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Development of new drug screening system using the blood-brain barrier transporter gene expression

Research Project

Project/Area Number 12557215
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section展開研究
Research Field 医薬分子機能学
Research InstitutionTohoku University

Principal Investigator

TERASAKI Tetsuya  Tohoku University, New Industry Creation Hatchery Center, Professor, 未来科学技術共同研究センター, 教授 (60155463)

Co-Investigator(Kenkyū-buntansha) MORI Shinobu  Tohoku University, Graduate School of Pharmaceutical Sciences, Graduate Student, 特別研究員
TAKANAGA Hitomi  Tohoku University, Graduate School of Pharmaceutical Sciences, Research Instructor, 大学院・薬学研究科, 助手 (20284523)
OHTSUKI Sumio  Tohoku University, Graduate School of Pharmaceutical Sciences, Assistant Professor, 大学院・薬学研究科, 講師 (60323036)
HOSOYA Ken-ichi  Toyama Medical and Pharmaceutical University, Faculty of Pharmaceutical Sciences, Professor, 薬学部, 教授 (70301033)
ABE Takaaki  Tohoku University, Graduate School of Medicine, Assistant Professor, 大学院・医学系研究科, 助手 (80292209)
石川 智久  東京工業大学, 大学院・生命理工学研究科, 教授 (60193281)
Project Period (FY) 2000 – 2001
Project Status Completed (Fiscal Year 2001)
Budget Amount *help
¥13,300,000 (Direct Cost: ¥13,300,000)
Fiscal Year 2001: ¥6,000,000 (Direct Cost: ¥6,000,000)
Fiscal Year 2000: ¥7,300,000 (Direct Cost: ¥7,300,000)
Keywordsblood-brain barrier / plasma membrane / gene expression / culture cell / conditionally immortalized cell line / brain capillary endothelial cells / drug screening / membrane transporter
Research Abstract

For the development of central nervous system (CNS) acting drug, it is very important subject to have in vitro screening system of the blood-brain barrier transport. We have established the conditionally immortalized cell lines of the brain capillary endothelial cell, astrocyte, pericyte, choroid plexus epithelial cell, retinal endothelial cell, bone marrow derived endothelial cell. Among these cell lines, the brain capillary endothelial cell lines expressed the function of P-glycoprotein, hexose transporter and organic anion transporter. Employing these cell lines, we have revealed the blood-brain barrier transporter gene. We found that ATA2 is responsible gene for the system A, located at the abluminal membrane of the brain capillary endothelial cells. mRNA and transport functio of ATA2 was induced by the hypertonic condition. We have also revealed that TAUT is responsible for the blood-brain barrier transport of taurine. TAUT was induced by hyperosmotic medium condition and cytokine, and reduced by excess cold of taurine. We have also clarified that organic anion transporter 3, OAT3, transport indoxyl sulfate, an uremic toxine, and dehydroepiandrosterone sulfate at the blood-brain barrier in rats. Moreover, we have also revealed that Roct is the mouse counter part of rOAT3. We have also found that the blood-brain barrier CRT play an important role of the uptake of creatine from the circulating blood to the brain. These findings would be very useful for the development of the CNS acting new drug.

Report

(3 results)
  • 2001 Annual Research Report   Final Research Report Summary
  • 2000 Annual Research Report
  • Research Products

    (26 results)

All Other

All Publications (26 results)

  • [Publications] K.Hosoya: "Conditionally immortalized brain capillary endothelial cell lines established from a transgenic mouse harboring temperature-sensitive Simian Virus 40 large T-antigen gene"AAPS Pharmsci. 2(article). 27 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] K.Hosoya: "mRNA expression and transport characterization of conditionally immortalized rat brain capillary endothelial cell lines ; A new in vitro BBB model for drug targeting"J. Drug Target. 8. 357-370 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] T.Kitazawa: "Characterization of the amino acid transport of new immortalized choroid plexus epithelial cell lines : A novel in vitro system for investigating transport functions at the blood-cerebrospinal fluid barrier"Pharm. Res.. 18. 16-22 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] K.Hosoya: "Conditionally immortalized retianl capillary endothelial cell lines (TR-iBRB) expressing differentiated endothelial cell functions derived from a transgenic rat harboring the temperature-sensitive SV 40 larae T-antigen gene"Exp. Eye Res.. 72. 163-172 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] K.Hattori: "Establishment of bone marrow-derived endothelial cell lines from ts-SV40 T-antigen gene transgenic rats"Pharm. Res.. 18. 9-15 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] 細谷健一: "血液網膜関門及び血液脳関門の再構築とドラッグデリバリー研究への応用"Drug Delivery System. 16. 29-38 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] K.Tetsuka: "Acidic amino acid transport characterization of a newly developed conditionally immortalized rat Type 2 astrocyte cell line (TR-AST)"Cell Struct. Func.. 26. 197-203 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] T.Asashima: "Newly derived rat brain pericyte cell line, TR-PCT, responds to transfroming growth factor-β1 and β-glycerophosphate"Eur. J. Cell Biol.. (in press). (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] T.Deguchi: "Major role of organic anion transporter 3 in the transport of indoxyl sulfate in the kidney"Kidney Int.. (in press). (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] H.Takanaga: "ATA2 is predominantly expressed as system A at the blood-brain barrier and acts as brain-to-blood efflux transport for L-proline"Mol. Pharmacol. (in press). (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] 大槻純男: "概説-血液脳関門研究の最近の進歩"生体の科学. 52. 532-540 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] 出口芳春: "脳微小透析法の血液脳関門輸送研究への応用"生体の科学. 52. 563-570 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] T.Terasaki: "Tissue Engineering for Therapeutic Use 4"Y.Ikada. 192 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] K.Tetsuka: "Acidic amino acid transport characterization of a newly developed conditionally immortalized rat Type2 astrocyte cell line (TR-AST)"Cell Struct. Func.. 26. 197-203 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] T.Asashima: "Newly derived rat brain pericyte cell line, TR-PCT, responds to transforming growth factor-β1 and β-glycerophosphate"Eur. J. Cell Biol.. in press. (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] T.Deguchi: "Major role of organic anion transporter 3 in the transport of indoxyl sulfate in the kidney"Kidney Int.. in press. (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] H.Takanaga: "ATA2 is predominantly expressed as system A at the blood-brain barrier and acts as brain-to-blood efflux transport for L-proline"Mol. Pharmacol.. in press. (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] 大槻純男: "概説-血液脳関門研究の最近の進歩"生体の科学. 52. 532-540 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 出口芳春: "脳微小透析法の血液脳関門輸送研究への応用"生体の科学. 52. 563-570 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] K.Hosoya: "Conditionally immortalized brain capillary endothelial cell lines established from a transgenic mouse harboring temperature-sensitive Simian Virus 40 large T-antigen gene."AAPS Pharmsci,. 2. article27 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] K.Hosoya: "mRNA expression and transport characterization of conditionally immortalized rat brain capillary endothelial cell lines ; A new in vitro BBB model for drug targeting."J.Drug Target.. 未定(in press). (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] T.Kitazawa: "Characterization of the amino acid transport of new immortalized choroid plexus epithelial cell lines : A novel in vitro system for investigating transport functions at the blood-cerebrospinal fluid barrier."Phar.Res.. 未定(in press). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] K.Hosoya: "Conditionally immortalized retianl capillary endothelial cell lines (TR-iBRB) expressing differentiated endothelial cell functions derived from a transgenic rat harboring the temperature-sensitive SV 40 large T-antigen gene."Exp.Eye Res.. 未定(in press). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] K.Hattori: "Establishment of bone marrow-derived endothelial cell lines from ts-SV4O T-antigen gene transgenic rats."Pharm.Res.. 未定(in press). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] 細谷健一: "血液網膜関門及び血液脳関門の再構築とドラッグデリバリー研究への応用"Drug Delivery System. 16. 29-38 (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] T.Terasaki: "Tissue Engineering for Therapeutic Use 4"Y.Ikada. 192 (2000)

    • Related Report
      2000 Annual Research Report

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Published: 2000-04-01   Modified: 2016-04-21  

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