Title Studies on the Role of Oxidative Stress in Mutagenesis by UsingNrf2-deficient Mice( 内容と審査の要旨(Summary) ) Author(s) 土屋, 卓磨 Report No.(Doctoral Degree) 博士(獣医学) 甲第509号 Issue Date 2018-09-21 Type 博士論文 Version ETD URL http://hdl.handle.net/20.500.12099/77270 ※この資料の著作権は、各資料の著者・学協会・出版社等に帰属します。
Ặྡ㸦ᮏ㸦ᅜ㸧⡠㸧 ᅵ ᒇ ༟ ☻㸦ᮾி㒔㸧 ᣦ ᑟ ᩍ ဨ Ặ ྡ ᒱ㜧Ꮫ ᩍᤵ ᰡ ᚫ ☻ Ꮫ ࡢ ✀ 㢮 ༤ኈ㸦⋇་Ꮫ㸧 Ꮫ グ ␒ ྕ ⋇་༤⏥➨㸳㸮㸷ྕ Ꮫ ᤵ ᖺ ᭶ ᪥ ᖹᡂ㸱㸮ᖺ㸷᭶㸰㸯᪥ Ꮫ ᤵ ࡢ せ ௳ Ꮫつ๎➨㸲᮲➨㸯㡯ヱᙜ ◊ ✲ ⛉ ཬ ࡧ ᑓ ᨷ 㐃ྜ⋇་Ꮫ◊✲⛉ ⋇་Ꮫᑓᨷ ◊✲ᣦᑟࢆཷࡅࡓᏛ ᒱ㜧Ꮫ Ꮫ ㄽ ᩥ 㢟 ┠ 6WXGLHVRQWKH5ROHRI2[LGDWLYH6WUHVVLQ 0XWDJHQHVLV E\8VLQJ1UIGHILFLHQW0LFH 㸦1UI Ḟᦆ࣐࢘ࢫࢆ⏝࠸ࡓኚ␗ཎᛶ࠾ࡅࡿ㓟ࢫࢺ ࣞࢫࡢᙺ㛵ࡍࡿ◊✲㸧 ᑂ ᰝ ጤ ဨ ᰝ ᮾி㎰ᕤᏛ ᩍ ᤵ ㇂ ῟ ᰝ ᖏᗈ␆⏘Ꮫ ᩍ ᤵ ྂ ᯘ ᚿᏳ ᰝ ᒾ ᡭ Ꮫ ᩍ ᤵ బ ⸨ ὒ ᰝ ᮾி㎰ᕤᏛ ᩍᤵ ྜྷ ⏣ ᩄ ๎ ᰝ ᒱ 㜧 Ꮫ ᩍ ᤵ ᰡ ᚫ ☻ Ꮫㄽᩥࡢෆᐜࡢせ᪨ ⚾㐩ࡣᖖ⎔ቃ୰࠾࠸࡚✀ࠎࡢⓎࡀࢇ≀㉁ࡢ⬣ጾࡉࡽࡉࢀ࡚࠸ࡿࠋᵝࠎ࡞⎔ቃ୰ Ꮫ≀㉁ࡢ୰࡛ࡶ㸪㣗ရࢆࡋ࡚ࣄࢺࡀᦤྲྀࡍࡿྍ⬟ᛶࡢ࠶ࡿ≀㉁ࡢⓎࡀࢇࣜࢫࢡホ౯ࡣ㸪 බ⾗⾨⏕ୖ᭱ࡶ㔜せ࡞ㄢ㢟ࡢ୍ࡘ࡛࠶ࡿࠋࡲࡓ㸪ࡑࢀࡽࡼࡾㄏⓎࡉࢀࡿ㓟ࢫࢺࣞࢫࡣ㸪 ᏛⓎࡀࢇࡢ㐣⛬࠾࠸࡚㔜せ࡞ᙺࢆᢸ࠺ࡇࡀ▱ࡽࢀ࡚࠸ࡿࠋ㌿ᅉᏊࡢ୍ࡘ࡛࠶ࡿ NRF2 ࡣᢠ㓟㓝⣲⩌ࡢⓎ⌧ㄪ⠇ࢆࡋ࡚⏕యෆ࡛㓟ࢫࢺࣞࢫ㜵ᚚ㔜せ࡞ᙺࢆᯝࡓ ࡋ࡚࠾ࡾ㸪ࡑࡢḞᦆື≀ࡣ㓟ࢫࢺࣞࢫᑐࡋ࡚㧗ឤཷᛶࢆ♧ࡍࡇࡀ▱ࡽࢀ࡚࠸ࡿࠋࡲ ࡓ㸪⭈⮚ࡣἥࡸ྾㐣⛬࡛ᵝࠎ࡞≀㉁ࡢ᭚㟢㸪ࡉࡽ᪲┒࡞㓟㑏ඖᛂࡢሙ࡛࠶ࡿ ࡓࡵ㸪㓟ࢫࢺࣞࢫࡢᙳ㡪ࢆ᭱ࡶᙉࡃཷࡅࡿ⮚ჾࡢ୍ࡘ࡛࠶ࡿࠋࡑࡢࡓࡵ㸪⭈Ⓨࡀࢇ㐣⛬ ࡣ㓟ࢫࢺࣞࢫࡀᙉࡃ㛵ࡋ࡚࠸ࡿ⪃࠼ࡽࢀ࡚࠸ࡿࠋࢽࢺࣟࣇࣛࣥࢺࣥ㸦NFT㸧࠾ ࡼࡧ⮯⣲㓟࣒࢝ࣜ࢘㸦KBrO3㸧ࡣࡑࢀࡒࢀṧ␃㎰⸆࠶ࡿ࠸ࡣ㣗ရῧຍ≀ࡋ࡚ࣄࢺࡀᦤྲྀ ࡍࡿྍ⬟ᛶࡢ㧗࠸Ꮫ≀㉁࡛࠶ࡿࡀ㸪࠸ࡎࢀࡶࣛࢵࢺ࠾࠸࡚⭈Ⓨࡀࢇᛶࡀሗ࿌ࡉࢀ࡚࠸ ࡿࠋࡲࡓ㸪୧⪅ࡣࡑࢀࡒࢀࢽࢺࣟᇶࡢ㑏ඖᛂ࠾ࡼࡧࣈ࣑ࣟࣥࣛࢪ࢝ࣝࡢ⏕ᡂࢆࡋ࡚㓟 ࢫࢺࣞࢫࢆㄏⓎࡍࡿࡓࡵ㸪ࡑࡢⓎࡀࢇᛶࡢ㓟ࢫࢺࣞࢫࡢ㛵ࡀࢃࢀ࡚࠸ࡿࠋ୍᪉㸪 άᛶ㓟⣲✀ࡼࡾᙧᡂࡉࢀࡿ᭱ࡶ௦⾲ⓗ࡞㓟ⓗ DNA ᦆയࡢ୍ࡘ࡛࠶ࡿ 8-OHdG ࡣ㸪⮫ ᗋ⌧ሙࡸື≀ᐇ㦂࠾࠸࡚㓟ࢫࢺࣞࢫ࣐࣮࣮࢝ࡋ࡚ᗈࡃ⏝࠸ࡽࢀ࡚࠸ࡿࡀ㸪㏆ᖺࡑࡢ ಟ࢚࣮ࣛࡀᵝࠎ࡞㑇ఏᏊࡢኚ␗ࡘ࡞ࡀࡿࡇࡀሗ࿌ࡉࢀ࡚࠸ࡿࠋᐇ㝿NFT KBrO3 ࡣ㸪࠸ࡎࢀࡶ⭈⮚࠾࠸࡚ 8-OHdG ࡢቑຍࢆకࡗ࡚㑇ఏᏊኚ␗㢖ᗘ㸦MFs㸧ࢆቑຍࡉࡏࡿ ࡀ㸪ࡑࢀࡽࡣࡑࢀࡒࢀtransversion ኚ␗Ḟኻኚ␗ࢆయࡋࡓ㑇ఏᏊኚ␗ࢆㄏᑟࡍࡿࡉ ࢀࡿࠋࡑࡇ࡛ᮏ◊✲࡛ࡣ㸪㓟ࢫࢺࣞࢫ㧗ឤཷᛶ࡛࠶ࡾ㸪ࡘᑐ㇟⮚ჾ࠾ࡅࡿin vivo ኚ␗ཎᛶࢆ᳨ฟྍ⬟࡞ື≀ࣔࢹ࡛ࣝ࠶ࡿNrf2-/- gpt delta ࣐࢘ࢫࢆ⏝࠸ࡿࡇ࡛㸪NFT ࠾ࡼ 㸦㸰㸧
ࡧKBrO3ࡼࡿኚ␗ཎᛶ࠾ࡅࡿ㓟ࢫࢺࣞࢫࡢ㛵ࡢᵝᘧࢆ᳨ウࡋࡓࠋ ➨㸯❶࡛ࡣ㸪NFT ࡼࡿᏛᵓ㐀౫Ꮡⓗ࡞㑇ఏẘᛶᶵᗎ࠾ࡅࡿ㓟ࢫࢺࣞࢫࡢᙺࢆ ᫂ࡽࡍࡿࡓࡵ㸪 NFT ࡑࡢ㓟ࢫࢺࣞࢫཬࡧ㑇ఏẘᛶࡢཎᅉ᥎ ࡉࢀࡿࢽࢺࣟᇶ ࢆ᭷ࡍࡿࢽࢺࣟࣇࣝࣇ࣮ࣛࣝ㸦NFA㸧ࡘ࠸࡚㸪Nrf2+/+࠾ࡼࡧNrf2-/- gpt delta ࣐࢘ࢫࢆ⏝࠸ ࡚Ⓨࡀࢇᶆⓗ࡛࠶ࡿ⭈⮚࠾ࡅࡿ㑇ఏᏊኚ␗ゎᯒࢆᐇࡋࡓࠋNRF2 ࡢไᚚࢆཷࡅࡿᢠ㓟 㓝⣲࡛࠶ࡿNQO1 ࡣ㸪ࡑࡢ㑇ఏᏊ࠾ࡼࡧ⺮ⓑ㉁ࡢⓎ⌧ࣞ࣋ࣝࡀ Nrf2+/+࣐࢘ࢫࡼࡾࡶNrf2 -/-࣐࢘ࢫ࠾࠸࡚ⴭࡋࡃᑠࡉࡃ㸪Nrf2-/- gpt delta ࣐࢘ࢫࡀ㓟ࢫࢺࣞࢫᑐࡋ࡚㧗ឤཷᛶࢆ♧ ࡍࡇࡀ☜ㄆࡉࢀࡓࠋࡇࡢࡼ࠺࡞᮲௳ୗ࡛㸪Nrf2-/-࣐࢘ࢫᑐࡋ࡚NFT ࢆ 70 mg/kg య㔜ࡢ ⏝㔞࡛⤒ཱྀᢞࡋࡓࡇࢁ㸪⭈⮚࠾࠸࡚8-OHdG ࡢቑຍࢆకࡗࡓ MFs ࡢቑຍࡀࡳࡽࢀࡓ ࡀ㸪ࡇࡢࢢࢽࣥሷᇶࡢ transversion ኚ␗ࢆయࡋ࡚࠸ࡓࠋ୍᪉㸪NFA ࡣ 8-OHdG ࢆ ቑຍࡉࡏࡓࡀMFs ࡣቑຍࡉࡏ࡞ࡗࡓࠋࡇࢀࡽࡢࡇࡽ㸪NFT ࡼࡿ㑇ఏẘᛶ㓟ࢫ ࢺࣞࢫࡣ㛵ࡍࡿࡀNFA ࡣ㓟ࢫࢺࣞࢫࢆㄏⓎࡍࡿࡶࡢࡢ㑇ఏẘᛶ⤖ࡧࡘ࡞࠸ࡇ㸪 ࡉࡽࢽࢺࣟᇶࡼࡿ㑇ఏẘᛶࡢⓎ⏕ഃ㙐ࡢ┦ᛂࡀᙳ㡪ࡋ࡚࠸ࡿࡇࡀ♧၀ࡉࢀ ࡓࠋࡇࢀࡽࡢ⤖ᯝࡣᚋ㛤Ⓨࡉࢀࡿ᪂つࢽࢺࣟࣇࣛࣥ㢮ࡢࣜࢫࢡホ౯ࡶ᭷⏝⪃࠼ࡽࢀ ࡓࠋ ➨㸰❶࡛ࡣ㸪KBrO3࠾ࡼࡧNFT ࡼࡾㄏⓎࡉࢀࡿ㓟ࢫࢺࣞࢫࡑࢀ⥆ࡃ㑇ఏᏊኚ␗ ࡢ㛵㐃ࢆ᫂ࡽࡍࡿࡓࡵ㸪KBrO3࠾ࡼࡧNFT ࡘ࠸࡚ྠᵝࡢ᪉ἲ࡛㑇ఏᏊኚ␗ゎᯒ࠾ࡼ ࡧ8-OHdG ᐃࢆᐇࡋࡓࠋNqo1 ࡢⓎ⌧ࣞ࣋ࣝゎᯒ࠾࠸࡚㸪Nrf2+/+࣐࢘ࢫ࡛ࡣ୧⪅ࡢᢞ ࡼࡾࡑࡢⓎ⌧ࡀ㢧ⴭቑຍࡋࡓࡢᑐࡋ㸪Nrf2-/-࣐࢘ࢫ࡛ࡣኚࡀࡳࡽࢀࡎ㸪ᢞࡢ᭷ ↓ࢃࡽࡎNrf2+/+࣐࢘ࢫࡼࡾࡶప್ࢆ♧ࡋࡓࠋࡇࡢࡇࡽNrf2-/- gpt delta ࣐࢘ࢫࡣ ➨㸯❶ྠᵝ㓟ࢫࢺࣞࢫᙉࡃ᭚㟢ࡉࢀ࡚࠸ࡿࡇࡀ☜ㄆࡉࢀࡓࠋࡇࡢࡁ㸪1,500 ppm ࡢ⏝㔞࡛ KBrO3 ࢆ㣧Ỉᢞࡍࡿ㸪8-OHdG ࡢቑຍࢆకࡗ࡚Ḟኻኚ␗ࢆయࡋ࡚ MFs ࡀ㢧ⴭቑຍࡋ㸪ࡑࡢቑຍࡢ⛬ᗘࡣ Nrf2-/-࠾࠸࡚Nrf2+/+ࡼࡾࡶࡁࡃ㸪ྠNrf2 -/-࣐࢘ࢫ࡛ࡣḞኻࢧࢬࡢቑຍࡶࡳࡽࢀࡓࠋ୍᪉㸪2,500 ppm ࡢ⏝㔞࡛ NFT ࢆΰ㣵ᢞࡍࡿ 㸪8-OHdG ࡢቑຍࢆకࢃࡎࢢࢽࣥሷᇶࡢ transversion ኚ␗ࢆయࡋ࡚ MFs ࡢቑຍࡀ ࡳࡽࢀ㸪ࡇࡢࡶࡑࡢቑຍࡢ⛬ᗘࡣ Nrf2-/-࠾࠸࡚ Nrf2+/+ࡼࡾࡶࡁࡗࡓࠋࡇࢀࡽࡢࡇ ࡽ㸪KBrO3ࡢᙉ࠸㓟ຊ㉳ᅉࡍࡿ8-OHdG ᙧᡂࡣ┤᥋ⓗḞኻኚ␗ࡢቑຍ㛵ࡋ ࡚࠸ࡿࡇࡀ♧၀ࡉࢀ㸪୍᪉࡛ NFT ࡼࡿࢢࢽࣥሷᇶࡢ transversion ኚ␗ࡣ 8-OHdG ௨እࡢ㓟ࢫࢺࣞࢫᅉᏊࡀ㛵ࡋ࡚࠸ࡿྍ⬟ᛶࡀ⪃࠼ࡽࢀࡓࠋ ᮏ◊✲࡛ࡣNrf2-/- gpt delta ࣐࢘ࢫࢆ⏝࠸ࡿࡇ࡛㸪ࡶ㓟ࢫࢺࣞࢫࡢ㛵ࡋࡓ⭈Ⓨ ࡀࢇᶵᗎࡀࢃࢀࡿ NFT ࠾ࡼࡧ KBrO3ࡘ࠸࡚㸪㓟ࢫࢺࣞࢫࡀࡑࢀࡒࢀ␗࡞ࡿᵝᘧ࡛ ኚ␗ཎᛶ㛵ࡍࡿࡇࢆ᫂ࡽࡋࡓࠋࡇࡢࡼ࠺㸪㓟ࢫࢺࣞࢫ㛵ࡍࡿࣜࢫࢡホ౯ ࠾࠸࡚8-OHdG ᙧᡂࡀཬࡰࡍᙳ㡪ࡢࡁࡉࡣ㸪Ꮫ≀㉁ࡈ␗࡞ࡿ⪃࠼ࡽࢀࡿࡇ ࡽ㸪㓟ࢫࢺࣞࢫࢆྵࡴヲ⣽࡞Ⓨࡀࢇᶵᗎࡢ᳨ウࡀ⎔ቃ୰Ꮫ≀㉁ࡼࡿⓎࡀࢇࣜࢫࢡ ホ౯ࡣ㔜せ࡛࠶ࡿ⪃࠼ࡽࢀࡓࠋᮏ◊✲ࡢᡂᯝࡣᏛⓎࡀࢇ࠾ࡅࡿ㓟ࢫࢺࣞࢫࡘ ࠸࡚ࡢࡼࡾṇ☜࡞ࣜࢫࢡホ౯㈉⊩ࡍࡿࡶࡢ࡛࠶ࡾ㸪㓟ࢫࢺࣞࢫ㛵ࡍࡿ᭦࡞ࡿ◊✲ࢆ 㐍ࡵ࡚࠸ࡁࡓ࠸ࠋ 㣗ရ୰Ꮫ≀㉁ࡢⓎࡀࢇࣜࢫࢡホ౯ࡣ㸪බ⾗⾨⏕ୖ᭱ࡶ㔜せ࡞ၥ㢟ࡢ1 ࡘ࡛࠶ࡿࠋ㓟 ࢫࢺࣞࢫࡢᙳ㡪ࢆᙉࡃཷࡅࡿ⭈⮚࡛ࡣ㸪Ⓨࡀࢇ㐣⛬࠾ࡅࡿ㓟ࢫࢺࣞࢫࡢ㛵ࡀከࡃሗ ࿌ࡉࢀ࡚࠸ࡿࠋࣛࢵࢺ࠾ࡅࡿ⭈Ⓨࡀࢇ≀㉁࡛࠶ࡿࢽࢺࣟࣇࣛࣥࢺࣥ㸦NFT㸧࠾ࡼࡧ⮯ ⣲㓟࣒࢝ࣜ࢘㸦KBrO3㸧ࡣ㸪࠸ࡎࢀࡶ⭈⮚࠾࠸࡚㓟ⓗDNA ᦆയࡢ㸯ࡘ࡛࠶ࡿ 8-OHdG ࡢቑຍࢆకࡗ࡚㑇ఏᏊኚ␗㢖ᗘ㸦MFs㸧ࢆቑຍࡉࡏࡿࡀ㸪ࡑࢀࡽࡣࡑࢀࡒࢀ transversion ኚ
␗Ḟኻኚ␗ࢆㄏᑟࡍࡿࠋࡑࡇ࡛ᮏ◊✲࡛ࡣ㸪㓟ࢫࢺࣞࢫ㧗ឤཷᛶ࡛ୟࡘin vivo ኚ␗ཎᛶࢆ᳨ฟฟ᮶ࡿNrf2-/- gpt delta ࣐࢘ࢫࢆ⏝࠸࡚ 2 ࡼࡿኚ␗ཎᛶ࠾ࡅࡿ㓟ࢫ ࢺࣞࢫࡢ㛵ࢆ᳨ウࡋࡓࠋ ➨㸯❶࡛ࡣ㸪NFT ࡑࡢᇶᮏ㦵᱁࡛࠶ࡿࢽࢺࣟࣇࣝࣛࣝ㸦NFA㸧ࡘ࠸࡚㑇ఏᏊኚ␗ゎ ᯒࢆᐇࡋࡓࠋࡑࡢ⤖ᯝ㸪Nrf2-/-࣐࢘ࢫ࠾࠸࡚㸪NFT ࡣ 8-OHdG ࡢቑຍࢆకࡗ࡚ transversion ኚ␗ࢆయࡋ࡚MFs ࢆቑຍࡉࡏࡓࡀ㸪 NFA ࡣ 8-OHdG ࢆቑຍࡉࡏࡓࡀ MFs ࡣቑຍࡉࡏ ࡞ࡗࡓࠋࡇࢀࡽࡢࡇࡽ㸪NFT ࡼࡿ㑇ఏẘᛶ㓟ࢫࢺࣞࢫࡣ㛵ࡍࡿࡀ NFA ࡣ ཧຍࢫࢺࣞࢫࢆㄏⓎࡍࡿࡶࡢࡢ㸪㑇ఏẘᛶ⤖ࡧࡘ࡞࠸ࡇ㸪ࡉࡽࢽࢺࣟᇶࡼࡿ㑇 ఏẘᛶࡢⓎ⏕ഃ㙐ࡢ┦ᛂࡀᙳ㡪ࡋ࡚࠸ࡿࡇࡀ♧၀ࡉࢀࡓࠋ ➨㸰❶࡛ࡣ㸪KBrO3ཬࡧ NFT ࡼࡾㄏⓎࡉࢀࡿ㓟ࢫࢺࣞࢫࡑࢀ⥆ࡃ㑇ఏᏊኚ␗ ࡢ㛵㐃ࢆ᳨ウࡋࡓࠋࡇࡢࡁ Nrf2-/-࣐࢘ࢫ࠾࠸࡚㸪KBrO3ᢞࡼࡾ 8-OHdG ࡢቑຍࢆ కࡗ࡚Ḟኻኚ␗ࡀNrf2+/+࣐࢘ࢫࡼࡾࡶቑຍࡋ㸪ྠḞኻࢧࢬࡢቑຍࡶࡳࡽࢀࡓࠋࡇࢀ ᑐࡋNFT ᢞ⩌࡛ࡣ㸪8-OHdG ࡢቑຍࢆకࢃࡎ transversion ኚ␗ࢆయࡋ࡚ MFs ࡀ ࡼࡾቑຍࡋࡓࠋࡇࢀࡽࡢࡇࡽ㸪KBrO3ࡢᙉ࠸㓟ຊ㉳ᅉࡍࡿ 8-OHdG ᙧᡂࡣ┤᥋ⓗ Ḟኻኚ␗ࡢቑຍ㛵ࡋ࡚࠸ࡿࡇࡀ♧၀ࡉࢀ㸪୍᪉࡛ NFT ࡼࡿ transversion ኚ␗ ࡣ8-OHdG ௨እࡢ㓟ࢫࢺࣞࢫᅉᏊࡀ㛵ࡋ࡚࠸ࡿྍ⬟ᛶࡀ⪃࠼ࡽࢀࡓࠋ ᮏ◊✲ࡼࡾ㸪NFT ࠾ࡼࡧ KBrO3ࡼࡿኚ␗ཎᛶ࠾࠸࡚㓟ࢫࢺࣞࢫࡀࡑࢀࡒࢀ␗ ࡞ࡿ㛵ࡢᵝᘧࢆ♧ࡍࡇࡀ᫂ࡽ࡞ࡗࡓࠋᮏ◊✲ࡢᡂᯝࡣᏛⓎࡀࢇ࠾ࡅࡿ㓟ࢫ ࢺࣞࢫࡘ࠸࡚ࡢࡼࡾṇ☜࡞ࣜࢫࢡホ౯㈉⊩ࡍࡿࡶࡢ࡛࠶ࡿࠋ ௨ୖࡘ࠸࡚㸪ᑂᰝጤဨဨ୍⮴࡛ᮏㄽᩥࡀᒱ㜧ᏛᏛ㝔㐃ྜ⋇་Ꮫ◊✲⛉ࡢᏛㄽ ᩥࡋ࡚༑ศ౯್ࡀ࠶ࡿㄆࡵࡓࠋ ᇶ♏࡞ࡿᏛ⾡ㄽᩥ 㸯㸧㢟 ┠㸸5ROHRIR[LGDWLYHVWUHVVLQWKHFKHPLFDOVWUXFWXUHUHODWHG JHQRWR[LFLW\RIQLWURIXUDQWRLQLQ1UIGHILFLHQWJSWGHOWDPLFH ⴭ ⪅ ྡ㸸7VXFKL\D7.LMLPD$,VKLL<7DNDVX6<RNRR<1LVKLNDZD$ <DQDL7DQG8PHPXUD7 Ꮫ⾡㞧ㄅྡ㸸-RXUQDORI7R[LFRORJLF3DWKRORJ\ ᕳ࣭ྕ࣭㡫࣭Ⓨ⾜ᖺ㸸㸦㸧㸸㸪,QSUHVV 㸰㸧㢟 ┠㸸0HFKDQLVPVRIR[LGDWLYHVWUHVVLQGXFHGLQYLYRPXWDJHQLFLW\E\ SRWDVVLXPEURPDWHDQGQLWURIXUDQWRLQ ⴭ ⪅ ྡ㸸7VXFKL\D7.LMLPD$,VKLL<7DNDVX6<RNRR<1LVKLNDZD$ <DQDL7DQG8PHPXUD7 Ꮫ⾡㞧ㄅྡ㸸-RXUQDORI7R[LFRORJLF3DWKRORJ\ ᕳ࣭ྕ࣭㡫࣭Ⓨ⾜ᖺ㸸㸦㸧㸸㸪,QSUHVV ᪤Ⓨ⾲Ꮫ⾡ㄽᩥ 㸯㸧㢟 ┠㸸$PHGLXPWHUPJSWGHOWDUDWPRGHODVDQLQYLYRV\VWHPIRUDQDO\VLV RIUHQDOFDUFLQRJHQHVLVDQGWKHXQGHUO\LQJPRGHRIDFWLRQ ⴭ ⪅ ྡ㸸0DWVXVKLWD.,VKLL<7DNDVX6.XURGD..LMLPD$ 7VXFKL\D7.DZDJXFKL+0L\RVKL11RKPL72JDZD. 1LVKLNDZD$DQG8PHPXUD7 Ꮫ⾡㞧ㄅྡ㸸([SHULPHQWDODQG7R[LFRORJLF3DWKRORJ\
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