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Development of drugs targeting secretory inhibition of transthyretin for familial amyloidotic polyneuropathy

Research Project

Project/Area Number 24790079
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field Biological pharmacy
Research InstitutionKumamoto University

Principal Investigator

SATO Takashi  熊本大学, 発生医学研究所, 特定事業研究員 (70555755)

Project Period (FY) 2012-04-01 – 2014-03-31
Project Status Completed (Fiscal Year 2013)
Budget Amount *help
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2013: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
Fiscal Year 2012: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Keywordsトランスサイレチン / アミロイド / 小胞体 / 小胞体関連分解 / 化合物スクリーニング / 薬理学
Research Abstract

The final goal of this study is to develop drug for treatment of Transthyretin (TTR)-Familial Amyloidotic Polyneuropathy (FAP). We previously identified that inhibition of TTR tetramerization in the endoplasmic reticulum that blocks secretion of mutant TTR could be a target of candidate drug for treatment of FAP. In this study, we performed in silico virtual screening of inhibitor for TTR tetramerization. Among 2.5 million compound, we selected about 20 compounds and examined the effect of selected compounds on secretion and tetramerization of mutant TTR. Finally, we identified 2 compounds that reduce secretion of mutant TTR, one of which inhibits tetramerization of mutant TTR. Moreover, to perform high-throughput screening of chemical libraries, we developed a fluorescence-based assay system that monitor TTR tetramerization in vitro and plan to use this system in future study.

Report

(3 results)
  • 2013 Annual Research Report   Final Research Report ( PDF )
  • 2012 Research-status Report
  • Research Products

    (18 results)

All 2014 2013 2012 Other

All Journal Article (4 results) (of which Peer Reviewed: 4 results,  Open Access: 1 results) Presentation (12 results) Remarks (2 results)

  • [Journal Article] Inhibition of post-translational N-glycosylation by HRD1 that controls the fate of ABCG5/8 transporter.2014

    • Author(s)
      Suzuki S, Shuto T, Sato T, Kaneko M, Takada T, Suico MA, Cyr DM, Suzuki H, Kai H
    • Journal Title

      Scientific reports

      Volume: 4 Issue: 1 Pages: 4258-4258

    • DOI

      10.1038/srep04258

    • Related Report
      2013 Annual Research Report 2013 Final Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Insulin receptor activation through its accumulation in lipid rafts by mild electrical stress2012

    • Author(s)
      Morino-Koga S
    • Journal Title

      J Cell Physiol.

      Volume: 228 Issue: 2 Pages: 439-446

    • DOI

      10.1002/jcp.24149

    • Related Report
      2013 Final Research Report 2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] STT3B-dependent posttranslational N-glycosylation as a surveillance system for secretory protein.2012

    • Author(s)
      Sato T., et.al.
    • Journal Title

      Molecular Cell

      Volume: 47(1) Issue: 1 Pages: 99-110

    • DOI

      10.1016/j.molcel.2012.04.015

    • Related Report
      2013 Final Research Report 2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Mild electrical stimulation and heat shock ameliorates progressive proteinuria and renal inflammation in mouse model of Alport syndrome.2012

    • Author(s)
      Tomoaki Koga
    • Journal Title

      PLoS One

      Volume: 7 Issue: 8 Pages: 43852-43852

    • DOI

      10.1371/journal.pone.0043852

    • Related Report
      2013 Final Research Report 2012 Research-status Report
    • Peer Reviewed
  • [Presentation] The endoplasmic reticulum-oriented drug development for familial amyloid polyneuropathy2013

    • Author(s)
      Chosa K, Yamakawa R, Sato T, Yokoyama T, Mizuguchi M, Suico MA, Shuto T, Kai H
    • Organizer
      ASCB Annual Meeting
    • Place of Presentation
      New Orleans, USA
    • Related Report
      2013 Annual Research Report 2013 Final Research Report
  • [Presentation] The endoplasmic reticulum-oriented drug development for transthyretin familial amyloid polyneuropathy. IXth International Symposium on Familial Amyloidotic2013

    • Author(s)
      Chosa K, Yamakawa R, Sato T, Yokoyama T, Mizuguchi M, Suico MA, Shuto T, Kai H
    • Organizer
      Polyneuropathy
    • Place of Presentation
      Rio de Janeiro, Brazil
    • Related Report
      2013 Final Research Report
  • [Presentation] 翻訳後N型糖鎖修飾を介した小胞体品質管理機構による家族性アミロイドーシスの発症性制御機構の解明2013

    • Author(s)
      佐藤卓史,庄美里,スイコメリーアン,首藤剛,甲斐広文
    • Organizer
      日本薬学会第133年会
    • Place of Presentation
      横浜
    • Related Report
      2013 Final Research Report
  • [Presentation] 異常な構造を持つ分泌タンパク質の新たな小胞体品質管理機構2013

    • Author(s)
      庄美里,佐藤卓史,帖佐圭佑,山川瑠斐子,スイコメリーアン,首藤剛,甲斐広文
    • Organizer
      第86回日本薬理学会年会
    • Place of Presentation
      福岡
    • Related Report
      2013 Final Research Report
  • [Presentation] The endoplasmic reticulum-oriented drug development for transthyretin familial amyloid polyneuropathy2013

    • Author(s)
      Hirofumi Kai
    • Organizer
      IXth International Symposium on Familial Amyloidotic Polyneuropathy
    • Place of Presentation
      Rio de Janeiro, Brazil
    • Related Report
      2013 Annual Research Report
  • [Presentation] 翻訳後N型糖鎖修飾を介した小胞体品質管理機構による家族性アミロイドーシスの発症性制御機構の解明2013

    • Author(s)
      佐藤卓史
    • Organizer
      日本薬学会第133年会
    • Place of Presentation
      パシフィコ横浜
    • Related Report
      2012 Research-status Report
  • [Presentation] 異常な構造を持つ分泌タンパク質の新たな小胞体品質管理機構2013

    • Author(s)
      庄美里
    • Organizer
      第86回日本薬理学会年会
    • Place of Presentation
      福岡国際会議場
    • Related Report
      2012 Research-status Report
  • [Presentation] 変異トランスサイレチンの翻訳後N型糖鎖修飾の意義とその制御因子の探索2012

    • Author(s)
      庄美里,佐藤卓史,西頭英起,小亀浩市,金子雅幸,和田郁夫,メリーアンスイコ,首藤剛,甲斐広文
    • Organizer
      第85回日本生化学会大会
    • Place of Presentation
      福岡
    • Related Report
      2013 Final Research Report
  • [Presentation] 変異トランスサイレチンの翻訳後N型糖鎖修飾の意義とその制御因子の探索2012

    • Author(s)
      庄美里,佐藤卓史,スイコメリーアン,首藤剛,和田郁夫,甲斐広文
    • Organizer
      第29回日本薬学会九州支部大会
    • Place of Presentation
      熊本
    • Related Report
      2013 Final Research Report
  • [Presentation] STT3B-dependent posttranslational N-glycosylation as a surveillance system for secretory protein2012

    • Author(s)
      Kai H, Sato T, Sho M, Sako Y, Suico MA, Shuto T
    • Organizer
      Quality Control From Molecules to Organelles
    • Place of Presentation
      Heidelberg, Germany
    • Related Report
      2013 Final Research Report 2012 Research-status Report
  • [Presentation] 変異トランスサイレチンの翻訳後N型糖鎖修飾の意義とその制御因子の探索2012

    • Author(s)
      庄美里
    • Organizer
      第85回日本生化学会大会
    • Place of Presentation
      福岡国際会議場・マリンメッセ福岡
    • Related Report
      2012 Research-status Report
  • [Presentation] 変異トランスサイレチンの翻訳後N型糖鎖修飾の意義とその制御因子の探索2012

    • Author(s)
      庄美里
    • Organizer
      第29回日本薬学会九州支部大会
    • Place of Presentation
      熊本大学薬学部
    • Related Report
      2012 Research-status Report
  • [Remarks] 熊本日日新聞 医療QQ「特定酵素「STT3B」、異常タンパク質を分解熊大グループが新たな仕組み発見」 平成24年7月20日

    • URL

      http://qq.kumanichi.com/medical/2012/07/post-1996.php

    • Related Report
      2013 Final Research Report
  • [Remarks] 熊本大学プレスリリース 「細胞内の異常なタンパク質を取り除く,新しいメカニズムを発見」 平成24年7月13日

    • URL

      http://www.kumamoto-u.ac.jp/daigakujouhou/kouhou/pressrelease/2012_file/release120713.pdf

    • Related Report
      2013 Final Research Report

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Published: 2013-05-31   Modified: 2019-07-29  

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