ޽ߚࠅEOࠪࡖ࡯࡟⚂ ᨎ‫㉄ࡦ࡝ࡦ࠾ࠝ࡟ࠬ࡮ࡦ࡝࠮ޔ‬ൻ⸃ᨆ↪ࠨࡦࡊ࡞ߦߟ޿ߡߪEOࠪࡖ࡯࡟⚂ᨎࠍ᧲ᄢߣ౒ ߦࠨࡦࡊ࡞ಣℂ᧦ઙࠍᬌ⸛ߒߚ‫⸃ࠗ࡟ࠕࡠࠢࠗࡑޕ‬ᨆ↪ߦߟ޿ߡߪฦᤨ㑆ὐ޽ߚࠅᨎ⒟ᐲ ߩ⚦⢩ߢ⦟ᅢߥࠨࡦࡊ࡞ࠍᓧࠆߎߣ߇ߢ߈ߚ‫ࡦࠚࡈࠪࠠࡕ࠲ޔߚ߹ޕ‬㕖ᗵฃᕈ⚦⢩ࠢࡠ࡯ ࡦߦߟ޿ߡ‫ࡦࠚࡈࠪࠠࡕ࠲ޔ‬ᛩਈᤨߩ⚦⢩ᔕ╵߇ૐ޿߽ߩࠍㆬ߱ߚ߼ࡑࠗࠢࡠࠕ࡟ࠗࠍ↪޿ ߡᬌ⸛ߒ‫ޕߚߞ⛉ߦࡦ࡯ࡠࠢޔ‬㕖ᗵฃᕈ⚦⢩ߦߟ޿ߡ߽㊁↢ᩣߣห᭽ߩ⚦⢩↪߅ࠃ߮ࠨࡦ ࡊ࡞⺞ᢛࠍⴕߞߡ޿ࠆ‫ޕ‬ =࡝ࡦ㉄ൻࡊࡠ࠹ࠝ࡯ࡓ⸃ᨆ? ᧄࡊࡠࠫࠚࠢ࠻ߦ߅޿ߡߪ‫♽ᤨޔ‬೉࠺࡯࠲ߩ૞ᚑߦะߌߡ‫ࠍ࠲࡯࠺ࡓ࡯ࠝ࠹ࡠࡊޔ‬ၮߦߒ ߚ⋧ኻቯ㊂࠺࡯࠲ߩ↢ᚑ෸߮⛔วࠍⴕ߁ᖱႎಣℂࡊ࡜࠶࠻ࡈࠜ࡯ࡓࠍᣂߚߦ᭴▽ߒߚ‫⿥ޕ‬ૐ ᵹㅦߩᶧ૕ࠢࡠࡑ࠻ࠣ࡜ࡈࠖ࡯ߣ㜞ಽ⸃⢻ߩ⾰㊂ಽᨆ⸘߇QPNKPGߢធ⛯ߐࠇߚPCPQ.%/5 /5ࠪࠬ࠹ࡓߪ࡚ࠪ࠶࠻ࠟࡦᑼߦ࠺࡯࠲ࠍ↥↢ߒ‫⚿ߩߘޔ‬ᨐᲧセ⊛ኈ㊂ߩᄢ߈޿↢࠺࡯࠲߇૞ ᚑߐࠇࠆ‫੹ޕ‬࿁᭴▽ߒߚ࠺࡯࠲ಣℂࡊ࡜࠶࠻ࡈࠜ࡯ࡓߦ߅޿ߡߪ‫ޔ‬᷹ቯߦࠃߞߡᓧࠄࠇࠆ↢ ࠺࡯࠲ࠍၮߦ⥄േߢቯ㊂ߒ‫ޔ‬ฦ࠲ࡦࡄࠢ⾰ߦ㑐ߔࠆᤨ♽೉ᵴᕈᄌേ࠺࡯࠲ࠍ㜞ㅦߢ⛔ว࡮৻ ⷩൻߔࠆߎߣ߇น⢻ߣߥߞߚ‫‛ߩ࠲࡯࠺ࡓ࡯ࠝ࠹ࡠࡊߩߣߏ࡞ࡊࡦࠨߦࠄߐޕ‬ᕈᖱႎࠍⷞⷡ ⊛ߦᲧセน⢻ߦߔࠆ࠺࡯࠲ಣℂࠪࠬ࠹ࡓࠍ૬ߖߡ᭴▽ߔࠆߎߣߦࠃࠅ‫↢↥ߩߣߏ࡞ࡊࡦࠨޔ‬ ࠺࡯࠲ࠍ൮᜝⊛ߦ⹏ଔߒ‫ޔ‬ታ㛎᧦ઙߩᬌ⸛ߦല₸⊛ߦࡈࠖ࡯࠼ࡃ࠶ࠢߔࠆߎߣ߽น⢻ߦߥߞ ߚ‫ޕ‬ ࡊࡠࠫࠚࠢ࠻㐿ᆎᒰೋ߆ࠄᣇᴺ⺰߇⏕┙ߒߡ޿ߚ࠴ࡠࠪࡦ࡝ࡦ㉄ൻߩᄌേ⸃ᨆߦ㑐ߒߡ ߪ‫ࡦࠚࡈࠪࠠࡕ࠲ޔ‬ᗵฃᕈ/%(⚦⢩ߦ߅ߌࠆࠛࠬ࠻ࡠࠥࡦ෸߮*4)ᛩਈᓟಽ߹ߢߩᤨ♽೉ ࠺࡯࠲ߩขᓧ߇ቢੌߒ‫⾰ࠢࡄࡦ࠲ޔ‬หቯᬌ⚝ߩ㑣୯㧔R㧨㧕ࠍḩߚߔ⒳㘃ߩ࠲ࡦࡄࠢ ⾰ߦ㑐ߒߡోᤨ♽೉࠺࡯࠲ߩᖱႎಣℂ࡮⛔วࠍⴕߞߚ‫()'ޕ‬4ࡈࠔࡒ࡝࡯࡝ࠟࡦ࠼ߩ৻ߟߢ޽ ࠆ*4)ࠍ↪޿ߚೝỗߦࠃߞߡ'TD$ࡈࠔࡒ࡝࡯ࡄࠬ࠙ࠚࠗߩਥⷐ࿃ሶߩᄙߊ߇࠴ࡠࠪࡦ࡝ࡦ㉄ ൻߩ੣ㅴࠍ␜ߒߡ޿ߚઁ‫ޔ‬ᒰ⹥ࠪࠣ࠽࡞ࡀ࠶࠻ࡢ࡯ࠢౝߩਥⷐࡄࠬ࠙ࠚࠗ਄ߦቯ⟵ߢ߈ߥ޿ ⷐ⚛߽หቯߐࠇߚ‫ޕ‬ .

(9) ৻ᣇ‫㉄ࡦ࡝ࡦ࠾ࠝ࡟ࠬ࡮ࡦ࡝࠮ޔ‬ൻࠍ฽߼ߚో࡝ࡦ㉄ൻࠪࠣ࠽࡞࿃ሶߩ⸃ᨆߦะߌߚᣇᴺ ⺰ߦ㑐ߒߡߪ‫ޔ‬ᐔᚑᐕᐲߦEOFKUJ৻ᨎಽએਅߩೋᦼ⚦⢩⹜ᢱࠍ↪޿ߚታ㛎᧦ઙߩᬌ⸛ ࠍⴕ޿‫ޔ‬2JQUVCIࠕࠟࡠ࡯ࠬߦࠃࠆ⚦⢩ౝ࡝ࡦ㉄ൻࡍࡊ࠴࠼ߩല₸⊛ߥỚ❗ᴺࠍ⏕┙ߒߚ‫ޕ‬ ᧄᣇᴺ⺰ࠍ↪޿ߚ⾰㊂ಽᨆ᷹ቯߦ߅޿ߡ⒳㘃એ਄ߩ࡝ࡦ㉄ൻࡍࡊ࠴࠼߇หቯߐࠇ‫ࡍోޔ‬ ࡊ࠴࠼ߦභ߼ࠆ࡝ࡦ㉄ൻࡍࡊ࠴࠼ߩഀวߪ㧑એ਄ߣല₸⊛ߦ᷹ቯኻ⽎ࠍỚ❗ߔࠆߎߣ߇ น⢻ߦߥߞߚ‫⃻ޕ‬࿷࠲ࡕࠠࠪࡈࠚࡦᗵฃᕈ/%(⚦⢩ߦ㑐ߒߡ‫ޔ‬਄⸥ߣห৻ߩೝỗ᧦ઙߦ߅ ߌࠆో࡝ࡦ㉄ൻࠪࠣ࠽࡞࿃ሶߦ㑐ߔࠆᤨ♽೉࠺࡯࠲ߩขᓧࠍㅴ߼ߡ޿ࠆᲑ㓏ߢ޽ࠆ‫ޔ߅ߥޕ‬ వᣣ᮸┙ߐࠇߚ࠲ࡕࠠࠪࡈࠚࡦ㕖ᗵฃᕈ/%(⚦⢩ߦ㑐ߒߡߪ‫⃻ޔ‬࿷ࡊࡠ࠹ࠝ࡯ࡓ⸃ᨆ↪ߦ ቟ቯห૏૕ᮡ⼂ࠍዉ౉ߒߡ޿ࠆߣߎࠈߢ޽ࠅ‫߽ࠄߜߎޔ‬ᔅⷐߥ⚦⢩⹜ᢱ߇ឥ޿ᰴ╙‫ޔ‬㗅ᰴࠨ ࡦࡊ࡞⺞⵾ࠍⴕ޿‫ࠍ࠲࡯࠺ޔ‬ขᓧߔࠆ੍ቯߢ޽ࠆ‫ޕ‬ =ቯ㊂࠙ࠛࠬ࠲ࡦࡉࡠ࠶࠹ࠖࡦࠣߦࠃࠆ࡝ࡦ㉄ൻⰮ⊕⾰ߩᤨ♽೉⸃ᨆ? ࠲ࡕࠠࠪࡈࠚࡦᗵฃᕈ MCF-7 ⚦⢩ߦ߅޿ߡ‫ޔ‬HRG ೝỗߦࠃߞߡᵴᕈൻߐࠇࠆࠪࠣ࠽࡞ࡀ ࠶࠻ࡢ࡯ࠢ਄ᣢ⍮ߩ㎛ಽሶߦߟ޿ߡ‫㉄ࡦ࡝ߩߘޔ‬ൻࠍᬌ಴ߔࠆ᛫૕ࠍ↪޿ߚቯ㊂࠙ࠛࠬ࠲ࡦ ࡉࡠ࠶࠹ࠖࡦࠣࠍⴕ޿‫㉄ࡦ࡝ޔ‬ൻࡊࡠ࠹ࠝ࡯ࡓߢขᓧߒߚᤨ♽೉ߣห᭽ߩᤨ♽೉㧔60 ಽ߹ߢ㧕 ߢ‫ޔ‬ಽሶߩ࡝ࡦ㉄ൻߩᤨ♽೉࠺࡯࠲ࠍขᓧߒߚ‫ޕ‬Ras/ERK ࡄࠬ࠙ࠛࠗߩ㎛ಽሶߣߒߡ MEK‫ޔ‬ ࠛࠬ࠻ࡠࠥࡦࡄࠬ࠙ࠛࠗߩࠢࡠࠬ࠻࡯ࠢ㎛ಽሶߣߒߡ‫ࡦࠥࡠ࠻ࠬࠛޔ‬ฃኈ૕ߩ࡝ࡦ㉄ൻߦߟ ޿ߡ࠺࡯࠲ࠍᓧߚ‫ ߽ࠇߕ޿ޕ‬5 ಽએౝߦ࡝ࡦ㉄ൻ࡟ࡌ࡞ߪࡇ࡯ࠢߦ㆐ߒ‫ޔ‬MEK ߪ৻ㆊᕈߩ ࡇ࡯ࠢߩᓟᣧᦼߦ࡝ࡦ㉄ൻ࡟ࡌ࡞߇ૐਅߔࠆ৻ᣇ‫ࡦࠥࡠ࠻ࠬࠛޔ‬ฃኈ૕࡝ࡦ㉄ൻߪ‫ޔ‬ᜬ⛯⊛ ߢ޽ߞߚ‫⃻ޕ‬࿷ઁߩⶄᢙߩ㎛ಽሶ߽฽߼ߡ‫ࡦࠥࡠ࠻ࠬࠛޔ‬ೝỗߦߟ޿ߡ߽࡝ࡦ㉄ൻ࠺࡯࠲ࠍ ขᓧߒߡ޿ࠆ‫੹ޕ‬ᓟ࠲ࡕࠠࠪࡈࠚࡦ⠴ᕈ MCF-7 ⚦⢩ߦ߅޿ߡ‫ޔ‬ห᭽ߩᤨ♽೉࠺࡯࠲ࠍขᓧ ߒ‫ࠗࠛ࠙ࠬࡄޔ‬਄ߩ㎛ಽሶߩേᘒᄌൻࠍ⸃ᨆߔࠆ‫ޕ‬ =ቯ㊂⊛2%4⸃ᨆߦࠃࠆ/%(⚦⢩ߦ߅ߌࠆࠛࠬ࠻ࡠࠥࡦᔕ╵ㆮવሶߩേ⊛ࡀ࠶࠻ࡢ࡯ࠢ⸃ᨆ? ࠛࠬ࠻ࡠࠥࡦᛩਈᓟߩO40#⊒⃻࡟ࡌ࡞ߩ೙ᓮࠍᤨ㑆ゲߦᴪߞߡ૕♽⊛ߦ⸃᣿ߔࠆߚ߼‫ޔ‬ /%(ᮡḰ⚦⢩ࠍ↪޿ߡP/ࠛࠬ࠻ࡠࠥࡦߢೝỗߒ‫ࡦࠥࡠ࠻ࠬࠛޔ‬ᛩਈᓟὐ㧔‫ޔޔޔޔ‬ ‫ᤨޔޔޔ‬㑆ᓟ㧕ߩᤨ㑆⚻ㆊߦᓥߞߡ40#ࠍ᛽಴ߒߚ‫ߩߘޕ‬40#ࠍ↪޿ߡᮮゲᯏ㑐㧔ℂ ൻቇ⎇ⓥᚲ㧦ᨋፒ⎇ⓥቶ㧕ߣߩ౒ห⎇ⓥߢቯ㊂⊛2%4ᴺࠍⴕ޿‫ޔ‬୘⿥ߩォ౮࿃ሶࠍਛᔃ ߣߔࠆㆮવሶߩᤨ㑆ゲߦᴪߞߚࠛࠬ࠻ࡠࠥࡦߦࠃࠆ⊒⃻ᄌൻߩ࠺࡯࠲ࠍขᓧߒߚ‫ࠄࠇߘޕ‬ㆮ વሶߩࠛࠬ࠻ࡠࠥࡦߦࠃࠆ⊒⃻㊂ߩᄌൻࠍࠦࡦࡇࡘ࡯࠲࡯ߦࠃࠅࠢ࡜ࠬ࠲࡯⸃ᨆࠍⴕߞߚ ߣߎࠈ‫ޔ‬ᢙᄙߊߩࠛࠬ࠻ࡠࠥࡦߦࠃߞߡ⊒⃻਄᣹ࠍ␜ߔㆮવሶ⟲߇หቯߐࠇߚ‫ࠥࡠ࠻ࠬࠛޕ‬ ࡦߦࠃࠅ⊒⃻਄᣹ࠍ␜ߔㆮવሶߩ߁ߜ‫⸃ߩ߆ࠇߕ޿ޔ‬ᨆࡐࠗࡦ࠻ߦ߅޿ߡ୚એ਄ߩ⊒⃻਄ ᣹ࠍ␜ߔ߽ߩߪ୘ሽ࿷ߒߡ߅ࠅ‫ߩࠄࠇߘޔ‬ㆮવሶߦ⌕⋡ߒߡ࠺࡯࠲ࡌ࡯ࠬߦࠃࠆㆮવሶ ᯏ⢻ߣߩ㑐ㅪઃߌࠍⴕߞߚ‫⚿ߩߘޕ‬ᨐ‫⚦ޔ‬⢩๟ᦼ‫ޔ‬40#ࠬࡊ࡜ࠗࠪࡦࠣ‫ୃࡦ࠴ࡑࡠࠢޔ‬㘼‫ޔ‬ ၮᧄォ౮࿃ሶ‫ޔ‬ᩭౝฃኈ૕‫&ޔ‬0#ୃᓳ‫ୃࡦ࠴ࠠࡆ࡙ޔ‬㘼‫⚦ޔࠬࠪ࡯࠻ࡐࠕޔ‬⢩㛽ᩰߥߤߣ㑐 ㅪߔࠆㆮવሶߩࠢ࡜ࠬ࠲࡯ߦಽ㘃ߔࠆߎߣ߇ߢ߈ߚ‫ߩߎޕ‬ਛߢ‫ࡦࠥࡠ࠻ࠬࠛޔ‬ฃኈ૕ࠍߪߓ ߼ߣߔࠆᩭౝฃኈ૕ߣߒߡ‫'ޔ‬54'4E‫ޔ‬2)4ߥߤ߇ࠛࠬ࠻ࡠࠥࡦߦࠃߞߡ⊒⃻਄᣹ߔࠆߎߣ ߇หቯߐࠇߚ‫'ޕ‬54ㆮવሶߩ⊒⃻߇⷗ࠄࠇࠆ੃≸ߢߪ੍ᓟ߇⦟ᅢߢ‫≮ࡦࡕ࡞ࡎޔ‬ᴺߦࠃࠆᴦ ≮ലᨐ߇⦟޿௑ะ߇ⷰኤߐࠇߡ޿ࠆ‫'ޔߚ߹ޕ‬54ㆮવሶߩᄌ⇣ߪᕈࠬ࠹ࡠࠗ࠼ࡎ࡞ࡕࡦߩ↢ ᚑ߿ઍ⻢߅ࠃ߮ࠪࠣ࠽࡞વ㆐⚻〝ߦᓇ㗀ࠍ෸߷ߔน⢻ᕈ߇⠨߃ࠄࠇߡ߅ࠅ‫ߦࠢࠬ࡝≸੃ޔ‬ᓇ 㗀ࠍ෸߷ߔน⢻ᕈ߇␜ໂߐࠇߡ޿ࠆ‫ޕ‬2)4ߪࠛࠬ࠻ࡠࠥࡦᔕ╵ㆮવሶߣߒߡ⍮ࠄࠇ‫ߢ≸੃ޔ‬ ߪ2)4㓁ᕈߩ߽ߩߪ੍ᓟ߇⦟ߊ‫≮ࡦࡕ࡞ࡎޔ‬ᴺߦኻߔࠆ෻ᔕ߇⦟޿ߎߣ߇⍮ࠄࠇߡ޿ࠆ‫ߎޕ‬ ࠇࠄߩᩭౝฃኈ૕ߩ⊒⃻ᄌൻߪࡎ࡞ࡕࡦ૞↪߅ࠃ߮ᴦ≮⮎ᛶ᛫ᕈࠍ⸃ᨆߔࠆ਄ߢၮᧄ⊛ߥ ᖱႎࠍਈ߃ࠆߣ⠨߃ࠄࠇߚ‫ߦࠄߐޕ‬ᣂⷙߩᩭౝฃኈ૕ߩ೙ᓮࠍ⷗಴ߒ‫ޔ‬ᯏ⢻⸃ᨆࠍㅴ߼ߡ޿ ࠆ‫ޔߚ߹ޕ‬ᩭౝฃኈ૕ߣ⚿วߒߡߘߩᵴᕈࠍ೙ᓮߔࠆࡈࠜ࡯ࠢࡋ࠶࠼ォ౮࿃ሶࡈࠔࡒ࡝࡯߇ ࠛࠬ࠻ࡠࠥࡦߦࠃߞߡ೙ᓮߐࠇߡ޿ࠆߎߣࠍ⷗޿಴ߒߚ‫ޕ‬ .

(10) =ࡑࠗࠢࡠࠕ࡟ࠗ⸃ᨆ? /%(㊁↢ᩣߦࠛࠬ࠻ࡠࠥࡦ߹ߚߪᚑ㐳࿃ሶࠍᛩਈߒߚᤨߩㆮવሶ⊒⃻ߩᤨ㑆ᄌൻࠍ‫ޔ‬ #HH[OGVTKZ)GPG%JKRࠍ↪޿ߡ⸃ᨆߒߚ‫߮ࠃ߅ࡦࠥࡠ࠻ࠬࠛޕ‬ᚑ㐳࿃ሶᛩਈߢ⊒⃻࡟ࡌ࡞߿ ࡄ࠲࡯ࡦߩ⇣ߥࠆㆮવሶࠍ᛽಴ߒ‫⸃࡯࠲ࠬ࡜ࠢޔ‬ᨆߦࠃߞߡ㘃ૃߒߚ⊒⃻ࡄ࠲࡯ࡦࠍ␜ߔㆮ વሶ⟲ߦಽ㘃ߒߚ‫⚿ߩߘޕ‬ᨐ‫ߣࡦࠥࡠ࠻ࠬࠛޔ‬ᚑ㐳࿃ሶߦࠃߞߡ⺃ዉߐࠇࠆㆮવሶ߅ࠃ߮ߘ ߩ⊒⃻ࡄ࠲࡯ࡦߦᄢ߈ߥ㆑޿߇޽ࠆߎߣ߇᣿ࠄ߆ߣߥߞߚ‫㉄ࡦ࡝ޔߚ߹ޕ‬ൻࡊࡠ࠹ࠝ࡯ࡓߣ ㆮવሶ⊒⃻㧔S462%4ߣ)GPG%JKR㧕ߩ⛔ว⸃ᨆߩ⚿ᨐ‫ޔ‬ਔ⠪ߢᄌേߩ޽ߞߚㆮવሶࠍหቯ ߒߚ‫ޕ‬ᢥ₂ᖱႎߩ࠺࡯࠲ࡑࠗ࠾ࡦࠣ߆ࠄߎࠇࠄߩ߶ߣࠎߤ߇ࠛࠬ࠻ࡠࠥࡦฃኈ૕㧙ࠪࠣ࠽࡞ વ㆐♽㧙$4%#ࡄࠬ࠙ࠚࠗߦ㑐ㅪߔࠆߎߣ߇᣿ࠄ߆ߣߥߞߚ‫ޔߦࠄߐޕ‬㊁↢ᩣߣ࠲ࡕࠠࠪࡈ ࠚࡦ㕖ᗵฃᕈᩣߦ߅ߌࠆㆮવሶ⊒⃻ߩᲧセࠍⴕ޿‫⚦ߩࠄࠇߎޔ‬⢩㑆ߢ⊒⃻ࡄ࠲࡯ࡦ߇ㅒ⋧㑐 ࠍ␜ߔㆮવሶ⟲ࠍหቯߒ‫⸃ࠗࠚ࠙ࠬࡄߩߘޔ‬ᨆࠍⴕߞߚ‫ޕ‬㊁↢ᩣߢߪ$4%#‫⚦ޔ‬⢩๟ᦼ‫ޔ‬N[CUG ᵴᕈࠍᜬߟ߽ߩ߇‫ޔ‬㕖ᗵฃᕈᩣߢߪ0QVEJࠪࠣ࠽࡞߿)RTQVGKPࠪࠣ࠽࡞ߥߤࠪࠣ࠽࡞વ㆐ߦ 㑐ਈߔࠆㆮવሶ߇㜞⊒⃻ߒߡ޿ࠆߎߣ߇ࠊ߆ߞߚ‫⸃ߩ࠻࠶ࡠࡉ࡮ࡦ࠲ࠬࠚ࠙ޕ‬ᨆߥߤߦࠃߞ ߡ‫ޔ‬㕖ᗵฃᕈᩣߢߪࠛࠬ࠻ࡠࠥࡦฃኈ૕ߩᯏ⢻ᄌൻ߇⿠ߞߡ޿ࠆน⢻ᕈ߇␜ໂߐࠇߚ‫ޕ‬ 㨐㧕ࡃࠗࠝࠗࡦࡈࠜࡑ࠹ࠖࠢࠬ‫ޔ‬ᢙℂ⑼ቇ⊛⸃ᨆߣ⚦⢩ౝಽሶേᘒ⸃ᨆ‫ߩ↥↢࠲࡯࠺ޔ‬ㅪ៤ 㧣᦬߆ࠄ‫⛔࠲࡯࠺ޔ‬ว૞ᬺࠍ㐿ᆎߒߚ‫ޔߪࠇߎޕ‬ᄢⷙᮨMAP਄ߦ‫ޔ‬ㆮવሶ⊒⃻‫㉄ࡦ࡝ޔ‬ൻ ࡊࡠ࠹ࠝ࡯ࡓ‫⛔ࠍ࠲࡯࠺ߩߤߥ࠻࠶ࡠࡉ࡮ࡦ࠲ࠬࠛ࠙ޔ‬วߒߡ‫ߩߘޔ‬േᘒࠍឬߊ૞ᬺߢ޽ࠆ‫ޕ‬ ߎߩ࠺࡯࠲⛔วࠍᓧߡ‫࡞࠽ࠣࠪޔ‬વ㆐ߩታᘒ߇นⷞൻߐࠇࠆߣ౒ߦ‫ޔ‬േ⊛ࡕ࠺࡞᭴▽ߩၮ⋚ ߇᭴▽ߐࠇࠆ‫ޕ‬ ‫ޣ‬㧳㧺㧼ߣߩ㑐ㅪ࡮㧳㧺㧼߳ߩ⽸₂‫ޤ‬ 㨍㧕ォ౮࡮೙ᓮߩ⸃᣿ߦ㑐ㅪߔࠆ⎇ⓥᚑᨐ ᧄ⎇ⓥߢߪ‫ޔ‬ォ౮೙ᓮࡀ࠶࠻ࡢ࡯ࠢߣ࠲ࡦࡄࠢ⾰⋧੕૞↪ࡀ࠶࠻ࡢ࡯ࠢߩਔᣇࠍ൮᜝⊛ߦ ࡕ࠺࡞ൻߒߘߩേᘒࠍℂ⸃ߔࠆᣇᴺ⺰ߩ⏕┙ߦ⽸₂ߔࠆߣ⠨߃ߡ޿ࠆ‫ޕ‬ 㨎㧕❑ゲ⎇ⓥ㧔෶ߪᮮゲ⎇ⓥ㧕߳ߩ⽸₂ߦ❬߇ࠆ⎇ⓥᚑᨐ ᖱႎၮ⋚ࠨࠗ࠼㧔ㆮવ⎇▤ロ㧕ߩ᧲੩ᄢቇߩ࠴࡯ࡓߣㅪ៤ߒ‫ޔ‬ᢥ₂ᖱႎࡑࠗ࠾ࡦࠣ࠷࡯࡞ PathTEXTࠍㅪേߐߖߚMAP㐿⊒ߦ೑↪ߔࠆࡊ࡜࠶࠻ࡈࠜ࡯ࡓߩ᭴▽. ‫ޣ‬ᒰ⹥⎇ⓥߦ㑐ߒߡᵴ↪ߒߚ⎇ⓥ࠺࡯࠲࡮࡝࠰࡯ࠬ‫ޤ‬ ߥߒ‫ޕ‬ .

(11) ‫ޣ‬ਥߥ⎇ⓥ⺰ᢥߣߘߩ᭎ⷐ‫ޤ‬ 1. Satre, Kemper, Oda, Okazaki, Matsuoka, Kikuchi, Kitano, Tsuruoka, Ananiadou, Tsujii. Connecting Text Mining and Pathways using the PathText Resource. LREC2008 Proceedings. 2.. Ken Suzuki, Samik Ghosh, Yukiko Matsuoka, Hiroaki Kitano. A comprehensive molecular map of crosstalk between the EGFR and the ER pathways in cancer cell lines. ICSB2008, Gothenburg Convention Centre, Sweden, Aug. 24-26, 2008. (poster presentation). 3.. Mariko Hatakeyama, Takeshi Nagashima, Kazuhiro Ikeda, Yoko Kuroki, Noriko Gotoh, Masaaki Oyama, Satoshi Inoue, Hiroaki Kitano. Difference and Commonality of Gene Regulatory Networks in Ligand-Stimulated Wild Type and Drug-Resistant MCF-7 Breast Cancer Cells. ICSB2008, Gothenburg Convention Centre, Sweden, Aug. 24-26, 2008. (poster presentation). 4.. Masaki Oyama, Hiroko Kozuka-Hata, Noriko Yumoto, Takeshi Nagashima, Yoko Kuroki, Satoshi Inoue, Mariko Hatakeyama and Hiroaki Kitano. Time-resolved description of global phosphoproteome dynamics for network-wide exploration of novel drug targets against breast cancer. ICSB2008, Gothenburg Convention Centre, Sweden, Aug. 24-26, 2008. (poster presentation). 5.. Satre, R.; Kemper, B.; Oda, K.; Okazaki,N.; Matsuoka, Y.; Kikuchi, N.; Kitano, H.; Tsuruoka, Y.; Ananiadou, S.; and Tsujii, J. PathText: Text Mining Integrated with Biological Pathway. Genomes to Systems 2008, Manchester, UK, March 17-19, 2008. (poster presentation). ‫⸵․ޣ‬಴㗿ᢙߩታ❣‫ޤ‬ ߥߒ‫ޕ‬ .

(12) ࠥࡁࡓࡀ࠶࠻ࡢ࡯ࠢࡊࡠࠫࠚࠢ࠻ߩ ⺖㗴ߩႎ๔. ࡊࡠࠣ࡜ࡓฬ. 㧔㧝㧕ࠥࡁࡓᯏ⢻ᖱႎߩ⸃ᨆ 㧔㧞㧕ࡅ࠻ࠥࡁࡓࡀ࠶࠻ࡢ࡯ࠢ ࡊ࡜࠶࠻ࡈࠜ࡯ࡓߩ᭴▽ 㧔㧟㧕ᰴ਎ઍࠥࡁࡓ⸃ᨆᛛⴚߩ㐿⊒ 㧔㧠㧕୘೎↢๮ᯏ⢻ߩ⸃ᨆ 㧔㧡㧕േ⊛ࡀ࠶࠻ࡢ࡯ࠢ⸃ᨆᛛⴚ㐿⊒. ⺖㗴ߩಽ㘃. 㧔㧝㧕ਛᩭᯏ㑐㧔㧞㧕ᜰቯ⺖㗴㧔㧟㧕౏൐⺖㗴 ⢽⢌⚦⢩࡮㛽⧘⚦⢩ಽൻࡀ࠶࠻ࡢ࡯ࠢߩౣ᭴ᚑߣ․ᕈ⸃ᨆ ⺖㗴 ฬ 㧔Reconstruction and Characterization of Adipocyte/Osteoblast 㧔๺⧷૬⸥㧕 Differentiation Networks㧕 ઍ⴫⎇ⓥ⠪ฬ ᧻↰ ⑲㓶㧔ᚲዻᯏ㑐࡮⡯ฬ㧕㧔࿖┙ᄢቇᴺੱᄢ㒋ᄢቇ࡮ᢎ᝼㧕㧝㧥ᐕᐲ 㧞㧜ᐕᐲ ว ⸘ ᐕᐲ೎⎇ⓥ⾌㧔ජ౞㧕. . . . ⎇ⓥ⠪ฬᚲዻᯏ㑐࡮ㇱዪ࡮⡯ ઍ⴫ᯏ㑐 ‫⑲ ↰᧻ڏ‬㓶 ᄢ㒋ᄢቇ࡮ᖱႎ⑼ቇ⎇ⓥ⑼࡮ᢎ᝼ ┻ਛ ⷐ৻ᄢ㒋ᄢቇ࡮ᖱႎ⑼ቇ⎇ⓥ⑼࡮ಎᢎ᝼ ἑየ ⨃ੱᄢ㒋ᄢቇ࡮ᖱႎ⑼ቇ⎇ⓥ⑼࡮ഥᢎ ಽᜂᯏ㑐 ‫ڏ‬ጟፒ ᐽม ၯ₹ක⑼ᄢቇ࡮ࠥࡁࡓකቇ⎇ⓥ࠮ࡦ࠲࡯࡮ᚲ㐳. ⎇ ⓥ ⚵ ❱ ࿑. ᢎ᝼. ᓼỈ ᳓㊁ ખ࿾ ဌㄘ. . ኾ㐷ಽ㊁ ࡃࠗࠝࠗࡦࡈࠜࡑ࠹ࠖࠢࠬ ࡃࠗࠝࠗࡦࡈࠜࡑ࠹ࠖࠢࠬ ࡃࠗࠝࠗࡦࡈࠜࡑ࠹ࠖࠢࠬ ࠥࡁࡓ⑼ቇ. ૫⟤ၯ₹ක⑼ᄢቇ࡮ࠥࡁࡓකቇ⎇ⓥ࠮ࡦ࠲࡯࡮⎇ⓥຬ ࠥࡁࡓ⑼ቇ ᵗ੺ၯ₹ක⑼ᄢቇ࡮ࠥࡁࡓකቇ⎇ⓥ࠮ࡦ࠲࡯࡮⎇ⓥຬ ࠥࡁࡓ⑼ቇ ⼾ ၯ₹ක⑼ᄢቇ࡮ࠥࡁࡓකቇ⎇ⓥ࠮ࡦ࠲࡯࡮⎇ⓥຬ ࠥࡁࡓ⑼ቇ ⑲㓷ၯ₹ක⑼ᄢቇ࡮ࠥࡁࡓකቇ⎇ⓥ࠮ࡦ࠲࡯࡮ቴຬ ↢‛ᖱႎ⑼ቇ ಎᢎ᝼. ጊਅ ᴰ ၯ₹ක⑼ᄢቇ࡮ࠥࡁࡓකቇ⎇ⓥ࠮ࡦ࠲࡯࡮ᄢቇ㒮↢ࠥࡁࡓ⑼ቇ ౎ᧁ ⎇ ၯ₹ක⑼ᄢቇ࡮ࠥࡁࡓකቇ⎇ⓥ࠮ࡦ࠲࡯࡮㕖Ᏹൕ ࠥࡁࡓ⑼ቇ ⻠Ꮷ ‫⎇ޣ‬ⓥ⋡⊛‫ޤ‬ ⢽⢌⚦⢩ߣ㛽⧘⚦⢩߳ߩಽൻㆊ⒟ߦ߅ߌࠆォ౮೙ᓮࠍਛᔃߣߒߚ⛔ว⊛ߥಽሶࡀ࠶࠻ࡢ ࡯ࠢߩ⸃᣿ࠍ⋡ᜰߒ‫․ߦࠇߘޔ‬ൻߒߚ⸃ᨆࠕ࡞ࠧ࡝࠭ࡓߩ㐿⊒ࠍⴕ߁‫ޕ‬ᖱႎ⸃ᨆࠣ࡞࡯ࡊߣ ታ㛎ࠣ࡞࡯ࡊ߇㕖Ᏹߦ✕ኒߦㅪ៤ߒߚ૕೙ࠍ⚵ࠎߢ߅ࠅ‫ޔ‬නߦ⊒⃻ᖱႎ╬߆ࠄォ౮೙ᓮࡀ࠶ ࠻ࡢ࡯ࠢࠍផቯߔࠆߛߌߢߥߊ‫࠭ࠗࡌޔ‬ផቯߩࠬࠦࠕ⸘▚ߩਛߢታ㛎⊛ߦ⏕⹺ߐࠇߚ೙ᓮ㑐 ଥࠍ㊀ߺઃߌߔࠆߎߣߦࠃࠅ‫ޔ‬ታ㛎஥߆ࠄߩ⍮⷗ࠍ෻ᤋߒߚ㜞♖ᐲߩࡀ࠶࠻ࡢ࡯ࠢߩౣ᭴ᚑ ࠍⴕ߁‫ޔߦࠄߐޕ‬ᓧࠄࠇߚࡀ࠶࠻ࡢ࡯ࠢߩ᭴ㅧࠍ⸃ᨆߔࠆߎߣߢ‫ߦࠢ࡯࠻ࠬࡠࠢ߿ࡉࡂޔ‬㑐 ਈߔࠆ㊀ⷐߥㆮવሶࠍត⚝ߔࠆߣߣ߽ߦ‫ߩࠇߙࠇߘޔ‬ㆮવሶߩ⊒⃻ᄌേ߇ਈ߃ࠆᓇ㗀ࠍ⸃ᨆ ߔࠆ‫ߩࠄࠇߎޔߚ߹ޕ‬㊀ⷐߥㆮવሶߦߟ޿ߡߪ‫ߩᦼᤨࠆ޿ߡߒ⃻⊒߇ࠇߘޔ‬๟࿐ߢ࠲ࠗࡓࡐ ࠗࡦ࠻ࠍჇ߿ߒߚ⊒⃻᷹ቯࠍⴕ߁ߎߣߢ‫ߩߘޔ‬ㆮવሶ๟ㄝߩォ౮೙ᓮࡀ࠶࠻ࡢ࡯ࠢߩߐࠄߥ ࠆ⹦⚦ൻ࡮㜞♖ᐲൻࠍⴕߞߡࡀ࠶࠻ࡢ࡯ࠢߩ⹦⚦ߥ․ᕈࠍ᣿ࠄ߆ߦߒߡ޿ߊߎߣࠍ⋡⊛ߣߔ ࠆ‫ޕ‬.

(13) ‫⺖ޣ‬㗴ߩ᭎ⷐ‫ޤ‬ એਅߩಽᜂߢ⎇ⓥ⺖㗴ࠍታᣉߒߡ޿ࠆ‫ޕ‬ ᐔᚑᐕᐲ 㧝㧚⸃ᨆ↪࠺࡯࠲ߩ↥↢㧔ၯ₹කᄢ㧕㧞㧚ಽሶ↢‛ቇ⊛ታ㛎ߦࠃࠆ⸃ᨆ⚿ᨐߩᬌ⸽Ḱ஻㧔ၯ₹කᄢ㧕㧟㧚ㆮવሶࡀ࠶࠻ࡢ࡯ࠢᲧセ⸃ᨆࡄࠗࡊ࡜ࠗࡦߩ᭴▽㧔ၯ₹කᄢ㧕㧠㧚ត⚝ኻ⽎ߣߔࠆォ౮࿃ሶߩㆬቯ㧔㒋ᄢ㧕㧡㧚ㅙᰴ᜛ᄢߦࠃࠆォ౮೙ᓮࡀ࠶࠻ࡢ࡯ࠢߩផቯ㧔㒋ᄢ㧕 ᐔᚑᐕᐲ 㧢㧚ᤨ㑆ㆃᑧࠍ⠨ᘦߒߚォ౮೙ᓮ㑐ଥߩ᜛ᄢ㧔㒋ᄢ㧕㧣㧚ࠢࡠࠬ࠻࡯ࠢㆮવሶߩត⚝ߦࠃࠆਔ⚦⢩ಽൻࡀ࠶࠻ࡢ࡯ࠢߩ⛔วߣ․ᕈ⸃ᨆ㧔㒋ᄢ㧕㧤㧚ಽሶ↢‛ቇ⊛ታ㛎ߦࠃࠆ⸃ᨆ⚿ᨐߩᬌ⸽㧔ၯ₹කᄢ㧕 ‫ޣ‬ᐔᚑ㧞㧜ᐕ㧤᦬ᧃ߹ߢߩ⎇ⓥᚑᨐ‫ޤ‬ 㧝㧚⸃ᨆ↪࠺࡯࠲ߩ↥↢㧔ၯ₹කᄢ㧕 ⊒⃻ࠕ࡟ࠗߩ࠺࡯࠲ߦߟ޿ߡ‫ޔ‬ᄢ㒋ᄢቇߣߩද⼏ߩ⚿ᨐ‫࡞ࡊࡦࠨޔ‬ᢙࠍ2ߩnਸ਼න૏ߢ⏕ ଻ߔࠆ੐ߦࠃࠅ⸘▚਄ߩല₸ൻ߇࿑ࠇࠆ੐߆ࠄ‫ޔ‬⢽⢌‫ޔ‬㛽⧘⚦⢩ಽൻᤨߩ⚻ᤨࠨࡦࡊ࡝ࡦࠣ ߩ࠲ࠗࡓࡐࠗࡦ࠻ࠍౣᬌ⸛ߒߚ‫⚿ߩߘޕ‬ᨐ‫ޔ‬࿑㧝‫⴫ޔ‬㧝ߦ␜ߔ࠲ࠗࡓࡐࠗࡦ࠻ߢࠨࡦࡊ࡝ࡦ ࠣࠍⴕ߁੐ࠍ᳿߼‫ޔ‬ታ㓙ߩࠨࡦࡊ࡝ࡦࠣࠍታᣉߒߚ‫ޕ‬ᓧࠄࠇߚࠨࡦࡊ࡞߆ࠄోRNAࠍ᛽಴ߒ‫ޔ‬ Affymetrix⊒⃻ࠕ࡟ࠗࠍ↪޿ߡ⊒⃻࠺࡯࠲ࠍขᓧߒߚ‫ޕ‬. ࿑㧝 ⊒⃻ࠕ࡟ࠗߩࠨࡦࡊ࡝ࡦࠣߦ߅ߌࠆ࠲ࠗࡓࡐࠗࡦ࠻ ⴫㧝 ⊒⃻ࠕ࡟ࠗߦ↪޿ߚࠨࡦࡊ࡞ߩಣℂౝኈ ಣℂ඙ฬ. ಣℂߩౝኈ. ಽൻ⺃ዉߩౝኈ. Long term. ಽൻ⺃ዉߩ㧢ᤨ㑆೨߆ࠄ‫ޔ‬ಽൻ⺃ዉࠍ⚻ߡ‫ޔ‬ಽൻ⺃ዉ ᓟ192ᤨ㑆ᓟ߹ߢߩ㧢ᤨ㑆ೞߺߢࠨࡦࡊ࡝ࡦࠣ. ⢽⢌⚦⢩ಽൻ 㛽⧘⚦⢩ಽൻ. Short term. ಽൻ⺃ዉߩ㧞ᤨ㑆೨߆ࠄ‫ޔ‬ಽൻ⺃ዉࠍ⚻ߡ‫ޔ‬ಽൻ⺃ዉ ᓟ30ᤨ㑆ᓟ߹ߢߩ㧝ᤨ㑆ೞߺߢࠨࡦࡊ࡝ࡦࠣ. ⢽⢌⚦⢩ಽൻ. Super Short term. ಽൻ⺃ዉ߆ࠄ 5 ಽᓟ‫ޔ‬15 ಽᓟ‫ޔ‬30 ಽᓟ‫ޔ‬45 ಽᓟ‫ޔ‬1 ᤨ 㑆ᓟߩࠨࡦࡊ࡝ࡦࠣ. ⢽⢌⚦⢩ಽൻ. Control. ਄⸥࠲ࠗࡓࡐࠗࡦ࠻ߩ߁ߜߩ޿ߊߟ߆ߦߟ޿ߡࠨࡦ ࡊ࡝ࡦࠣ. 㛽⧘⚦⢩ಽൻ 㛽⧘⚦⢩ಽൻ ಽൻ⺃ዉߥߒ.

(14) ోߡߩ࠲ࠗࡓࡐࠗࡦ࠻ߦߟ޿ߡ‫ޔ‬⢽⢌ಽൻ⺃ዉ‫ޔ‬㛽⧘⚦⢩ಽൻ⺃ዉߩ⚦⢩ࠨࡦࡊ࡞ࠍ㧟࿁ ➅ࠅ㄰ߒߡߘࠇߙࠇ↪ᗧߒߚ‫ޕ‬਄⸥ߩਛߩ․ቯߩ࠲ࠗࡓࡐࠗࡦ࠻ߦߟ޿ߡߪ‫⺃ޔ‬ዉࠍ߆ߌߥ ޿⚦⢩ࠨࡦࡊ࡞߽ࠦࡦ࠻ࡠ࡯࡞ߣߒߡ㧟࿁➅ࠅ㄰ߒߡ↪ᗧߒߚ‫ޕ‬ว⸘ߢ137ࡐࠗࡦ࠻ߩࠨࡦࡊ ࡞ࠍಣℂߒߚ‫ޕ‬ 㧞㧚ಽሶ↢‛ቇ⊛ታ㛎ߦࠃࠆ⸃ᨆ⚿ᨐߩᬌ⸽Ḱ஻㧔ၯ₹කᄢ㧕 ⸃ᨆ⚿ᨐࠍᬌ⸽ߔࠆߚ߼ߩ࡞ࠪࡈࠚ࡜࡯࠯ࠕ࠶࠮ࠗታ㛎߿RNAᐓᷤታ㛎ߥߤߩಽሶ↢ ‛ቇ⊛ߥታ㛎♽ߩḰ஻ࠍⴕߞߚ‫ࠬ࠙ࡑޔߕ߹ޕ‬PPARJㆮવሶߩ਄ᵹࡊࡠࡕ࡯࠲࡯㗔ၞࠍ࡞ ࠪࡈࠚ࡜࡯࠯ㆮવሶ਄ᵹߦ⚵ߺㄟࠎߛ߽ߩࠍ⚦⢩ߦዉ౉ߒ‫ޔ‬⢽⢌⚦⢩ಽൻ⺃ዉಣℂߔࠆ੐ ߦࠃࠅࠪࡈࠚ࡜࡯࠯ᵴᕈ߇਄᣹ߔࠆ੐ࠍ⏕⹺ߒߚ‫ ࠬ࠙ࡑޔߚ߹ޕ‬Osteocalcinㆮવሶ਄ᵹ ߩRunx2ᔕ╵㈩೉ࠍ฽߻㗔ၞࠍ࡞ࠪࡈࠚ࡜࡯࠯ㆮવሶ਄ᵹߦ⚵ߺㄟࠎߛ߽ߩࠍRunx2ㆮ વሶߣ౒ߦ⚦⢩ߦዉ౉ߒ‫ޔ‬Runx2ᔕ╵㈩೉߇Runx2ߩᓇ㗀ࠍฃߌߡ࡞ࠪࡈࠚ࡜࡯࠯ᵴᕈࠍ ਄᣹ߐߖࠆߎߣࠍ⏕⹺ߒߚ‫ޕ‬ ߹ߚ‫ޔ‬siRNAࠍࡑ࠙ࠬST2⚦⢩ߦዉ౉ߒ‫․ޔ‬ቯߩㆮવሶࠍࡁ࠶ࠢ࠳࠙ࡦߒߡ⊒⃻㊂ࠍല₸ ࠃߊૐਅߐߖ‫⚿ߩߘޔ‬ᨐߣߒߡ⢽⢌‫ޔ‬㛽⧘⚦⢩ಽൻߩ⴫⃻ဳߦᓇ㗀ࠍਈ߃ࠆ੐߇น⢻ߥ੐ࠍ ⏕⹺ߒߚ‫ ࠬ࠙ࡑޔߕ߹ޕ‬OsterixㆮવሶߦኻߔࠆsiRNAࠍ⚦⢩ߦዉ౉ߔࠆߎߣߦࠃࠅ‫ޔ‬ౝ࿷ ᕈߩOsterixㆮવሶ⊒⃻㊂߇⪺ߒߊᛥ೙ߐࠇ‫⚿ߩߎޔ‬ᨐ㛽⧘⚦⢩ಽൻ߇⪺ߒߊᛥ೙ߐࠇࠆ੐ࠍ ⏕⹺ߒߚ‫ޕ‬ ᰴߦࡑ࠙ࠬPPARJㆮવሶߦኻߔࠆsiRNAࠍ⚦⢩ߦዉ౉ߔࠆߎߣߦࠃࠅ‫ޔ‬ౝ࿷ᕈߩPPARJ ㆮવሶ⊒⃻㊂߇⪺ߒߊᛥ೙ߐࠇ‫⚿ߩߎޔ‬ᨐ⢽⢌⚦⢩ಽൻ߇⪺ߒߊᛥ೙ߐࠇࠆߎߣࠍ⏕⹺ߒߚ‫ޕ‬ ߎࠇࠄߩࠦࡦ࠻ࡠ࡯࡞ታ㛎ࠍኻᾖߣߔࠆߎߣߦࠃࠅ‫੹ޔ‬ᓟࡌࠗ࠭ផቯߦࠃࠅࡀ࠶࠻ࡢ࡯ ࠢߦട߃ࠄࠇࠆㆮવሶߩ⢽⢌‫ޔ‬㛽⧘⚦⢩ಽൻ߳ߩᓇ㗀ࠍsiRNAዉ౉ታ㛎ߦࠃࠅᬌ⸽ߢ߈ࠆ ߎߣ߇᣿ࠄ߆ߦߥߞߚ‫ޕ‬ 㧟㧚ㆮવሶࡀ࠶࠻ࡢ࡯ࠢᲧセ⸃ᨆࡄࠗࡊ࡜ࠗࡦߩ᭴▽㧔ၯ₹කᄢ㧕 ߎࠇ߹ߢߦ‫ޔ‬ၯ₹කᄢߦߡ↥಴ߒߚ⸃ᨆ↪࠺࡯࠲ߦߟ޿ߡ‫ޔ‬ᄢ㒋ᄢቇߦߡ࠺࡯࠲ߩࡈࠖ࡞ ࠲࡝ࡦࠣߣ‫ޔ‬⢽⢌‫ޔ‬㛽⧘⚦⢩ಽൻߦ㑐ߔࠆᣢ⍮ߩࠦࠕࡀ࠶࠻ࡢ࡯ࠢㆮવሶߣ⊒⃻ࡄ࠲࡯ࡦߦ ⋧㑐ߩ޽ࠆㆮવሶߩ᛽಴ࠍⴕߞߚ‫ޔߚ߹ޕ‬ฦ࠲ࠗࡓࡐࠗࡦ࠻ߦ߅޿ߡ㗼⪺ߦ⊒⃻ߔࠆㆮવሶ ࠍ᛽಴ߒ‫⺃ޔ‬ዉᤨ㑆ߦᔕߓߡォ౮߇㗅ᰴ⿠ߎߞߡ޿ߊㆮવሶࠍᄢ㒋ᄢቇߦߡ⸃ᨆߒߚ‫ᤨ⃻ޕ‬ ὐߦ߅޿ߡ߽ᒁ߈⛯߈‫ޔ‬ᄢ㒋ᄢቇߣਅ⸥ߩࠃ߁ߥㅪ៤ࠍⴕߞߡ޿ࠆ‫ޕ‬. ⢽⢌࡮㛽⧘⚦⢩㑐ㅪਥⷐォ౮࿃ሶߩ⊒⃻ perturbation ߦࠃࠆઁߩㆮવሶ⊒⃻߳ߩᓇ㗀 ࠍⷰኤߔࠆታ㛎ࠍⴕߞߡ޿ࠆ‫ౕޕ‬૕⊛ߦߪ‫ޔ‬Osterix, PPARJ, Runx2, Dlx5, Msx2, C/EBPE/G/D, Id4 ╬ߦߟ޿ߡ‫ޔ‬siRNA ߦࠃࠆࡁ࠶ࠢ࠳࠙ࡦ߿⊒⃻ࡌࠢ࠲࡯ߦࠃࠆᒝ೙⊒ ⃻ࠍⴕ޿‫ߩߘޔ‬ᓇ㗀ࠍฃߌߡ⊒⃻ᄌേߔࠆㆮવሶࠍ⊒⃻ࠕ࡟ࠗࠍ↪޿ߡត⚝ߒ‫ޔ‬ᓧࠄࠇ ߚ࠺࡯࠲ࠍᄢ㒋ᄢቇߢ⸃ᨆߦ૶↪ߒߡ޿ࠆ‫ޕ‬. ᄢ㒋ᄢቇ߆ࠄឭ␜ߐࠇߚᤨ㑆ㆃᑧ⸵ኈ⋧㑐ㆮવሶࡀ࠶࠻ࡢ࡯ࠢࠍᬌ⸽ߔࠆታ㛎ࠍⴕߞ ߡ޿ࠆ‫ޕ‬. ᄢ㒋ᄢቇ߆ࠄឭ␜ߐࠇߚ‫ߦ⊛ᤨ৻ޔ‬㗼⪺ߥ⊒⃻ࠍ␜ߔㆮવሶ⟲ߩ࠺࡯࠲ߦߟ޿ߡ‫⃻⊒ޔ‬ ߩ㑐ㅪᕈࠍᬌ⸽ߔߴ߈ㆮવሶࠍㆬቯਛߢ޽ࠆ‫ޕ‬. ᄢ㒋ᄢቇ߆ࠄㅙᰴឭ␜ߐࠇࠆ‫࠭ࠗࡌޔ‬ផቯߦࠃࠅᣂߚߦឬ಴ߐࠇࠆࡀ࠶࠻ࡢ࡯ࠢࠍᬌ⸽ ߔࠆታ㛎ࠍⴕߞߡ޿ࠆ‫ޕ‬. ⊒⃻ࠕ࡟ࠗ࠺࡯࠲ࠍⷞⷡൻߔࠆ࠷࡯࡞(Maror3)ࠍᢛ஻ߒߚ‫ޔࠅࠃߦࠇߎޕ‬ฦㆮવሶߩ⊒ ⃻㊂ߩ⚻ᤨᄌൻࡊࡠࡈࠖ࡯࡞ࠍ◲ଢߦⷞⷡൻߢ߈ࠆࠃ߁ߦߥߞߚ‫ޔߚ߹ޕ‬છᗧߩㆮવሶ ߩ⊒⃻ࡄ࠲࡯ࡦߣ⋧㑐ߩ㜞޿ㆮવሶࠍ⴫␜ߐߖߚࠅ‫ޔ‬ᒰ⹥ㆮવሶߦ㑐ߔࠆᖱႎࠍߐࠄߦ ขᓧߔࠆߚ߼ߦ‫ޔ‬GEO, ENSEMBL, NetAffx ╬ߩᄖㇱ࠺࡯࠲ࡌ࡯ࠬ߳࡝ࡦࠢࠍ੺ߒߡ ኈᤃߦࠕࠢ࠮ࠬߢ߈ࠆⅣႺࠍ᭴▽ߒߚ‫ࠍࡓ࠹ࠬࠪߩߎޕ‬ᄢ㒋ᄢቇߦ߽⒖ᬀߒ‫ޔ‬ᄢ㒋ᄢቇ ߢ߽ห᭽ߩⷞⷡൻ߇ⴕ߃ࠆࠃ߁ߦߥߞߚ‫ޕ‬.

(15) 㧠㧚ត⚝ኻ⽎ߣߔࠆォ౮࿃ሶߩㆬቯ㧔㒋ᄢ㧕ォ౮೙ᓮࡀ࠶࠻ࡢ࡯ࠢߩផቯߩߚ߼ߩ೨ಣℂߢ޽ࠆ೙ᓮㆮવሶ୥⵬ߩㆬቯࠍታᣉߔࠆߚ ߼ߩࠪࠬ࠹ࡓࠍ㐿⊒ߒߚ‫ߩࡓ࠹ࠬࠪᧄޕ‬ㆬቯᚻ㗅ߪᰴߩㅢࠅߢ޽ࠆ‫ޕ‬ Step 1. ోㆮવሶਛ߆ࠄォ౮࿃ሶߩߺࠍ᛽಴ Step 2. ⊒⃻ࠕ࡟ࠗ࠺࡯࠲߆ࠄ⊒⃻ᄌേ߇ᄢ߈޿ㆮવሶࠍ᛽಴ Step 3. Step 1 ߣ Step 2 ߢㆬ߫ࠇߚㆮવሶߩⓍ㓸วࠍ୥⵬ㆮવሶߣߒߡㆬቯ Step 1 ߩォ౮࿃ሶߩㆬቯߢߪ‫ޔ‬Gene Ontology ࠍࡌ࡯ࠬߦߒߚォ౮࿃ሶᯏ⢻ᖱႎ߿⊒⃻⚵❱ ᖱႎࠍ৻ㇱ⠨ᘦߒߡ޿ࠆ‫ޕ‬Step 2 ߢߪ⎇ⓥಽᜂᯏ㑐ߢ޽ࠆၯ₹ක⑼ᄢቇߦࠃࠅ⸘᷹ߒߚ⊒⃻ ࠺࡯࠲ࠍ૶↪ߒߚ‫ߦ࠲࡯࠺⃻⊒ߩߎޕ‬ኻߒߡᧄࠪࠬ࠹ࡓࠍㆡ↪ߔࠆߎߣߦࠃࠅ‫ޔ‬339 ୘ߩ೙ ᓮㆮવሶߩ୥⵬ࠍㆬቯߒߚ‫ޕ‬ 㧡㧚ㅙᰴ᜛ᄢߦࠃࠆォ౮೙ᓮࡀ࠶࠻ࡢ࡯ࠢߩផቯ㧔㒋ᄢ㧕 ㆮવሶ㑆ߩ೙ᓮ㑐ଥߩផቯߦߪ‫࠭ࠗࡌޔ‬ផቯᴺࠍ↪޿ߚ‫ޕ‬ㆮવሶߦ㑐ߔࠆ⇣⒳ⶄᢙߩᖱႎ ࠍ⏕₸⊛⴫⃻ߦᄌ឵ߒߚᓟ‫ߥ⊛₸⏕ޔ‬ᗧ๧ߢ⁛┙ᕈߩᒙ޿ㆮવሶ㑆ߦ೙ᓮ㧛ⵍ೙ᓮ㑐ଥࠍ⴫ ࠊߔㄝࠍᒁߊᚻᴺߢ޽ࠆ‫ᧄޕ‬ᚻᴺߪᦨ߽ዕᐲߩ㜞޿೙ᓮࡀ࠶࠻ࡢ࡯ࠢߩ᭴ㅧࠍ᳞߼ࠆߎߣ߇ น⢻ߛ߇‫⤘ޔ‬ᄢߥ⸘▚ᤨ㑆ࠍⷐߔࠆߎߣ෸߮‫ߦ࠭ࠗࡁޔ‬ᒙ޿ߣ޿߁ᰳὐࠍ᦭ߒߡ޿ߚ‫ߦ․ޕ‬ ࡁࠗ࠭ߦࠃࠅ೙ᓮ㧛ⵍ೙ᓮ㑐ଥߩᣇะ߇ኈᤃߦ෻ォߒߡߒ߹߁‫ᤨ▚⸘ߢߎߘޕ‬㑆ߦኻߒߡ ߪ‫ޔ‬ㄭૃ⊛⸃ᴺࠍ೑↪ߔࠆ੐෸߮‫ޔ‬ផቯߔࠆࡀ࠶࠻ࡢ࡯ࠢߩⷙᮨࠍዊߐߊߔࠆ੐ߢኻಣߒߚ‫ޕ‬ ౕ૕⊛ߦߪ‫ޔ‬ᓥ᧪ߩᣇᴺߢࡌࠗ࠭ࡀ࠶࠻ࡢ࡯ࠢផቯࠍല₸⊛ߦⴕ߁ߚ߼ߦߪ‫৻ޔ‬ᐲߦਈ߃ࠆ ㆮવሶᢙࠍ5୘߆ࠄ10୘⒟ᐲߦ೙㒢ߔࠆᔅⷐ߇޽ߞߚ‫߫߃଀ޔߒ߆ߒޕ‬PPARJߦ೙ᓮߐࠇࠆㆮ વሶߪᢙච୘⍮ࠄࠇߡ޿ࠆߚ߼৻ᐲߦࡀ࠶࠻ࡢ࡯ࠢࠍផቯߔࠆߎߣߪ࿎㔍ߢ޽ࠆ‫ᧄߢߎߘޕ‬ ⎇ⓥߢߪ‫ޔ‬PPARJߦኻߒߡ⋥ធ⊛ߥ೙ᓮ㧛ⵍ೙ᓮ㑐ଥ߇್᣿ߒߡ޿ࠆዊⷙᮨߥᣢ⍮೙ᓮࡀ࠶ ࠻ࡢ࡯ࠢߦኻߒߡㅙᰴ⊛ߦㆮવሶࠍㅊടߒߡ޿ߊᚻᴺࠍ㐿⊒ߒߚ‫ޕ‬ㅊടߒߡ޿ߊㆮવሶߪ‫ޔ‬ 㧠㧚ߢㆬቯߒߚ߽ߩࠍ೑↪ߔࠆ‫ౕޕ‬૕⊛ߦߪᰴߩᚻ㗅ߢࡀ࠶࠻ࡢ࡯ࠢࠍ᜛ᄢߒߡ޿ߊ‫ޕ‬. ࡑࠗࠢࡠࠕ࡟ࠗߩᤨ♽೉⊒⃻࠺࡯࠲ࠍၮߦ‫࠭ࠗࡌޔ‬ᴺߢߩࡀ࠶࠻ࡢ࡯ࠢផቯࠍⴕ߁ߎߣ ߢ‫ޔ‬ᣢ⍮ࡀ࠶࠻ࡢ࡯ࠢߦߟߥ߇ࠆᣂⷙߩォ౮࿃ሶࠍត⚝. UK40#ߦࠃࠆࡁ࠶ࠢ࠳࠙ࡦ‫ߢ╬ࠗ࠮࠶ࠕ࠯࡯࡜ࠚࡈࠪ࡞ޔ‬ታ㛎⊛ߦᬌ⸽ߐࠇࠇ߫‫ޔ‬ᣂߚߥ ᣢ⍮ࡀ࠶࠻ࡢ࡯ࠢߣߒߡㅊട. ࠍ➅ࠅ㄰ߔߎߣߢࡀ࠶࠻ࡢ࡯ࠢࠍ᜛ᄢ 㧢㧚ᤨ㑆ㆃᑧࠍ⠨ᘦߒߚォ౮೙ᓮ㑐ଥߩ᜛ᄢ㧔㒋ᄢ㧕㧡㧚ߩᣇᴺߢߪ‫ޔ‬ォ౮೙ᓮߩ೙ᓮ࡮ⵍ೙ᓮߩㆮવሶ⊒⃻ߦᤨ㑆ߕࠇ‫ߜࠊߥߔޔ‬೙ᓮㆮવሶ ߩ⊒⃻߆ࠄㆃࠇߡⵍ೙ᓮㆮવሶߩ⊒⃻߇ᆎ߹ࠆ႐วߦߪ‫ޔ‬೙ᓮ㑐ଥ߇ផቯߢ߈ߥ޿น⢻ᕈ߇ ޽ࠆ‫ࠗ࡟ࠕࡠࠢࠗࡑޔߢߎߘޕ‬ታ㛎ߢ૶߁40#ߩขᓧࠍ╬ᤨ㑆㑆㓒ߢ⹦⚦ߦⴕ߁ߎߣߦࠃࠅ‫ޔ‬ ផቯᤨߦ᷹ቯ࠲ࠗࡓࡐࠗࡦ࠻ࠍࠪࡈ࠻ᠲ૞ߦࠃࠅߕࠄߒߡ޿ߊߎߣߢᤨ㑆ߕࠇߩ޽ࠆ೙ᓮ㑐 ଥߩផቯࠍน⢻ߣߒߚ‫࠻ࡈࠪߩ࠻ࡦࠗࡐࡓࠗ࠲ߩߎޔߒߛߚޕ‬ᠲ૞ࠍട߃ߚ೙ᓮࡀ࠶࠻ࡢ࡯ ࠢផቯࠍߔߴߡߩㆮવሶߩ⚵วߖߢⴕ߁ߎߣߪ‫▚⸘ޔ‬㊂⊛ߦ࿎㔍ߢ޽ࠆߚ߼‫࠻ࡈࠪޔ‬ᠲ૞ߪ 㧡㧚ߩㅙᰴ᜛ᄢߢട߃ࠆㆮવሶߣᣢ⍮ࡀ࠶࠻ࡢ࡯ࠢߩㆮવሶߩ㑆ߦ㒢ቯߒ‫߼ߓ߆ࠄ޽ߟ߆ޔ‬ ࠪࡈ࠻ᠲ૞ߦࠃࠅ‫ޔ‬ᣢ⍮ࡀ࠶࠻ࡢ࡯ࠢߩㆮવሶߣߩ㑆ߢ⊒⃻ࡄ࠲࡯ࡦ㑆ߩ⋧㑐ଥᢙ߇ะ਄ߔ ࠆㆮવሶࠍࠬࠢ࡝࡯࠾ࡦࠣߒߡ⛉ࠅㄟ߻ߎߣߢ‫ޔ‬ㆬᛯߒߚㆮવሶߩߺࠍኻ⽎ߦ‫࠻ࡈࠪޔ‬ᠲ૞ ࠍ฽߼ߚ೙ᓮࡀ࠶࠻ࡢ࡯ࠢߩផቯࠍⴕߞߚ‫ᧄޕ‬ᚻᴺߦࠃࠅ‫ޔ‬ផቯߐࠇߚォ౮೙ᓮࡀ࠶࠻ࡢ࡯ ࠢࠍ࿑㧞ߦ␜ߔ‫ޕ‬.

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