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Development of ER-targeted therapeutics against protein aggregation diseases

Research Project

Project/Area Number 15K08404
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Experimental pathology
Research InstitutionThe University of Tokushima

Principal Investigator

YAMAZAKI Tetsuo  徳島大学, 大学院医歯薬学研究部(薬学系), 教授 (90330208)

Project Period (FY) 2015-04-01 – 2018-03-31
Project Status Completed (Fiscal Year 2017)
Budget Amount *help
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywords小胞体 / CLN6 / 凝集体 / クリスタリン / リソゾーム病 / 難病
Outline of Final Research Achievements

The aim of this project is to develop therapeutic interventions against protein aggregation diseases. Mutations within the alphaB-crystallin (aBC) gene are linked to crystallinopathy, characterized by intracellular accumulation of protein aggregates. We previously demonstrated that enforced expression of aBC on the endoplasmic reticulum (ER) prevented aggregation of the R120G aBC mutant, suggesting that manipulation of the ER-anchored aBC (ERaBC) target is effective for protein aggregation diseases. In this study, CLN6, an ER transmembrane protein, was isolated as an ERaBC binder. We revealed that CLN6 not only mediates the anti-aggregate activity of ERaBC but also prevents the R120G mutant from aggregating independently of ERaBC. CLN6 profoundly inhibited aggregation of the ALS-associated TDP-43 variant as well. Overall, we conclude that dictating CLN6 would be a promising strategy for a wide array of protein aggregation diseases.

Report

(4 results)
  • 2017 Annual Research Report   Final Research Report ( PDF )
  • 2016 Research-status Report
  • 2015 Research-status Report
  • Research Products

    (10 results)

All 2017 2016 2015 Other

All Journal Article (1 results) (of which Peer Reviewed: 1 results,  Open Access: 1 results) Presentation (8 results) (of which Int'l Joint Research: 2 results,  Invited: 1 results) Remarks (1 results)

  • [Journal Article] Identification of CLN6 as a molecular entity of endoplasmic reticulum-driven anti-aggregate activity2017

    • Author(s)
      Yamashita Arisa、Hiraki Yuri、Yamazaki Tetsuo
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 487 Issue: 4 Pages: 917-922

    • DOI

      10.1016/j.bbrc.2017.05.002

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] タンパク質凝集体難病の克服に向けた小胞体操作法の開発2017

    • Author(s)
      山崎哲男
    • Organizer
      稀少疾患プロジェクト オープンセミナー
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] 小胞体マニピュレーションがもたらす抗凝集体活性の分子基盤2017

    • Author(s)
      山下ありさ, 山崎哲男
    • Organizer
      第16回四国免疫フォーラム
    • Related Report
      2017 Annual Research Report
  • [Presentation] タンパク質凝集体難病の克服に向けた小胞体操作法の開発2017

    • Author(s)
      平木友理, 山崎哲男
    • Organizer
      第90回蔵本免疫懇話会
    • Related Report
      2017 Annual Research Report
  • [Presentation] ER manipulation: A promising therapeutic intervention for protein aggregation diseases2017

    • Author(s)
      Yamashita A., Nakatsuru T., Saito H., Hiraki Y. and Yamazaki T.
    • Organizer
      The 3rd International Symposium on Regenerative Rehabilitation in Kyoto
    • Place of Presentation
      京都大学 杉浦地域医療研究センター(京都府京都市)
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] ER as a potential therapeutic target for protein aggregation disease2016

    • Author(s)
      山崎哲男
    • Organizer
      The Fifth Bizan Immunology Symposium at University of Tokushima
    • Place of Presentation
      徳島大学藤井記念ホール(徳島県徳島市)
    • Year and Date
      2016-03-03
    • Related Report
      2015 Research-status Report
    • Int'l Joint Research
  • [Presentation] タンパク質凝集体難病の克服に向けた小胞体操作の分子基盤2016

    • Author(s)
      山下ありさ, 山崎哲男
    • Organizer
      四国免疫フォーラム
    • Place of Presentation
      高知大学医学部(高知県南国市)
    • Related Report
      2016 Research-status Report
  • [Presentation] 小胞体を標的とした凝集体難病治療法開発2015

    • Author(s)
      山下ありさ, 山崎哲男
    • Organizer
      第54回日本薬学会・日本薬剤師会・日本病院薬剤師会 中国四国支部学術大会
    • Place of Presentation
      高知市文化プラザかるぽーと(高知県高知市)
    • Year and Date
      2015-10-31
    • Related Report
      2015 Research-status Report
  • [Presentation] 小胞体マニピュレーションに基づく凝集体難病治療法の創出2015

    • Author(s)
      山下ありさ, 山崎哲男
    • Organizer
      第14回四国免疫フォーラム
    • Place of Presentation
      愛媛大学医学部40周年記念講堂(愛媛県東温市)
    • Year and Date
      2015-06-20
    • Related Report
      2015 Research-status Report
  • [Remarks] とくtalk 最先端研究探訪「小胞体操作によって凝集体形成を防ぎ、タンパク質凝集体難病を予防する」

    • URL

      http://www.tokushima-u.ac.jp/docs/2018040300019/files/171_2saisentan.pdf

    • Related Report
      2017 Annual Research Report

URL: 

Published: 2015-04-16   Modified: 2019-03-29  

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