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

2016 Fiscal Year Final Research Report

• 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)
• Research Collaborator: MATSUDA Kuniko 日本医科大学, 実験助手
• Project Period (FY): 2014-04-01 – 2017-03-31
• Keywords: mTORC2 / XPLN / SPARC / IPF / HDAC inhibitor

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.

Free Research Field

呼吸器内科学