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The role of mTORC2-SPARC pathway in the pathogenesis of pulmonary fibrosis

Research Project

Project/Area Number 26461202
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Respiratory organ internal medicine
Research InstitutionNippon Medical School

Principal Investigator

Azuma Arata  日本医科大学, 医学部, 教授 (10184194)

Co-Investigator(Kenkyū-buntansha) 神尾 孝一郎  日本医科大学, 医学部, 助教 (20465305)
Research Collaborator MATSUDA Kuniko  日本医科大学, 実験助手
Project Period (FY) 2014-04-01 – 2017-03-31
Project Status Completed (Fiscal Year 2016)
Budget Amount *help
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
KeywordsmTORC2 / XPLN / SPARC / IPF / HDAC inhibitor / 肺線維芽細胞 / 特発性肺線維症
Outline of Final Research Achievements

Pathogenesis of idiopathic pulmonary fibrosis (IPF) remains unclear. SPARC is a matricellular protein, whose expression is regulated by TGF-β1 through activation of mTORC2. Exchange factor found in platelets, leukemic, and neuronal tissues (XPLN) is an endogenous inhibitor of mTORC2. Herein, we investigated the regulatory mechanisms of XPLN in human lung fibroblasts.
XPLN depletion stimulated SPARC expression and Akt phosphorylation on Ser473. TGF-β1 treatment down-regulated XPLN via Smad 2/3. XPLN mRNA expression was up-regulated upon treatment with HDAC inhibitors in a concentration-dependent manner, and TGF-β1-induced SPARC expression was reversed by entinostat treatment. mTORC1 inhibition by rapamycin and Raptor depletion stimulated SPARC expression. These findings may help uncover the regulatory mechanisms of the mTORC2-SPARC axis. The up-regulation of XPLN by HDAC inhibitors may be a novel therapeutic approach in patients with IPF.

Report

(4 results)
  • 2016 Annual Research Report   Final Research Report ( PDF )
  • 2015 Research-status Report
  • 2014 Research-status Report
  • Research Products

    (2 results)

All 2017 2016

All Journal Article (1 results) (of which Peer Reviewed: 1 results,  Acknowledgement Compliant: 1 results) Presentation (1 results) (of which Int'l Joint Research: 1 results)

  • [Journal Article] XPLN is modulated by HDAC inhibitors and negatively regulates SPARC expression by targeting mTORC2 in human lung fibroblasts2017

    • Author(s)
      Koichiro Kamio, Arata Azuma, Jiro Usuki, Kuniko Matsuda, Minoru Inomata, Nobuhiko Nishijima, Shioto Itakura, Hiroki Hayashi, Takeru Kashiwada, Nariaki Kokuho, Kenichiro Atsumi, Tomoyoshi Yamaguchi, Kazue Fujita, Yoshinobu Saito, Shinji Abe, Kaoru Kubota, Akihiko Gemma
    • Journal Title

      Pulmonary Pharmacology & Therapeutics

      Volume: 44 Pages: 61-69

    • DOI

      10.1016/j.pupt.2017.03.003

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Presentation] XPLN Negatively Regulates SPARC Expression by Targeting mTORC2 in Human Lung Fibroblasts2016

    • Author(s)
      Koichiro Kamio, Arata Azuma, Jiro Usuki, Kuniko Matsuda, Minoru Inomata, Nobuhiko Nishijima, Shioto Itakura, Nariaki Kokuho, Hiroki Hayashi, Tomoyoshi Yamaguchi, Kazue Fujita, Yoshinobu Saito, Shinji Abe, Kaoru Kubota, Akihiko Gemma
    • Organizer
      American Thoracic Society
    • Place of Presentation
      米国サンフランシスコ
    • Year and Date
      2016-05-14
    • Related Report
      2016 Annual Research Report 2015 Research-status Report
    • Int'l Joint Research

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Published: 2014-04-04   Modified: 2018-03-22  

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