Exploration of innovative biomarkers in pulmonary fibrosis by quantitative proteomics of exosomes

• Project/Area Number: 16K09580
• 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: Osaka University
• Principal Investigator: HIRATA HARUHIKO 大阪大学, 医学系研究科, 寄附講座助教 (30546867)
• Co-Investigator(Kenkyū-buntansha): 武田 吉人 大阪大学, 医学系研究科, 講師 (40452388)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: エクソソーム / 肺線維症 / バイオマーカー / プロテオミクス / 特発性肺線維症 / 肺線維症疾患モデルマウス / 間質性肺炎

Outline of Final Research Achievements

By quantitative proteomics of serum exosomes of lung fibrosis model mice, we searched for disease-specific BMs useful not only for diagnosis but also for pathogic clarification and treatment.
By label-free proteomics, 697 proteins were obtained from exosomes isolated by size-exclusion chromatography. Of note, these exosomal proteins reflected its characteristics of fibrosis to some degree. Among them, 82 proteins were listed as BM candidates whose expression increased 3-fold or more in fibrosis model. Furthermore, 21 BMs were narrow downed by disease activity using fibrotic score. In addition, it was confirmed by immunostaining that these BM candidate proteins are increased in fibrotic lesions.Now, we are going to verify these BM candidates in mice and human.

Academic Significance and Societal Importance of the Research Achievements

特発性肺線維症は予後不良の疾患であり、遺伝的素因に外的要因が加わることで発症する複雑かつ多様な為、診断・治療・新薬開発に役立つ特異性の高いバイオマーカー(BM)の開発が求められている。
種々の細胞が分泌するエクソソーム(小胞)は、新たな細胞間・臓器間のコミュニケーション手段として病態形成・診断・治療応用から注目されている。本研究目的は、最新のタンパク解析技術を用いて、血清エクソソームから肺線維症に特異的なBMを探す。

Research Products

• [Journal Article] Double deletion of tetraspanins CD9 and CD81 in mice leads to a syndrome resembling accelerated aging (2018)
  • Author(s): Jin Y, Takeda Y, Kondo Y, Tripathi LP, Kang S, Takeshita H, Kuhara H, Maeda Y, Higashiguchi M, Miyake K, Morimura O、Koba T、Hayama Y、Koyama S、Nakanishi K、Iwasaki T、Tetsumoto Si、Tsujino K、Kuroyama M、Iwahori K、Hirata H、Takimoto Ti、Suzuki M、Nagatomo I、Sugimoto K、Fujii Y、Kida H、et al.
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 5145-5145
  • DOI: 10.1038/s41598-018-23338-x
  • Peer Reviewed / Open Access
• [Journal Article] Classification of idiopathic interstitial pneumonias using anti-myxovirus resistance-protein 1 autoantibody (2017)
  • Author(s): Hamano Y, Kida H, Ihara S, Murakami A, Yanagawa M, Ueda K, Honda O, Tripathi LP, Arai T, Hirose M, Hamasaki T, Yano Y, Kimura T, Kato Y, Takamatsu H, Otsuka T, Minami T, Hirata H, Inoue K, Nagatomo I, Takeda Y, Mori M, Nishikawa H, Mizuguchi K, Kijima T, Kitaichi T, Tomiyama N, Inoue Y, Kumanogoh A
  • Journal Title: Scientific Reports Volume: 23 Issue: 1 Pages: 43201-43201
  • DOI: 10.1038/srep43201
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Rapid intracranial response to osimertinib, without radiotherapy, in nonsmall cell lung cancer patients harboring the EGFR T790M mutation: Two Case Reports (2017)
  • Author(s): Koba T, Kijima T, Takimoto T, Hirata H, Naito Y, Hamaguchi M, Otsuka T, Kuroyama M, Nagatomo I, Takeda Y, Kida H, Kumanogoh A
  • Journal Title: Medicine (Baltimore) Volume: 96 Issue: 6 Pages: 6087-6087
  • DOI: 10.1097/md.0000000000006087
  • Peer Reviewed / Open Access
• [Journal Article] Clarifying the biological significance of the CHK2 K373E somatic mutation discovered in The Cancer Genome Atlas database. (2016)
  • Author(s): Higashiguchi M, Nagatomo I, Kijima T, Morimura O, Miyake K, Minami T, Koyama S, Hirata H, Iwahori K, Takimoto T, Takeda Y, Kida H, Kumanogoh A
  • Journal Title: FEBS Lett. Volume: 590 Pages: 4275-4286
  • Peer Reviewed / Open Access
• [Journal Article] Pneumodynamics: Respiratory Physiology Related to Anesthesiology]. (2016)
  • Author(s): Kitaoka H, Hirata H, Kijima T
  • Journal Title: Masui. Volume: 65 Pages: 452-460
  • NAID: 40020840424
• [Presentation] 結節性硬化症診療における肺疾患；LAM及びmTOR阻害剤による肺障害について (2016)
  • Author(s): 平田陽彦
  • Organizer: 第4回結節性硬化症学会
  • Place of Presentation: 大阪
  • Year and Date: 2016-11-12
  • Invited
• [Presentation] 最大努力呼気4DCTが明らかにした気流制限の実態とそのメカニズム (2016)
  • Author(s): 平田陽彦，木島貴志，北岡裕子
  • Organizer: 第56回日本呼吸器学会学術講演会
  • Place of Presentation: 京都
  • Year and Date: 2016-04-08