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Transcript
臨床試験中での新薬候補のドロップアウト
䇸⎇ⓥ↪䊝䊂䊦⚦⢩䌐䌊䇹 ╙䋱࿁ᓟ⹏ଔಽ⑼ળ⺑⾗ᢱ ⾗ᢱ䋵䋭䋲䋭䋲䋨㐿䋩 㐿 ⶄᱛ 䇸⎇ⓥ↪䊝䊂䊦⚦⢩䈱ഃᛛⴚ㐿⊒䊒䊨䉳䉢䉪䊃䇹 ╙䋱࿁ ᓟ⹏ଔಽ⑼ળ⺑⾗ᢱ ⼏㗴䋴䋮䋲 䊒䊨䉳䉢䉪䊃䈱ⷐ⺑ 䋨㐿䋩 䇸⎇ⓥ㐿⊒ᚑᨐ䇹䈶䇸ታ↪ൻ䈱ㅢ䈚䇹 ᐔᚑ䋲䋲ᐕ䋶䋸ᣣ䋨Ἣ䋩 ⥃ᐥ⹜㛎ਛ䈪䈱ᣂ⮎䈱䊄䊨䉾䊒䉝䉡䊃 ⥃ᐥ⹜㛎䊐䉢䊷䉵Iએ㒠䈱ᚑഞ₸ 䊄䊨䉾䊒䉝䉡䊃ℂ↱ ⮎‛േᘒ ലᕈ Ქᕈ Kola and Landis, Nature Review Drug Discovery 2004 ⥃ᐥ⹜㛎ᓟᦼ䈪䈱䊄䊨䉾䊒䉝䉡䊃 ⤘ᄢ䈭㐿⊒⾌䈱៊ᄬ ⮎ଔ䈱 Frank and Hargreaves, Nature Review Drug Discovery 2003 ⥃ᐥ⹜㛎ਛ䈪䈱ᣂ⮎䈱䊄䊨䉾䊒䉝䉡䊃 ၮ␆⎇ⓥ 㕖⥃ᐥ⹜㛎 ታ㛎േ‛ ലᨐ䉍 Ქᕈή䈚 ⥃ᐥ⹜㛎 䊍䊃 ലᨐή䈚 Ქᕈ䉍 ⒳䈮䉋䉎⮎‛ᔕᕈ䈱㆑䈇 䊍䊃⚦⢩䉕↪䈚䈢䉝䉾䉶䉟♽ ᄙ⢻ᕈᐙ⚦⢩ᩣ䈱․ᕈ 䋨䋨䋱䋩㐳ᦼ㑆䈱⚦⢩Ⴧᱺ䉕䇮ᱜᏱ䈭ᕈ⾰䉕ᜬ䈚 䋩㐳ᦼ㑆 ⚦⢩Ⴧᱺ䉕 Ᏹ䈭ᕈ⾰䉕ᜬ 䈢䉁䉁ή㒢䈮⛽ᜬ䈪䈐䉎⚦⢩ᩣ䈪䈅䉎 䋨䋲䋩⚵❱䊶⤳ེ䉕᭴ᚑ䈜䉎䈾䈿ో䈩䈱⒳㘃䈱⚦ 䋨䋲䋩⚵❱ ⤳ེ䉕᭴ᚑ䈜䉎䈾䈿ో䈩䈱⒳㘃䈱⚦ ⢩䈮ಽൻ䈪䈐䉎ᄙ⢻ᕈ䉕䉅䈦䈩䈇䉎 䊍䊃ᄙ⢻ᕈ⚦⢩ᩣ䈱㊀ⷐᕈ 䋨䋱䋩⚦⢩ᴦ≮䈮↪䈇䉎䈢䉄䈮ᔅⷐ䈭ᯏ⢻䉕䉅 䈧⚦⢩䉕ଏ⛎䈪䈐䉎น⢻ᕈ 䋨䋨䋲䋩⚵❱Ꮏቇ䈮䉋䉎ੱᎿ⚵❱䊶⤳ེ䈱䈢 䋩⚵❱ ቇ䈮䉋䉎ੱ ⚵❱ ⤳ེ 䈢 䉄䈱ᄙ⒳㘃⚦⢩᧚ᢱ䈱ଏ⛎น⢻ᕈ 䋨䋳䋩ၮ␆⎇ⓥ䉇ഃ⮎⎇ⓥ䈮ᔅⷐ䈭ᄙ⒳㘃䊍 䊃⚦⢩䋺ຠ⾰▤ℂ䈚䈩ᄢ㊂ଏ⛎น⢻ ᄙ⢻ᕈᐙ⚦⢩ᩣ䈏䉅䈧ఝ䉏䈢․⾰ 䇸㊀ᄢ䈭․ᕈᄌൻ䈭䈚䈱ή㒢Ⴧᱺ⢻䇹 ㊀ᄢ䈭․ᕈᄌൻ䈭䈚䈱ή㒢Ⴧᱺ⢻䇹 • ㅦ䈇⚦⢩Ⴧᱺ䉕㐳ᦼ㑆䋨ή㒢䈮䋩⛽ᜬ䈪䈐䉎䈫䈫䉅䈮䇮ᄙಽ ൻ⢻䈭䈬䈱ᕈ⾰䈏ᜬ䈘䉏䉎䈖䈫䈮䉋䈦䈩䋺 ൻ⢻䈭䈬䈱ᕈ⾰䈏ᜬ䈘䉏䉎䈖䈫䈮䉋䈦䈩 • ᄙ᭽䈭ㆮવሶᡷᄌ䉕ട䈋䉎䈖䈫䈏น⢻䋨⋡⊛䈮ᔕ䈛䈩⚦⢩䈱 ․ᕈ䉕ടᎿ䊶ᡷༀ䈜䉎䈖䈫䈏䈪䈐䉎䋩 • ห৻․ᕈ䉕䉅䈧⚦⢩㓸࿅䋨ടᎿ䊶ㆬ䈚䈢⚦⢩ᩣ䈱䉰䊑䊤䉟䊮 䈭䈬 ಓ⚿ሽ䉅น⢻䋩䈮䈧䈇䈩 ⚦⢩ᯏ⢻䉇ోᕈ䈭䈬䉕ච 䈭䈬䇮ಓ⚿ሽ䉅น⢻䋩䈮䈧䈇䈩䇮⚦⢩ᯏ⢻䉇ోᕈ䈭䈬䉕ච ಽ䈮ᬌ⸽䈚䈢䈱䈤↪䈜䉎䈖䈫䈏䈪䈐䉎 • ৻ቯ䈱․ᕈ䈫ຠ⾰䉕䉅䈧ᄙ⒳㘃䈱⚦⢩䉕ᄢ㊂䈮ଏ⛎䈜䉎䈖䈫 䈏䈪䈐䉎䋨ᄢ㊂↢↥䈏น⢻䋩 䊍䊃ᄙ⢻ᕈᐙ⚦⢩ᩣ䈱 ഃ⮎⎇ⓥ䈮䈍䈔䉎㊀ⷐᕈ ഃ⮎⎇ⓥ䈮ᔅⷐ䈭ᄙ⒳㘃䊍䊃⚵❱⚦⢩䈱ᄢ㊂ଏ⛎ 䊶ဋ৻䈭․ᕈ䋨䉭䊉䊛䋩䉕䉅䈧䊍䊃⚦⢩ 䊶ᄖ᧪ㆮવሶ䊔䉪䉺䊷䉕⚵䉂ㄟ䉖䈣䊍䊃⚦⢩ ᄖ᧪ㆮવሶ䊔䉪䉺 䉕⚵䉂ㄟ䉖䈣䊍䊃⚦⢩ 䊶ౝㆮવሶ䉕ᡷᄌ䈚䈢䊍䊃⚦⢩䋨∔ᖚ䊝䊂䊦䊍䊃⚦⢩䋩 䊶ฦ⒳⚦⢩ౝᵴᕈ䉕ᬌ䈜䉎䊧䊘 䉺 ㆮવሶዉ䊍䊃⚦⢩ 䊶ฦ⒳⚦⢩ౝᵴᕈ䉕ᬌ䈜䉎䊧䊘䊷䉺䊷ㆮવሶዉ䊍䊃⚦⢩ 䊶ฦ⒳䊍䊃䊝䊂䊦⚦⢩䈻䈱⮎‛ലᨐ䈫↢ℂᵴᕈ䈱䉝䉾䉶䉟♽ ฦ⒳䊍䊃䊝䊂䊦⚦⢩䈻䈱⮎‛ലᨐ䈫↢ℂᵴᕈ䈱䉝䉾䉶䉟♽ 䊶䊍䊃⚦⢩䋨⢄⚦⢩䉇ᔃ╭⚦⢩䋩䉕䈦䈢ోᕈ⹜㛎 䊶ฦ⒳⚻⚦⢩䇮ᔃ╭䇮✂⤑⚦⢩䇮⊹⤏䇮エ㛽䇮⢽⢌⚦⢩ 䊶⢄⚦⢩䇮⤟ፉ⚦⢩ ഃ⮎⎇ⓥ䈱䈢䉄䈱䊍䊃ES⚦⢩↱᧪䈱䊝䊂䊦⚦⢩ᚑ 䋨2005~2009ᐕ䋩 • ត⚝♽ 䋨∔ᖚ䊝䊂䊦⚦⢩䉕↪䈇䈢䊊䉟䉴䊦䊷䊒䉾䊃䉴䉪䊥䊷䊆䊮䉫䋩 䋨∔ᖚ䊝䊂䊦⚦⢩䉕↪䈇䈢 䉟䉴䊦 䊒 䊃䉴䉪䊥 䊮䉫䋩 • ోᕈ ⹜㛎䋨⢄䊝䊂䊦⚦⢩䇮ᔃ╭䊝䊂䊦⚦⢩䉕↪䈇䈢⹜㛎䋩 ಽൻ⺃ዉ♽ 䊝䊂䊦⚦⢩䈱᭴▽ ൻว‛䊤䉟䊑䊤䊥䊷 䉴䉪䊥䊷䊆䊮䉫 䉪䊥 䉫 ∔ᖚ․⇣⊛ ES⚦⢩ 䋨䋺䉝䊦䉿 䊊䉟䊙䊷∛䋩 ⚻⚦⢩ ∔ᖚ䊝䊂䊦⚦⢩ 䊍䉾䊃 䊥 䊄 䊍䉾䊃䊶䊥䊷䊄 ൻว‛ ⢄Ქᕈ⹜㛎 ⢄⚦⢩ ⢄䊝䊂䊦⚦⢩ ᔃᲥᕈ⹜㛎 䊍䊃ES⚦⢩ ᔃ╭⚦⢩ ᔃ╭䊝䊂䊦⚦⢩ ត ⚝ ♽ ᣂ⮎ൻว‛ ో ᕈ ⹜ 㛎 䊍䊃ES⚦⢩↱᧪䈱∔ᖚ䊝䊂䊦⚦⢩ • ᣢሽ䊍䊃ES⚦⢩䈱ㆮવሶᡷᄌ ES⚦⢩ ㆊ⊒ 䋨ᕡᏱ⊛䉁䈢䈲 䉁䈢䈲⊒ᛥ ⺃ዉ⊛䋩 ∔ᖚES⚦⢩ • ห䈛ㆮવ⊛⢛᥊䉕䉅䈦䈢ஜᐽ䈭⚦⢩䈫∔ᖚ⚦⢩䈱Ყセ䈏 ห䈛ㆮવ⊛⢛᥊䉕䉅 䈢ஜᐽ䈭⚦⢩䈫∔ᖚ⚦⢩䈱Ყセ䈏 น⢻䈪䈅䉎 • ⊒⺃ዉဳ䊒䊨䊝䊷䉺䊷䉲䉴䊁䊛䋨Tet-On䇮 Tet-Off䈭䈬䋩䉕 ↪䈇䈢∔ᖚේ࿃ㆮવሶ䈱⊒ᓮ䈏น⢻䈪䈅䉎 • ․ቯ䈱ㆮવሶᐳ䈮ㆮવሶ䉕ᝌ䈜䉎䈖䈫䈏น⢻䈪䈅䉎 • ∔ᖚ⊒∝䉕ᣧ䉄䉎䈖䈫䈏᧪䉎น⢻ᕈ䈏䈅䉎 䊍䊃ᄙ⢻ᕈᐙ⚦⢩ᩣ䈱ㆮવሶᡷᄌ䈮䉋䉎∔ᖚ䊝䊂䊦⚦⢩䈫 ᖚ⠪↱᧪iPS⚦⢩ᩣ䈮䉋䉎∔ᖚ䊝䊂䊦⚦⢩䈱ὐᲧセ ᖚ⠪䈱⚦⢩↱᧪ iPS⚦⢩ᩣ䈱ᚑ ᣢሽ䊍䊃ES䋨䉁䈢䈲iPS) ⚦⢩ᩣ䈱ㆮવሶᡷᄌ 䈭ὐ •ห䈛ㆮવ⊛⢛᥊䉕䉅䈦䈢⚦⢩ᩣ䈪∛࿃ㆮવ ሶ䈫ஜᏱဳㆮવሶ⚦⢩䈱෩ኒ䈭Ყ ὐ 䊶∛࿃ㆮવሶ䈏ਇ䉁䈢䈲ᄙᢙㆮવሶ㑐ਈ䈱 ႐ว䈮䉅ᖚ⠪䈱䉭䊉䊛䉕䉅䈧⚦⢩ᩣ᮸┙䈏น⢻ ∔ᖚ ∔ᖚ䊝䊂䊦䈫䈚䈩䈋䉎น⢻ᕈ 䊂䊦䈫䈚䈩䈋䉎น⢻ᕈ セኻᾖ䈏น⢻ • ⊒⺃ዉဳ䊒䊨䊝䊷䉺䊷䉕↪䈇䈢∛࿃ㆮવ ਇ䈭ὐ ሶ䈱⊒ᓮ䈏น⢻ ∛࿃ㆮવሶ⊒䈱 •ᖚ⠪䈫ஜᏱ⠪䈎䉌䈱iPS⚦⢩ᩣ䈲⇣䈭䉎ㆮવ ᓇ㗀䉕෩ኒ䈭ᤨ㑆ゲ䈪⸃ᨆน⢻ ⊛⢛᥊䉕䉅䈧 ෩ኒ䈭Ყセኻᾖ䈏࿎㔍 • ⇣ᏱⰮ⊕⾰䈭䈬䈱ㆊ⊒䈮䉋䉍∔ᖚ㑐ㅪ •ਇቢో䈭ౣ䊒䊨䉫䊤䊛ൻ䋨ೋᦼൻ䋩䈮䉋䉎䉣䊏 ⇣Ᏹ䈱⊒∝䉕ᣧ䉄䉎䈖䈫䈏᧪䉎น⢻ᕈ 䉳䉢䊈䊁䉞䉪䉴䈱⇣Ᏹ䈏⚦⢩ဳ䈱⸃ᨆ䉕ੂ 䈜น⢻ᕈ ਇ䈭ὐ 䊶∛࿃ㆮવሶ䈏ਇ䉁䈢䈲ᄙᢙㆮવሶ㑐ਈ䈱 ႐ว䈮䈲䊝䊂䊦ᚑ䈏࿎㔍 •ᘟᕈ∔ᖚ䉇ട㦂∔ᖚ䈭䈬䈪䈲ታ㛎น⢻ᦼ㑆 ౝ䈮⚦⢩䈱⇣Ᏹ⊒↢䈏⏕䈪䈐䈭䈇น⢻ᕈ ӑӀҫӔӦһ ඩQM҇ѤэѶႏӊӠҫҚҢһઅ݈ଅсളѣకෞࢴ҇Ѡࢣᄜь̝ ҲҗӒӦңᆖф̝หಃџၒষౖпѽѨફ҇ୟю 2̠ӝ̷ҳ̷ߵ ݶၙೖᄅय़ࢅ ႛॉϨގ ݸ અ݈ଅ̢ඩQMпѽѨߵၙೖᄅय़ࢅѣHM ჭษ̢य़ࢅѣၒষౖ̝пѽѨ̝కෞѣޱ 3̠࢝ൌ.ߵၙೖᄅय़ࢅ৾ຎ ݶႛॉϨގ ݸ ჭษ̢࢝ൌпѽѨߵၙೖᄅय़ࢅީңӞ̷ӊѣय़ࢅफݦ၈ਇ̡၈ফߺ̝ກᇫ ࢝ൌѝ ѣ၈̡࡚ୠফߺ ၈ ࡚ୠফߺ 4̠य़ࢅၒষѣంєџग़ກѣєѶѣᆤࡣݶ ჭษ̢ຠѠྣᅆџय़ࢅၒষѣग़ກ̝ᆰнѥ̝ࠏၙခ݂ᄥຐय़ࢅѝྵ݆पय़ࢅѝѣᇍण ളࢬ݂҇ჭษѠގ 5̠ЅϼϻІളࡣݶ ݶ ჭษ̢OFEPӊӠҫҚҢһളѣకෞࠊᅬ̝ѝѿѳѝѶ 6̠य़ࢅގݶۀښ ⎇ⓥ↪䊝䊂䊦⚦⢩䈱ഃᛛⴚ㐿⊒䋨ㅪ៤䉕ኒ䈮䈚䈢ห⎇ⓥ䉕ዷ㐿䋩 䊍䊃ES⚦⢩䈱ടᎿᛛⴚ㐿⊒ 䊶䊍䊃ES⚦⢩䈻䈱ㆮવሶዉ䈫ዉㆮવሶ⊒ᓮ䋨੩ᄢ䇮ᐙ⚦⢩ഃ⮎⎇䈱ห⎇ⓥ䋩 䊶䊍䊃ES⚦⢩䈱⋧ห⚵឵䈋ᛛⴚ㐿⊒䋨੩ᄢ䇮ᐙ⚦⢩ഃ⮎⎇䈱ห⎇ⓥ䋩 䊶䉡䉟䊦䉴䊔䉪䉺䊷䉕↪䈇䈢㜞ല₸ㆮવሶዉ䈫⋧ห⚵឵䈋䋨ၯ₹කᄢ䇮੩ᄢ䇮ᐙ⚦⢩ഃ⮎⎇䇮ᾢᧄ 䉡䉟䊦䉴䊔䉪䉺 䉕↪䈇䈢㜞ല₸ㆮવሶዉ䈫⋧ห⚵឵䈋䋨ၯ₹කᄢ ੩ᄢ ᐙ⚦⢩ഃ⮎⎇ ᾢᧄ ᄢ䈱ห⎇ⓥ䋩 䊍䊃ES⚦⢩䈱ಽൻ⺃ዉᓮᛛⴚ㐿⊒ 䊶⚻ᐙ⚦⢩䊶⚻೨㚟⚦⢩ 䈶ㆇേ⚻⚦⢩䈻䈱ಽൻ⺃ዉ䋨ᐙ⚦⢩ഃ⮎⎇䇮੩ᄢ䇮ၯ₹කᄢ䈱 ห⎇ⓥ䋩 䊶ᔃ╭⚦⢩䈻䈱ಽൻ⺃ዉᴺ䈫ోᕈ⮎ℂ⹜㛎䈻䈱ᔕ↪䋨ᐙ⚦⢩ഃ⮎⎇ ੩ᄢ䈱ห⎇ⓥ䋩 䊶ᔃ╭⚦⢩䈻䈱ಽൻ⺃ዉᴺ䈫ోᕈ⮎ℂ⹜㛎䈻䈱ᔕ↪䋨ᐙ⚦⢩ഃ⮎⎇䇮੩ᄢ䈱ห⎇ⓥ䋩 䊶㜞ല₸䈭⢄⚦⢩䈻䈱ಽൻ⺃ዉᴺ䈱⏕┙䈫ᚑᾫ⢄⚦⢩⺃ዉᴺ䈱㐿⊒䋨੩ᄢ䇮ᾢᧄᄢ䇮᧲ᄢ䇮ၯ₹ක ᄢ䇮ᐙ⚦⢩ഃ⮎⎇䈱ห⎇ⓥ䋩 䌅䌃䌍ᚑಽ䉇ੱᎿၮᐩ⤑䈮䉋䉎⚦⢩ᓮᛛⴚ㐿⊒ 䊶䊍䊃ES⚦⢩䈱⚵឵䈋䌅䌃䌍න৻ಽሶ䉮䊷䊁䉞䊮䉫䈮䉋䉎ᧂಽൻ⛽ᜬၭ㙃ഞ䋨੩ᄢ䇮㒋ᄢ䈱ห⎇ⓥ䋩 䊶ੱᎿၮᐩ⤑╬䈮䉋䉎ಽൻ⺃ዉ♽䈱㐿⊒䋨㒋ᄢ ⅣႺ⎇ ᾢᧄᄢ ᐙ⚦⢩ഃ⮎⎇䈱ห⎇ⓥ䋩 䊶ੱᎿၮᐩ⤑╬䈮䉋䉎ಽൻ⺃ዉ♽䈱㐿⊒䋨㒋ᄢ䇮ⅣႺ⎇䇮ᾢᧄᄢ䇮ᐙ⚦⢩ഃ⮎⎇䈱ห⎇ⓥ䋩 ⎇ⓥ↪䊝䊂䊦⚦⢩䈱᭴▽ᛛⴚ䈱㐿⊒ 䊶⚻ᄌᕈ∔ᖚේ࿃ㆮવሶ⚵ㄟ䉂䈮䉋䉎∔ᖚ䊝䊂䊦⚦⢩ᚑ䋨ᐙ⚦⢩ഃ⮎⎇䇮੩ᄢ䈱ห⎇ⓥ䋩 䊶⣖ⴊᶧ㑐㐷䊝䊂䊦᭴▽䈫⚻ⴊ▤♽⚦⢩⺞ᛛⴚ䋨ᐙ⚦⢩ഃ⮎⎇䇮੩ᄢ䇮ⅣႺ⎇䈱ห⎇ⓥ䋩 䊶䊊䉟䉴䊦䊷䊒䉾䊃䉴䉪䊥䊷䊆䊮䉫䋨HTS䋩ᛛⴚ᭴▽䋨੩ᄢ䇮ᐙ⚦⢩ഃ⮎⎇䈱ห⎇ⓥ䋩 HPRT site-specific integration Insulator LoxP HPRT prom 1a Insulator LoxP PGK neo 1b HygroM Targeted HPRT locus on KhES1 LoxP EF1D CAG M Cre EGFP PGK neo Insulator LoxP Insulator LoxP EGFP 1a CAG HPRT prom EF1D M HygroM 1b Cre-mediated recombination with a plasmid carrying the desired transgene and EF1D promoter with an ATG codon results in the rescue of hygromycin resistance. + Hygro Hygro yg r GFP+ 186 186 Efficiency y ((%)) 100 We established the HPRT site-specific integration with high efficiency, indicating that this system can circumvents the silencing problem of transgenes Cre/loxP mediated site-specific gene integration EGFP Sakurai et al. Nucleic Acids Research (2010) ࠙ࠗ࡞ࠬࡌࠢ࠲ࠍ↪ߚ㜞ല₸ߥㆮવሶዉ ၯ₹ක⑼ᄢቇ 㧝㧚࠙ࠗ࡞ࠬࡌࠢ࠲ߩ․ᓽ 㧞㧚ߎࠇ߹ߢߦ㆐ᚑߒߚᚑᨐ ࠕ࠺ࡁ ৻ㆊᕈ㧕 ㆊᕈ㧕 ##8 ৻ㆊᕈ㧕 ##8 ㆊᕈ㧕 • ∛ේᕈࠍ㒰ߒჇᱺ߇ߢ߈ߥᄌ⇣࠙ࠗ࡞ࠬ㧔Ზ㧕ࠍ↪ • ࠙ࠗ࡞ࠬᗵᨴߩᏁᅱߥ⚵ߺࠍ↪ߒߚ㜞ല₸ • ⚦⢩⒳߿⚦⢩ᢙߦᓇ㗀ࠍฃߌߦߊߩߢᐢ▸ߥᔕ↪߇น⢻ ࡦ࠴ ቯ㧕 ⚦⢩ᩣ ࠕ࠺ࡁ ⋧ห⚵឵߃㧕 ` ` ` HPRT 䊔䉪䉺䊷 ⋧ห⚵឵䈋㗫ᐲ 䉝䊂䊉 3-14% (7-45%) 㕖䉡䉟䊦䉴 0-0.6% (0-1%) 䈠䈱ઁ 4ㆮવሶᐳ 䉝䊂䊉 䉝䊂 13-55% 3 55% ((40-81%) 0 8 %) ⢄⚦⢩․⇣⊛ 䉝䊂䊉 29-56% (83-90%) 䉝䊂䊉 7% ((57%)) 㕖䉡䉟䊦䉴 0% ࠙ࠗ࡞ࠬ㊂ 㕖 ࠙ࠗ࡞ࠬ 㧟㧚↥ᬺൻ߳ߩ╭ ࠙ࠗ࡞ࠬ㊂ ࠙ࠗ࡞ࠬ㊂ ㆇേ⚻ ․⇣⊛ ߪPGICVKXGUGNGEVKQPᓟ • UK40#߿ㆮવሶ⊒⺃ዉᴺ߳ߩ↪ • `ߩ'5⚦⢩߳ߩㆮવሶ⊒ಽൻ⺃ዉߦࠃࠆᯏ⢻⚦⢩ߩ㊂↥ • ࡂࠗࠬ࡞ࡊ࠶࠻ൻߦࠃࠆ✂⟜⊛ߥㆮવሶࡁ࠶ࠢࠕ࠙࠻'5⚦⢩ࠗࡉߩഃ Simple procedure of QT interval assay using ESC-derived CMs 100Pm Multiwell MEAs or 96 well plates by ReproCELL, Tokyo, Japan with integrated reference and recording electrodes can be used f higher for hi h throughput h h screening i Recording field of micro electrode arrays (MEA) (Multi Channel Systems, Reutlingen, G Germany) ) 100Pm A Assay data using cardiomyocytes derived from Monkey ESCs, Human ESCs and Human iPSCs C B 20.0 D H5 G8 H4 0pM 300pM 1nM 3nM 10nM 30nM 100nM 0.0 30nM 100nM 300nM 4.0 0pM 300pM 1nM 3nM 10nM 30nM 100nM 300nM 1μM 3μM 2.0 30μM 10μM F P [μ V ] 300nM 1μM 3 M 3μM 10μM 6.0 1μM 3μM 10μM 5.0 FP P [μV] FP [μV] F 10.0 10.0 0pM 300pM 1nM 3nM 10nM 0.0 30μM 0.0 -2.0 30μM -5.0 -10.0 -4.0 -10.0 -6.0 -20.0 0 200 400 600 Time [ms] 800 50 100 150 200 250 300 350 400 450 500 Time [ms] 550 600 650 700 0 50 100 150 200 250 300 350 400 450 Time [ms] Fig. 7. Assay results for Astemizole, a potent histamine H1-receptor antagonist, which was withdrawn from the market due to QT prolongation,. A: Structure of Astemizole B, C, D: Overlay of waveforms recorded with control (comound solvent) and in the presence of each concentration of Astemizole on monkey ES(B), human ES(C), or human iPS (D) cellderived cardiomyocytes. Although detailed waveform shapes for each cell differ differ, a common analysis method can be applied since the waveform from each cell contains the same ion components. Upon treatment with Astemizole, a prolonged Na+-K+ interval indicates this compound’s potential toxicity to heart. ⢄⚦⢩߳ߩ㜞ല₸ಽൻ⺃ዉᴺߩ㐿⊒ߦᚑഞ㧔ᾢᧄᄢቇ㧕 ᡰᜬ⚦⢩ߣߩ ၭ㙃ᴺ ․ᓽ ಽൻᡰᜬ⚦⢩㧔⚦⢩ᩣ㧕ࠍ⺃ዉḮߣߔࠆ UECNGWR߇◲නߢࠆ ߎࠇ߹ߢߩᚑᨐ ٨ ࡅ࠻'5⚦⢩߆ࠄ⢄೨㚟⚦⢩ #(2㓁ᕈ㧑㧕ߩ㜞ല₸ಽൻ⺃ዉߦᚑഞߒߚޕ ٨ ᚑᾫ⢄⚦⢩߹ߢಽൻߔࠆᛛⴚ߽⏕┙ߒߚ㧔Alb㓁ᕈ⚦⢩㧪 ᚑᾫ⢄⚦⢩߹ߢಽൻߔࠆᛛⴚ߽⏕┙ߒߚ㧔Alb㓁ᕈ⚦⢩㧪㧑㧕 㧑㧕 ࿑ ࡅ࠻'5⚦⢩߆ࠄౝ⢦⪲ޔ⢄೨㚟⚦⢩ޔ⢄⚦⢩ߩ㗅⇟ߢಽൻ⺃ዉ䈘䉏䈢 ౝ⢦⪲ ⢄೨㚟⚦⢩ D10 D20 Sox17 AFP ᚑᾫ⢄⚦⢩ D30 ALB ٨ ࠣࠦࠥࡦ⫾Ⓧ‛⮎ޔઍ⻢㉂⚛ޔᛴว♽㉂⚛ޔ⊒ߩ࠲ࡐࠬࡦ࠻ޔ ⮎‛ߦࠃࠆ% #ߩ⺃ዉ ࡅ࠻ೋઍၭ㙃⢄⚦⢩ߣห╬ߥ ⮎‛ߦࠃࠆ%[R#ߩ⺃ዉ࠻ࡅޕೋઍၭ㙃⢄⚦⢩ߣห╬ߥࠕ࡞ࡉࡒࡦಽᴲ⢻߇ ࡉࡒ ಽᴲ⢻߇ ⏕ߐࠇߚޕ ᬺේ★ 䋺㪐㪊㪧㩷䌾 㪐㪍㪧 ᄙ⢻ᕈᐙ⚦ ᄙ⢻ᕈᐙ⚦⢩䈱ᔕ↪䈮ᔅⷐ䈭ၭ㙃ᴺ䈱⏕┙ ↪ ᔅⷐ ၭ㙃ᴺ ⏕ • ήⴊᷡၭ䈎䉌ቢోวᚑၭ䈻 䊶䈜䈪䈮ⴊᷡᷝട䈚䈭䈇ၭ䈪᮸┙䊶Ⴧᱺ⛽ᜬ䈘䉏䈩䈇䉎 䊶േ‛Ⱞ⊕⾰䈭䈬䉕䉁䈭䈇ቢోวᚑၭ䈱㐿⊒䈏ㅴ䉖䈪䈇 䉎䇯 • 䊐䉞䊷䉻䊷⚦⢩ 䉻 ⚦⢩ 䊶䈜䈪䈮䊍䊃⚦⢩䉕↪䈇䈢᮸┙䈫Ⴧᱺ⛽ᜬ䈏ᚑഞ䈚䈩䈇䉎 䊶䊐䉞䊷䉻䊷⚦⢩䉕䉒䈭䈇ၭ㙃⛽ᜬᣇᴺ䈱㐿⊒䈲ㅴⴕਛ䈪䈅 䉻 䉎䈏䇮䊙䊃䊥䉭䊦䋨䊙䉡䉴䈏䉖⚦⢩ᩣ↱᧪䌅䌃䌍䋩↪䈭䈬㗴 ὐᱷ䉎 Human ES cell colony cultured without feeder cells 䊐䉞 䉻 ⚦⢩䈭䈚䈪ၭ㙃䈘䉏䈢䊍䊃䌅䌓⚦⢩䉮 䊐䉞䊷䉻䊷⚦⢩䈭䈚䈪ၭ㙃䈘䉏䈢䊍䊃䌅䌓⚦⢩䉮䊨䊆䊷 ಽሶ⚵ᚑ䉕䉦䉴䉺䊙䉟䉵䈚䈢ቢోวᚑဳੱᎿၮᐩ⤑䈱᭴▽ᛛⴚ䉕㐿⊒ 䋨ᄢ㒋ᄢቇ ᣣᧄ⊹㕟⎇ⓥᚲ䋩 䋨ᄢ㒋ᄢቇ䊶ᣣᧄ⊹㕟⎇ⓥᚲ䋩 ቢోวᚑဳੱᎿၮᐩ⤑䈱᭴▽ᚢ⇛ 㪂㩷䊆䊄䉭䊮 㪂 䊆䊄䉭䊮 㪂㩷䊌䊷䊦䉦䊮 㪂㩷䊤䊚䊆䊮 ᡷ⦟ ᡷ⦟ဳ㪠㪭ဳ 䉮䊤䊷䉭䊮䉭䊦 ╙ੑઍੱᎿၮᐩ⤑ ╙ ઍੱᎿၮᐩ⤑ ╙৻ઍੱᎿၮᐩ⤑ 㩿䊤䊚䊆䊮㪆㪠㪭ဳ䉮䊤䊷䉭䊮㪀 ¾ ਥⷐၮᐩ⤑᭴ᚑಽሶ䈱㜞⊒䊶ቯଏ⛎♽䈱⏕┙ 9 ో䊤䊚䊆䊮䉝䉟䉸䊐䉤䊷䊛䇮䊌䊷䊦䉦䊮䇮䊆䊄䉭䊮䈱⚵឵䈋Ⱞ⊕⾰䈱⊒♽䉕᭴▽ 9 䉭䊦ൻ⢻䉕ᜬ䈚䈢IVဳ䉮䊤䊷䉭䊮䈱ቯଏ⛎♽䉕⏕┙ ¾ 䌉Vဳ䉮䊤䊷䉭䊮䉭䊦䈱⣀ᒙᕈ䉕స䈚䈢ᡷ⦟ဳ䉮䊤䊷䉭䊮䉭䊦䈱㐿⊒䈮ᚑഞ ဳ 䉭 䉭 ⣀ᒙᕈ䉕స䈚䈢ᡷ⦟ဳ 䉭 䉭 㐿⊒䈮ᚑഞ 9 I ဳ䉮䊤䊷䉭䊮䈱ቯᕈ䈫IVဳ䉮䊤䊷䉭䊮䈱↢‛ᵴᕈ䉕 ૬䈞ᜬ䈧ᷙᚑ䉮䊤䊷䉭䊮䉭䊦䈱㐿⊒ 䋪․⸵㗿䋺䇸I ဳ䊷䌉䌖ဳ䉮䊤䊷䉭䊮ᷙᚑ䉭䊦䇹䋨․㗿2009-235348䋩 ¾ 䌉ဳ/IVဳᷙᚑ䉭䊦䈮䊤䊚䊆䊮䇮䊆䊄䉭䊮䇮䊌䊷䊦䉦䊮䉕⚵䉂 ㄟ䉖䈣㵰╙ੑઍੱᎿၮᐩ⤑㵱䈱᭴▽䈮ᚑഞ ㄟ䉖䈣 ╙ੑઍੱᎿၮᐩ⤑ 䈱᭴▽䈮ᚑഞ ⇇ೋ䈱ቢోวᚑဳੱᎿၮᐩ⤑䋣 䌉 ဳ䉮䊤䊷䉭䊮 න⁛䉭䊦 䌉 ဳ/䌉䌖ဳ ᷙᚑ䉭䊦 ⚵឵䈋䊤䊚䊆䊮䉕↪䈚䈢䊍䊃䌅䌓⚦⢩䈱䊐䉞䊷䉻䊷䊐䊥䊷ၭ㙃䈮ᚑഞ 䋨ᄢ㒋ᄢቇ䈫੩ㇺᄢቇ䈱ห⎇ⓥ䋩 ⚵឵䈋䊍䊃䊤䊚䊆䊮䈪䈱Ⴧᱺ 㪢㪿㪜㪪㪄㪊 Matrigel LN332 LN511 LN111 LN211 LN411 ¾ ⚵឵䈋䊤 䊤䊚䊆䊮-511䈍䉋䈶-332䉕 䉮䊷䊃䈚䈢ၮ⾰䈪䇮䊍䊃䌅䌓⚦⢩䈲 ᧂಽൻᕈ䉕⛽ᜬ䈚䈢䉁䉁Ⴧᱺ䈜䉎䇯 ¾ 䊤䊚䊆䊮 䊤䊚䊆䊮-511䈍䉋䈶-332䈲䇮䈬䈤䉌 511䈍䉋䈶 332䈲 䈬䈤䉌 䉅䉟䊮䊁䉫䊥䊮61䈫ᒝ䈒⚿ว䇯 ¾ 䊍䊃䌅䌓⚦⢩䈲䉟䊮䊁䉫䊥䊮61 䉕ᒝ䈒⊒䈚䈩䈇䉎䇯 M t i l LN332 Matrigel LN511 ((Miyazaki y et al.,, Biochem Biophys p y Res Commun,, 2008)) 䊍䊃⚵឵䈋䊤䊚䊆䊮䉕↪䈚䈢䊍䊃䌅䌓⚦⢩䈱 䊐䉞䊷䉻䊷䊐䊥䊷ၭ㙃䈱⇇ೋ䈱ᚑഞ䋣 䉝䊦䉦䊥䊐䉤䉴䊐䉜䉺䊷䉷 ᵴᕈᨴ⦡ 䊍䊃ES⚦⢩䈎䉌 ⚻ᄌᕈ∔ᖚ䊝䊂䊦⚦⢩䈱ഃ ⚻ಽൻ⺃ዉᛛⴚ ⚻ᄌᕈ∔ᖚ᭽ ⚻⚦⢩ ES⚦⢩↱᧪ ⚻೨㚟⚦⢩ ES⚦⢩ ES⚦⢩ㆮવሶᡷᄌᛛⴚ ⚻ᄌᕈ∔ᖚේ࿃ㆮવሶ 䊝䊂䊦⚦⢩䈱᭴▽ᛛⴚ ⊒∝ᯏ᭴⸃䈫ഃ⮎⎇ ⓥ䈮↪น⢻䈭 ∔ᖚ䊝䊂䊦⚦⢩ ⚻ᄌᕈ∔ᖚ䊝䊂䊦⚦⢩䈱ഃ ⚻ᄌᕈ∔ᖚ ᄢ⣖ ∔ᖚ䈮䉋䉍 ේ࿃ㆮવሶ䈲 ⇣䈭䉎 ㆇേ ⚻⚦⢩ 䉝䊦䉿䊊䉟䊙䊷∛䋨AD䋩 APP, PS1䈭䈬 䊊䊮䉼䊮䊃䊮∛䋨HD䋩 HTT ╭⪜❗ᕈ⚝⎬ൻ∝䋨ALS䋩 SOD1, TDP43䈭䈬 ⋡⊛䈫䈜䉎⚻ᄌᕈ∔ᖚ䈱ේ࿃ㆮવሶ䈱ᄌ⇣ဳㆮવሶ䉕⊒ 䈜䉎䊍䊃ES⚦⢩䋨∔ᖚES⚦⢩䋩䈱ᚑ䈫ಽൻ⺃ዉ ES⚦⢩↱᧪⢄⚦⢩䉕↪䈇䈢䇮ഃ⮎ᡰេ䈱䈢䉄䈱⮎‛േᘒ䊶Ქᕈ⹏ ଔ♽䈱⏕┙ 䋨᧲ᄢ㒮䊶⮎䋯᧖ጊ㓶৻䋩 1 䊍䊃⢄⚦⢩䉕↪䈇䈢⮎‛േᘒ䈱⹏ଔ䊶੍᷹♽䈱⏕┙ 1. 䊍䊃⢄⚦⢩䉕↪䈇䈢⮎‛േᘒ䈱⹏ଔ ੍᷹♽䈱⏕┙ ㆆ㔌⢄⚦⢩䉕↪䈇䈢 ⢄ข䉍ㄟ䉂䉪䊥䉝䊤䊮䉴䈱੍᷹ In vivo CLnnon-renal (mL/min n/kg) 100 1:3 4 1:1 8 2 10 1 In vitro䊂䊷䉺䈮ၮ䈨䈒in vivo⮎ ‛േᘒ䈱੍᷹䊝䊂䊦䈱᭴▽ 3:1 5 3 1 6 In vivo⢄䉪䊥䉝䊤 䊮䉴䉕in vitroታ㛎 䈎䉌⦟ᅢ䈮੍᷹ 7 01 0.1 0.1 1 10 100 In vitro CLh,predicted (mL/min/kg) 䉰䊮䊄䉟䉾䉼ၭ㙃⢄⚦⢩䉕↪䈇䈢 ⢙᳝ឃᴭ䉪䊥䉝䊤䊮䉴䈱੍᷹ Matrigel overlay ⛔ ว tight junction bile pocket (⢙▤⣧) ⢙᳝ឃᴭ䊃䊤䊮䉴䊘䊷䉺䊷䈱ነਈ₸䊶ᯏ⢻䈱 ቯ㊂⊛੍᷹䈮䈧䈭䈕䉎 ES⚦⢩↱᧪⢄⚦⢩䉕↪䈇䈢䇮ഃ⮎ᡰេ䈱䈢䉄䈱⮎‛േᘒ䊶Ქᕈ⹏ ଔ♽䈱⏕┙ 䋨᧲ᄢ㒮䊶⮎䋯᧖ጊ㓶৻䋩 2. 䊍䊃ES⚦⢩↱᧪⢄⚦⢩䈮䈍䈔䉎⮎‛േᘒ㑐ㅪㆮવሶ䈱⊒ 䊃 ⚦⢩↱᧪⢄⚦⢩䈮䈍䈔䉎⮎‛േᘒ㑐ㅪㆮવሶ ⊒ 䈱⹏ଔᴺ䈱ᮡḰൻ ข䉍ㄟ䉂䊃䊤䊮䉴䊘䊷䉺䊷OATP1B1 ᵦᵦᵋ ᵔᵎᵗ ᵐᵎᵔ ឃ䊃䊤䊮䉴䊘䊷䉺䊷MRP2 ᵦᵣᵩ ᵫᵢᵡᵩᵧᵧ ᵲᵢᵦ ᵫᶍᶁᶉ ᵭᵟᵲᵮ ᵫᶍᶁᶉ ᵭᵟᵲᵮ ᵏᵠᵏ ᵏᵠᵏ ᵡᶐᶓᶂᶃ ᶋᶃᶋᶀᶐᵿᶌᶃ ઍ⻢㉂⚛CYP3A4 ᵦᵦᵋ ᵐᵎᵔ ᵔᵎᵗ ᵲᵢᵦ ᵦ ᶋᶇ ᶓᶋᵿ ᶁᶐ ᶌᴾ ᶍᶑ ᶊᶇᶔ ᶍᶋ ᶃᶐ ᶃᶑ ᴾ ᵓᵎ᷈ᶅᵍᶊᵿᶌᶃ ᵡᶃᶊᶊᴾ ᶊᶗᶑᵿᶒᶃ ᵏᵎ᷈ᶅᵍᶊᵿᶌᶃ ઍ⻢㉂⚛CYP2C9 ᵓ ᷈ᶅᵍᶊᵿᶌᶃ ⶄᢙ䊨䉾䊃䈱䊍䊃ಓ⚿⢄⚦⢩䉰䊮䊒䊦 䈪䈱⮎‛േᘒ㑐ㅪㆮવሶ䈱mRNA, ⮎‛േᘒ㑐ㅪㆮવሶ RNA Ⱞ⊕⊒㊂䉕ၮḰ䈮䇮ES⚦⢩↱᧪⢄ ⚦⢩䈱ഃ⮎↪䈻䈱น⢻ᕈ䉕ቯ㊂⊛ 䈮⹏ଔน⢻䈫䈚䈢䇯 Screening system with a reporter GFP gene f cardiomyocyte for di t differentiation, diff ti ti and d detection of effective chemical compounds GFP fluorescence fl EffectivecompoundX p a 400 350 300 250 96wellplate 96 well plate scanningimage Moleculardevice/MetaMorphimagingsystem 200 0 20 40 60 80 AnalysisofGFP fluorescence 䌂䌂䌂䊝䊂䊦ഃ 䋱䋮ᬺౝኈ䈫⋡ᮡ 㽲 䊍䊃㪜㪪⚦⢩䈎䉌ⴊ▤♽䊶⚻♽⚦⢩䈱ಽൻ⺃ዉᛛⴚ 䈍䉋䈶㊂↥⺞ᛛⴚ䈱⏕┙ ಽൻ⺃ዉᛛⴚ 㽳 ⴊᶧ⣖㑐㐷䋨㪙㪙㪙䋩䊝䊂䊦䈱ഃ 䊝䊂䊦⚦⢩ഃ 䉺䉟䊃䉳䊞䊮䉪䉲䊢䊮 ⣖Ძ⚦ ⴊ▤ౝ⊹⚦⢩ ⚻⚦⢩ 䊍䊃㪜㪪⚦⢩ ⴊ▤೨㚟⚦⢩ ⚻೨㚟⚦⢩ ⴊᶧ ၮᐩ⤑ 䉥䊥䉯 䊂䊮䊄䊨䉰䉟䊃 ⴊ▤⊹⚦⢩ 䉝䉴䊃䊨䉰䉟䊃 ⣖ ↢ౝ䈱ⴊᶧ⣖㑐㐷䈱᭴ㅧ ⴊ▤ౝ⊹⚦⢩ ⴊ▤⊹⚦⢩ 䉝䉴䊃䊨䉰䉟䊃 䋨㪊⒳ၭ㙃♽䋩 ⴊ▤ౝ⊹⚦⢩ 䋿 䉝䉴䊃䊨䉰䉟䊃 ⴊ▤⊹⚦⢩ 㫀㫅㩷㫍㫀㫋㫉㫆 㪙㪙㪙䊝䊂䊦 䊝䊂䊦ൻ䈱ၮᧄᒻᘒ ⺰ᢥ ቇળ⊒ ․⸵ ႎ ⺰ᢥ䇮ቇળ⊒䇮․⸵䇮ႎ ᐔᚑ䋱䋷ᐕ䋶䌾ᐔᚑ䋲䋲ᐕ䋳 ⺰ᢥ ቇળ⊒ ․⸵ ႎ 19䋳 3䋳䋲 24 4䋵 ਼ହჭྯѭѣ൦๘ ჭྯ൦๘ 2/ ӅһFTၙѣ݈ী࡚ୠގ ၙ ݈ ࡚ୠގ̡̡̡̡̡̡̡̡̡̡̡̡̡̡ ൌтф൦ ൌ ൦ UfuPO0PGGॶᄥຐपޱᅶ̝3B༖ᇀѠѽҀిڭเથઍѣຎॶपޱᅶ̝IQSUڕѭѣ ߺҞҮҶһೱຎਕѴѠѽҀޓᅗڭเથڋซॶपޱᅶ̝ђѣߋᅀޫсҀ ،ڭเથຐ࡚ୠѝॶট࡚ୠѣގ ؍ೱຎߺн࡚ୠѣގ ؎SOBߴறၔѠѽҀڭเથॶট࡚ ୠѣގ 3/!ӅһFTၙѣခ݂ᄥຐট࡚ୠގ ၙ ခ݂ᄥຐট࡚ୠގ ̡̡̡̡̡̡̡̡ ൌтф൦ ൌ ൦ ߺӅһ༭Ҧ̷ҹҖӦңѠѽҀႵခ݂ڦૐഄ௮पޱᅶ̝ީଠఋफၙѭѣ৹ᅵခ݂ᄥຐ पޱᅶ̝ࣗခ݂݂ѝᄜคခથ݂৾ѣҤӒҞӞҬҢӝ̷ҾӦңল ،ఋफपၙ ѣခ݂ᄥຐট࡚ୠѣގ ؍ࣗၙ ،ఋफपၙѭѣခ݂ᄥຐট࡚ୠѣގ ؍ࣗၙѭѣခ݂ᄥຐট࡚ୠѣގ ѣခ݂ᄥຐট࡚ୠѣގ ؎ࠏၙ ؎ࠏၙѭѣခ݂ ѣခ݂ ᄥຐট࡚ୠѣގ ؏ఘী࠱ญ႟ѹ࡛ӑһӝҶҢҬѠѽҀခ݂টྵ݆ 4/!य़ࢅᅀӕҺӞၙѣඞ࡚ୠގ̡̡̡̡̡̡̡̡̡̡ ൌтф൦ ҕӞҷӂҗӑ̷ྐྵ̺ӂӦҴӦһӦྐྵ̺ϸЃЊӕҺӞၙѠলౖ̝ࣗҕҶҮҗपѣ ҕӞҷӂҗӑ ྐྵ̺ӂӦҴӦһӦྐྵ̺ϸЃЊӕҺӞၙѠল ౖࣗҕ Үҗपѣ ޱᅶ ،ఋफဦౖ૱߶ӕҺӞၙѣೖ౦ ۼे؍࠙ჸͅCCC͆ӕҺӞѣೖ౦ ؎FTၙᄢᅗࠏၙ҇ᅀйєೖᄅ બѣєѶѣᄅຍ഻ౖ̡ྵ݆पѣޱᅶ ؏ҝӦҴҶӊ̡Ӆһ௰̡ആ࠰ӕҺӞ҇ᅀйєౖ̡ೖ ᄅબ࡚ୠѣय़ࢅގ 5/!ގ࡚ୠѣઍࣅ̡݂ᅀ̡̡̡̡̡̡̡̡̡̡̡̡̡̡݂ ൌтф൦ ౖࣗુ६ѣᅀ݂ގઢ̝ӕҺӞၙѠѽҀૉࣅ݂ѣलݭ ،ခ݂ࣗၙ҇ѷійєRU܋ේુ६ᅀ݂ ؍ఋफဦౖ૱߶џўӕҺӞၙѠѽҀૉࣅ݂लݭ ႆ২ᘐƷоᕤࣖဇ ESኬᏘǛdzǢƴᢡˡ܇ો٭২ᘐŴೞᏡኬᏘЎ҄২ᘐƓǑƼƦǕǒǛဇƍƨǹǯȪ ESኬᏘǛdzǢƴᢡˡ܇ો٭২ᘐ ೞᏡኬᏘЎ҄২ᘐƓǑƼƦǕǒǛဇƍƨǹǯȪȸȋȳǰ২ᘐǛԃljɭမưNj ȋȳǰ২ᘐǛԃljɭမưNj ǛᙸƳƍѼਙႎƳ২ᘐႆƷௐǛƋƛƭƭƋǔŵѼਙႎƳ২ᘐႆޒƴǑǓŴܱဇ҄Njᡈƍŵ ਊѣ࣎ሂኬᏘǛဇƍƯŴ оᕤư36ࡨᧈƷӧᏡࣱƷ ஊƷᚸ̖ ਊѣȢȇȫ࣎ሂኬᏘ HTS২ᘐ ࣎ሂЎ҄২ᘐ ᏁኬᏘЎ҄২ᘐ ᢡˡ܇ો٭২ᘐ dzǢᲴESኬᏘ ᅕኺЎ҄২ᘐ ȢȇȫᏁኬᏘ ǷȈǯȭȠ P450 Ტcytochrome P450, CYPᲣᚾ᬴ƴ ǑǔᕤдƷCYPᛔ ܹ᧹ ݰHTS ݰȷ᧹ܹHTS ȢȇȫኬᏘǛဇƍƨHTS ၌धȢȇȫᅕኺኬᏘ ᕤཋѣ७ܤμࣱᚾ ᬴ưƷМဇ ၲᕤͅᙀኧƷ ƨNJƷHTS ᘉ෩Ꮿ᧙ᧉȢȇȫ ႆ২ᘐƷငಅ҄ оᕤƴƓƚǔQTࡨᧈƴ̅ဇưƖǔ࣎ሂЎ҄২ᘐƴ᧙ƠƯƸ19࠰6உƴఇࡸ˟ ᅈȪȗȭǻȫƴȩǤǻȳǹ̓ɨƠƨŵ ȪȗȭǻȫᅈưƸ20࠰4உƴǵȫESኬᏘဌஹ࣎ሂኬᏘŴ21࠰4உƴ ȒȈiPSኬᏘဌஹ࣎ሂኬᏘƷᝤ٥ƓǑƼӖᚠᚾ᬴ʙಅǛڼƠƯƍǔŵ NEDO䊒䊨䉳䉢䉪䊃 ੩ㇺᄢቇ ၮ␆⎇ⓥ 㘈ቴ ᐙ⚦⢩ഃ⮎⎇ⓥᚲ ታ↪ൻ⎇ⓥ ห⎇ⓥ ᬺൻ 䊤䉟䉶䊮䉴 ࣎ሂЎ҄২ᘐ јྙႎƳ࣎ሂЎ҄ƱਊѣȢȇȫ࣎ሂ ኬᏘǛဇƍƨ36ࡨᧈ҄ӳཋᚸ̖২ᘐ NEDO䊒䊨䉳䉢䉪䊃䈪䈱ES⚦⢩ᛛⴚ䉕iPS⚦⢩䈻ㆡ↪䊶ታ↪ൻ ⇇䬶ᦨೋ䬺䎨䎶䎒䏌䎳䎶⚦⢩↱᧪ᔃ╭⚦⢩䭡䬲䬮ᔃ╭Ქᕈ䭩䮊䮂䭫ᬺታ↪ൻ㐿ᆎ䬽ႎ⸥ 䮴䭫䮆䯃㔚ሶ 䎋䎕䎓䎓䎜ᐕ䎗䎕䎕ᣣ䎌 SocietyforBiomolecularScience15thAnnual Conference(2009) B P BestPoster StemCellsandRegenerativeMedicineEurope (2009) BestPoster ᣣᧄ⚻ᷣᣂ⡞ ᦺೀ䎔㕙 䎋䎕䎓䎓䎜ᐕ䎕䎕䎚ᣣ䎌 ᣣᧄ⚻ᷣᣂ⡞ ᦺೀ䎜㕙 䎋䎕䎓䎓䎜ᐕ䎗䎜ᣣ䎌 ྵנႆɶƷ২ᘐƷʙಅ҄ǹDZǸȥȸȫ(࣎ሂᲣ 19࠰ࡇ ࣎ሂЎ҄২ᘐ ࣎ሂјྙЎ҄ ˯Ў҄܇ӳཋ ২ᘐႆ ȩǤǻȳǹแͳ 20࠰ࡇ ȩǤǻȳǹ ငಅ҄ႆ 21࠰ࡇ 22࠰ࡇˌᨀ ʙಅਘٻ ʙಅ҄ ২ᘐႆ ȩǤǻȳǹแͳ ཎᚩЈᫍ ȩǤǻȳǹʖܭ ငಅ҄ႆ ʙಅ҄ 2710 ཎᚩЈᫍ ȩǤǻȳǹʖܭ ငಅ҄ႆ ʙಅ҄ 11474 ஜȗȭǸǧǯȈƷφ˳ႎƳʙಅ҄ႸƱǹDZǸȥ ȫǛˌɦƴᅆƢ ஜȗȭǸǧǯȈƷφ˳ႎƳʙಅ҄ႸƱǹDZǸȥȸȫǛˌɦƴᅆƢŵ ᲿኬᏘဌஹƷ࣎ሂኬᏘǛဇƍƨࣱᚾ᬴Ტ36ࡨᧈᲣᲴ࠰ࡇʙಅ҄ฎLj ᲿኬᏘဌஹƷ࣎ሂኬᏘǛဇƍƨࣱᚾ᬴Ტ36ࡨᧈᲣǛؕႴƴK25ኬᏘưNjʙಅ҄Ჴ࠰ࡇʙ ಅ҄ฎLj *65ưᙸЈƠƨ˯Ў҄܇ӳཋƷཎᚩЈᫍƱƜǕǒƷ҄ӳཋǛဇƍƨјྙЎ҄Ʒʙಅ҄࠰ࡇ *65ưᙸЈƠƨ˯Ў҄܇ӳཋƷཎᚩЈᫍƱƜǕǒƷ҄ӳཋǛဇƍƨјྙЎ҄Ʒʙಅ҄࠰ࡇ ྵנႆɶƷ২ᘐƷʙಅ҄ǹDZǸȥȸȫᲢᅕኺᲣ 19࠰ࡇ ᅕኺЎ҄২ᘐ ȑ ǭȳǽȳ၏Ȣȇȫ ȑȸǭȳǽȳ၏Ȣȇȫ ᅕኺЎ҄২ᘐ ALSȢȇȫ ᅕኺЎ҄২ᘐ ǢȫȄȏǤȞ ၏Ȣȇȫ ǢȫȄȏǤȞȸ၏Ȣȇȫ 20࠰ࡇ 21࠰ࡇ 22࠰ࡇˌᨀ ২ᘐႆ ȩǤǻȳǹแͳ ȩǤǻȳǹʖܭ ငಅ҄ႆ ʙಅ҄ ২ᘐႆ ȩǤǻȳǹแͳ ȩǤǻȳǹʖܭ ငಅ҄ႆ ʙಅ҄ ২ᘐႆ ȩǤǻȳǹแͳ ȩǤǻȳǹʖܭ ငಅ҄ႆ ʙಅ҄ ஜȗȭǸǧǯȈƷφ˳ႎƳʙಅ҄ႸƱǹDZǸȥ ȫǛˌɦƴᅆƢ ஜȗȭǸǧǯȈƷφ˳ႎƳʙಅ҄ႸƱǹDZǸȥȸȫǛˌɦƴᅆƢŵ ᆔƷᅕኺ၌धȢȇȫኬᏘᲴ࠰ࡇƴʙಅ҄Ƣǔ 䊍䊃ES⚦⢩/iPS⚦⢩ᛛⴚ䈱ᬺൻ䈱ዷ㐿䋨੍ᗐ䋩 ᬺ㗔ၞ ⎇ⓥ⹜⮎䊶⎇ⓥᯏེ ↪‛⾰↥↢ ഃ⮎ၮ⋚ᛛⴚ ౣ↢ක≮䊶⚦⢩ᴦ≮ ᬺ䉟䊜䊷䉳 ታᤨᦼ Ꮢ႐ⷙᮨ • • ᢙච䌾ᢙ⊖ం • ⹜⮎䈱ឭଏ • 䊂䊋䉟䉴䊶ᯏེ䈱ឭଏ 䊎䉳䊈䉴䊝䊂䊦 • ⚦⢩䋨⎇ⓥ↪䋩䈱ឭଏ ᣣᧄ ᬺ ታᣉ * ᶏᄖ * ⚫䈪䈅䉍䇮ᔅ䈝䈚䉅✂⟜⊛䈪䈲䈭䈇 ౖ: 38 ડᬺ㐿ᖱႎ:╩⠪ᚑ • 1䌾2ᐕᓟ – • 䌾1ᐕᓟ – • 5䌾10ᐕᓟ – • ᢙච䌾ᢙ⊖ం • ᢙ⊖䌾৻ජం? • ᢙళ? • ⹜⮎䈱ឭଏ • 䊂䊋䉟䉴䊶ᯏེ䈱ឭଏ • ක⮎ຠ䈱ឭଏ • • • • ⹜⮎䈱ឭଏ 䊂䊋䉟䉴䊶ᯏེ䈱ឭଏ ⚦⢩䋨ᬺ↪䋩䈱ឭଏ ഃ⮎ฃ⸤⹜㛎䉰䊷䊎䉴 䈱ឭଏ • • • • ⹜⮎䈱ឭଏ 䊂䊋䉟䉴䊶ᯏེ䈱ឭଏ ⚦⢩䋨ක≮↪䋩䈱ឭଏ ⚦⢩䊋䊮䉨䊮䉫䊶䉰䊷䊎 䉴䈱ឭଏ