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

• Project/Area Number: 26461202
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: Nippon 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: ¥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)
• Keywords: mTORC2 / 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.

Research Products

• [Journal Article] XPLN is modulated by HDAC inhibitors and negatively regulates SPARC expression by targeting mTORC2 in human lung fibroblasts (2017)
  • 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
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] XPLN Negatively Regulates SPARC Expression by Targeting mTORC2 in Human Lung Fibroblasts (2016)
  • 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
  • Int'l Joint Research