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New drug therapy of the transporter-related diseases through the modulation of membrane trafficking

Research Project

Project/Area Number 21790146
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeSingle-year Grants
Research Field Medical pharmacy
Research InstitutionThe University of Tokyo

Principal Investigator

HAYASHI Hisamitsu  The University of Tokyo, 大学院・薬学系研究科, 助教 (10451858)

Project Period (FY) 2009 – 2010
Project Status Completed (Fiscal Year 2010)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2010: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2009: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
Keywordsトランスポーター / 肝内胆汁うっ滞 / 細胞内ソーティング / 胆汁酸 / フェニルブチレート / コレステロール
Research Abstract

Bile salt export pump (BSEP) localizes on canalicular membrane of hepatocytes and mediates biliary excretion of bile salts. BSEP dysfunction attributed to its internalization from hepatocanalicular membrane and subsequent degradation causes intrahepatic cholestasis. At present, no medical therapy for this disease state has been established, because the regulatory mechanism of cell surface expression of BSEP remains to be elucidated. In this study, we explored it focusing on posttranslational machinery and demonstrated that ubiquitination, a posttranslational modification, is an internalization signal of BSEP and that AP2, an adaptor protein for clathrin-mediated endocytosis, is associated with BSEP internazliation through its direct interaction with BSEP.

Report

(3 results)
  • 2010 Annual Research Report   Final Research Report ( PDF )
  • 2009 Annual Research Report
  • Research Products

    (45 results)

All 2011 2010 2009 Other

All Journal Article (7 results) (of which Peer Reviewed: 3 results) Presentation (35 results) Book (2 results) Remarks (1 results)

  • [Journal Article] Calpain-mediated cleavage negatively regulates the expression level of ABCG1.2011

    • Author(s)
      Hori N, Hayashi H, Sugiyama Y.
    • Journal Title

      Atherosclerosis. 215(2)

      Pages: 383-391

    • NAID

      130004640071

    • Related Report
      2010 Final Research Report
  • [Journal Article] Ubiquitination is associated with lysosomal degradation of cell surface-resident ABCA1 through the ESCRT pathway2011

    • Author(s)
      Mizuno T, Hayashi H, Naoi S, Sugiyama Y : equally contributed
    • Journal Title

      Hepatology

      Volume: (In press)(掲載確定)

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Calpain-mediated cleavage negatively regulates the expression level of ABCG12011

    • Author(s)
      Hori N, Hayashi H, Sugiyama Y : equally contributed
    • Journal Title

      Atherosclerosis.

      Volume: 215 Pages: 383-91

    • NAID

      130004640071

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Short- and medium-chain fatty acids enhance the cell surface expression and transport capacity of the bile salt export pump (BSEP/ABCB11).2010

    • Author(s)
      Kato T, Hayashi H, Sugiyama Y.
    • Journal Title

      Biochim Biophys Acta. 1801(9)

      Pages: 1005-1012

    • Related Report
      2010 Final Research Report
  • [Journal Article] Favorable effect of 4-phenylacetate on liver functions attributable to enhanced bile salt export pump expression in ornithine transcarbamylase-deficient children.2010

    • Author(s)
      Nagasaka H, Yorifuji T, Kobayashi K, Takikawa H, Komatsu H, Inui A, Fujisawa T, Miida T, Tsukahara H, Takatani T, Hayashi H.
    • Journal Title

      Mol Genet Metab. 100(2)

      Pages: 123-128

    • Related Report
      2010 Final Research Report
  • [Journal Article] Short- and medium-chain fatty acids enhance the cell surface expression and transport capacity of the bile salt export pump(BSEP/ABCB11)2010

    • Author(s)
      Kato T, Hayashi H, Sugiyama Y : equally contributed
    • Journal Title

      BBA_molecular and cell biology of lipids (in press)

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Ubiquitination is associated with lysosomal degradation of cell surface-resident ABCA1 through the ESCRT pathway.

    • Author(s)
      Mizuno T, Hayashi H, Naoi S, Sugiyama Y.
    • Journal Title

      Hepatology. in press

    • Related Report
      2010 Final Research Report
  • [Presentation] 胆汁酸トランスポーターBile salt export pump(BSEP/ABCB11)の細胞膜からの内在化、分解過程に対するユビキチン化の検討2011

    • Author(s)
      相田健佑、林久允、稲村香央里、水野忠快、杉山雄一
    • Organizer
      第131回日本薬学会
    • Place of Presentation
      静岡
    • Related Report
      2010 Annual Research Report
  • [Presentation] 胆汁酸トランスポーターBile salt export pump (BSEP/ABCB11)の内在化機構の解析2010

    • Author(s)
      林久允、稲村香央里、相田健佑、直井壮太朗、杉山雄一
    • Organizer
      第32回胆汁酸研究会
    • Place of Presentation
      仙台
    • Year and Date
      2010-11-06
    • Related Report
      2010 Final Research Report
  • [Presentation] 胆汁酸トランスポーターBile salt export pump(BSEP/ABCB11)の内在化機構の解析2010

    • Author(s)
      林久允、稲村香央里、相田健佑、直井壮太朗、杉山雄一
    • Organizer
      第32回胆汁酸研究会
    • Place of Presentation
      仙台
    • Year and Date
      2010-11-06
    • Related Report
      2010 Annual Research Report
  • [Presentation] 胆汁酸トランスポーターBile salt export pump(BSEP/ABCB11)の細胞膜からの分解過程における短鎖ユビキチン化の役割2010

    • Author(s)
      林久允、杉山雄一
    • Organizer
      第18回肝病態生理研究会
    • Place of Presentation
      山形
    • Year and Date
      2010-05-26
    • Related Report
      2010 Annual Research Report 2010 Final Research Report
  • [Presentation] Effect of short and middle chain fatty acids on the cell surface expression and transport capacity of Bile Salt Export Pump(BSEP/ABCB11)2010

    • Author(s)
      加藤卓也、林久允、杉山雄一
    • Organizer
      3rd FEBS Special meeting ATP-Binding Cassette(ABC)Proteins : From Multidrug Resistance to Genetic Diseases
    • Place of Presentation
      インスブルック、オーストリア
    • Year and Date
      2010-03-02
    • Related Report
      2009 Annual Research Report
  • [Presentation] 胆汁酸トランスポーターBile salt export pump(BSEP/ABCB11)の細胞膜発現制御を標的とした新規肝内胆汁うっ滞治療法の開発2010

    • Author(s)
      林久允
    • Organizer
      第19回日本小児胆汁酸研究会
    • Place of Presentation
      東京
    • Year and Date
      2010-02-20
    • Related Report
      2010 Final Research Report
  • [Presentation] 胆汁酸トランスポーター Bile salt export pump(BSEP/ABCB11)の細胞膜発現制御を標的とした新規肝内胆汁うっ滞治療法の開発2010

    • Author(s)
      林久允
    • Organizer
      第19回日本小児胆汁酸研究会
    • Place of Presentation
      山の上ホテル、東京
    • Year and Date
      2010-02-20
    • Related Report
      2009 Annual Research Report
  • [Presentation] Clathrin Adaptor Protein Complex 2 (AP2) Regulates The Internalization Of Bile Salt Export Pump (BSEP/ABCB11).2010

    • Author(s)
      Hisamitsu Hayashi, Kaori Inamura, Kensuke Aida, Yuichi Sugiyama.
    • Organizer
      9th ISSX international meetings
    • Place of Presentation
      Istanbul, Turkey
    • Related Report
      2010 Final Research Report
  • [Presentation] Clathrin Adaptor Protein Complex 2 (AP2)-Dependent Internalization Of Bile Salt Export Pump (BSEP/ABCB11).2010

    • Author(s)
      Hisamitsu Hayashi, Kaori Inamura, Kensuke Aida, Yuichi Sugiyama.
    • Organizer
      Falk symposium 175, XXI International Bile Acid Meeting
    • Place of Presentation
      Freiburg, Germany
    • Related Report
      2010 Final Research Report
  • [Presentation] 胆汁酸トランスポーターBSEPの内在化機構の解析2010

    • Author(s)
      林久允、稲村香央里、杉山雄一
    • Organizer
      第25回日本薬剤学会
    • Place of Presentation
      徳島
    • Related Report
      2010 Annual Research Report 2010 Final Research Report
  • [Presentation] Association of Clathrin Adaptor Protein Complex 2 (AP2) with Bile Salt Export Pump (BSEP/ABCB11) internalization2010

    • Author(s)
      Hisamitsu Hayashi, Kaori Inamura, Kensuke Aida, Sotaro Naoi, Yuichi Sugiyama
    • Organizer
      第4回次代を担う若手医療薬科学シンポジウム
    • Place of Presentation
      東京
    • Related Report
      2010 Annual Research Report 2010 Final Research Report
  • [Presentation] 肝機能障害改善薬の開発を指向した胆汁酸トランスポーターBile salt export pump(BSEP/ABCB11)の内在化制御機構の解析2010

    • Author(s)
      林久允、稲村香央里、相田健佑、直井壮太朗、杉山雄一
    • Organizer
      第32回生体膜と薬物の相互作用シンポジウム
    • Place of Presentation
      富山
    • Related Report
      2010 Annual Research Report 2010 Final Research Report
  • [Presentation] Regulation of cell surface expression of multidrug resistance-associated protein 4 (MRP4) through its interaction with PDZ-adaptor proteins2010

    • Author(s)
      Hisamitsu Hayashi
    • Organizer
      第88回日本生理学会大会/第116回日本解剖学会総会・全国学術集会 合同大会
    • Place of Presentation
      横浜
    • Related Report
      2010 Annual Research Report 2010 Final Research Report
  • [Presentation] Clathrin Adaptor Protein Complex 2 (AP2) Regulates The Internalization Of Bile Salt Export Pump (BSEP/ABCB11)2010

    • Author(s)
      Hisamitsu Hayashi, Kaori Inamura, Kensuke Aida, Yuichi Sugiyama
    • Organizer
      9^<th> ISSX international meetings
    • Place of Presentation
      Istanbul, Turkey
    • Related Report
      2010 Annual Research Report
  • [Presentation] Clathrin Adaptor Protein Complex 2 (AP2)-Dependent Internalization Of Bile Salt Export Pump (BSEP/ABCB11)2010

    • Author(s)
      Hisamitsu Hayashi, Kaori Inamura, Kensuke Aida, Yuichi Sugiyama
    • Organizer
      Falk symposium 175, XXI International Bile Acid Meeting
    • Place of Presentation
      Freiburg, Germany
    • Related Report
      2010 Annual Research Report
  • [Presentation] CALPAIN-MEDIATED CLEAVAGE NEGATIVELY REGULATES THE EXPRESSION LEVEL OF ABCG12010

    • Author(s)
      Natsuki Hori, Hisamitsu Hayashi, Yuichi Sugiyama
    • Organizer
      第25回日本薬物動態学会
    • Place of Presentation
      大宮
    • Related Report
      2010 Annual Research Report
  • [Presentation] UBIQUITIN-DEPENDENT DEGRADATION OF ATP-BINDING CASSETTE TRANSPORTER A1 (ABCA1) IN ENDOSOMAL-LYSOSOMAL PATHWAY2010

    • Author(s)
      Tadahaya Mizuno, Hisamitsu Hayashi, Yuichi Sugiyama
    • Organizer
      第25回日本薬物動態学会
    • Place of Presentation
      大宮
    • Related Report
      2010 Annual Research Report
  • [Presentation] 細胞膜上からのABCA1分解プロセスに対するユビキチン化の関与の検討2010

    • Author(s)
      水野忠快、林久允、杉山雄
    • Organizer
      第32回生体膜と薬物の相互作用シンポジウム
    • Place of Presentation
      富山
    • Related Report
      2010 Annual Research Report
  • [Presentation] 脂質トランスポーターABCG1の分解機構におけるカルパインの関与の検討2010

    • Author(s)
      堀奈津貴、林久允、杉山雄
    • Organizer
      第32回生体膜と薬物の相互作用シンポジウム
    • Place of Presentation
      富山
    • Related Report
      2010 Annual Research Report
  • [Presentation] ATP-binding cassette transporter A1(ABCA1)の分解に対するユビキチン化の関与2010

    • Author(s)
      水野忠快、林久允、杉山雄
    • Organizer
      Biochemistry and Molecular Biology BMB2010
    • Place of Presentation
      神戸
    • Related Report
      2010 Annual Research Report
  • [Presentation] 脂質トランスポーターABCG1の分解機構の解析2010

    • Author(s)
      堀奈津貴、林久允、杉山雄
    • Organizer
      Biochemistry and Molecular Biology BMB2010
    • Place of Presentation
      神戸
    • Related Report
      2010 Annual Research Report
  • [Presentation] Development of new choleretic drugs targeting the regulation of Bile Salt Export Pump (BSEP/ABCB11) expression at the cell surface2009

    • Author(s)
      Hisamitsu Hayashi, Yuichi Sugiyama
    • Organizer
      第31回生体膜と薬物の相互作用シンポジウム
    • Place of Presentation
      大阪
    • Year and Date
      2009-12-01
    • Related Report
      2010 Final Research Report
  • [Presentation] Development of new choleretic drugs targeting the regulation of Bile Salt Export Pump(BSEP/ABCB11)expression at the cell surface2009

    • Author(s)
      林久允、杉山雄一
    • Organizer
      第31回生体膜と薬物の相互作用シンポジウム
    • Place of Presentation
      大阪大学、大阪
    • Year and Date
      2009-12-01
    • Related Report
      2009 Annual Research Report
  • [Presentation] CLATHRIN ADAPTOR AP2 REGULATES THE INTERNALIZATION OF BILE SALT EXPORT PUMP(BSEP/ABCB11)2009

    • Author(s)
      稲村香央里、林久允、杉山雄一
    • Organizer
      第24回日本薬物動態学会
    • Place of Presentation
      京都国際会館、京都
    • Year and Date
      2009-11-28
    • Related Report
      2009 Annual Research Report
  • [Presentation] 短鎖ユビキチン化がBile salt export pump (BSEP/ABCB11)の細胞膜からの分解過程に及ぼす影響2009

    • Author(s)
      林久允、杉山雄一
    • Organizer
      第31回胆汁酸研究会
    • Place of Presentation
      東京
    • Year and Date
      2009-11-07
    • Related Report
      2010 Final Research Report
  • [Presentation] 短鎖ユビキチン化が Bile salt export pump(BSEP/ABCB11)の細胞膜からの分解過程に及ぼす影響2009

    • Author(s)
      林久允、杉山雄一
    • Organizer
      第31回胆汁酸研究会
    • Place of Presentation
      山上会館、東京
    • Year and Date
      2009-11-07
    • Related Report
      2009 Annual Research Report
  • [Presentation] 胆汁酸トランスポーター Bile salt export pump(BSEP/ABCB11)の内在化過程におけるクラスリンアダプタータンパク質 adaptor protein complex2(AP2)の寄与の解析2009

    • Author(s)
      稲村香央里、林久允、杉山雄一
    • Organizer
      第31回胆汁酸研究会
    • Place of Presentation
      山上会館、東京
    • Year and Date
      2009-11-07
    • Related Report
      2009 Annual Research Report
  • [Presentation] 胆汁酸トランスポーターBile salt export pump(BSEP/ABCB11)の細胞膜からの分解過程におけるユビキチン化の関与の検討2009

    • Author(s)
      林久允、杉山雄一
    • Organizer
      第82回生化学大会
    • Place of Presentation
      神戸
    • Year and Date
      2009-10-22
    • Related Report
      2010 Final Research Report
  • [Presentation] 胆汁酸トランスポーター Bile salt export pump(BSEP/ABCB11)の細胞膜からの分解過程におけるユビキチン化の関与の検討2009

    • Author(s)
      林久允、杉山雄一
    • Organizer
      第82回生化学大会
    • Place of Presentation
      神戸ポートアイランド、神戸
    • Year and Date
      2009-10-22
    • Related Report
      2009 Annual Research Report
  • [Presentation] Effect of short and middle chain fatty acids on the cell-surface expression and transport capacity of Bile Salt Export Pump(BSEP/ABCB11)2009

    • Author(s)
      加藤卓也、林久允、杉山雄一
    • Organizer
      16th North American Regional Meeting of ISSX
    • Place of Presentation
      ボルティモア、米国
    • Year and Date
      2009-10-18
    • Related Report
      2009 Annual Research Report
  • [Presentation] Development of a therapeutic method to combat cholestasis by regulation of the cell-surface expression of Bile salt export pump(BSEP/ABCB11)2009

    • Author(s)
      Hisamitsu Hayashi, Yuichi Sugiyama
    • Organizer
      日本薬剤学会Global Education Seminar East 2009-1^<st>
    • Place of Presentation
      東京
    • Year and Date
      2009-06-23
    • Related Report
      2010 Final Research Report
  • [Presentation] Development of a therapeutic method to combat cholestasis by regulation of the cell-surface expression of Bile salt export pump(BSEP/ABCB11)2009

    • Author(s)
      林久允、杉山雄一
    • Organizer
      日本薬剤学会 Global Education Seminar East 2009-1^<st>
    • Place of Presentation
      東京薬科大学、東京
    • Year and Date
      2009-06-23
    • Related Report
      2009 Annual Research Report
  • [Presentation] Choleretic effect of 4-phenylbutyrate(4PBA)induced by an increase in Bile Salt Export Pump(BSEP/ABCB11)expression at the cell surface2009

    • Author(s)
      林久允、杉山雄一
    • Organizer
      第5回武田科学振興財団薬科学シンポジウム
    • Place of Presentation
      高輪プリンス、東京
    • Year and Date
      2009-05-25
    • Related Report
      2009 Annual Research Report
  • [Presentation] 脂肪酸類による Bile salt export pump(BSEP)の輸送機能の亢進作用2009

    • Author(s)
      加藤卓也、林久允、杉山雄一
    • Organizer
      第24回日本薬剤学会
    • Place of Presentation
      静岡県コンベンションアーツセンター、静岡
    • Year and Date
      2009-05-22
    • Related Report
      2009 Annual Research Report
  • [Presentation] Choleretic effect of 4-phenylbutyrate (4PBA) induced by an increase in Bile Salt Export Pump (BSEP/ABCB11) expression at the cell surface2009

    • Author(s)
      Hisamitsu Hayashi, Yuichi Sugiyama.
    • Organizer
      第5回武田科学振興財団薬科学シンポジウム
    • Place of Presentation
      東京
    • Year and Date
      2009-05-02
    • Related Report
      2010 Final Research Report
  • [Book] トランスポートソーム生体膜輸送機構の全体像に迫る基礎,臨床,創薬応用研究の最新成果2011

    • Author(s)
      金井好克
    • Total Pages
      6
    • Publisher
      株式会社 メディカルドゥ
    • Related Report
      2010 Annual Research Report
  • [Book] トランスポートソーム 生体膜輸送機構の全体像に迫る 基礎,臨床,創薬応用研究の最新成果

    • Author(s)
      林久允、杉山雄一
    • Publisher
      株式会社メディカルドゥ
    • Related Report
      2010 Final Research Report
  • [Remarks] ホームページ等

    • Related Report
      2010 Final Research Report

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Published: 2009-04-01   Modified: 2016-04-21  

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