Research aimed to overcome the intracableness of lung fibrosis by regulation of ageing-related long non-coding RNAs

• Project/Area Number: 18K15948
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: Nagoya University
• Principal Investigator: Koji Sakamoto 名古屋大学, 医学部附属病院, 病院講師 (00635633)
• Project Period (FY): 2018-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥520,000 (Direct Cost: ¥400,000、Indirect Cost: ¥120,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 肺線維症 / エピゲノム / RNA / 細胞老化 / 老化 / lncRNA / ミトコンドリアDNA / ＲＮＡ / リプログラミング / ノンコーディングRNA / エピジェネティクス / 非コードRNA

Outline of Final Research Achievements

While the importance of cellular senescence in the pathogenesis of idiopathic pulmonary fibrosis, an age-related intractable disease, has attracted much attention, the involvement of long non-coding RNAs (lncRNAs), a new epigenomic factor responsible for cellular fate determination including cellular senescence, remains unclear. We identified a number of lncRNAs that are specifically altered in idiopathic pulmonary fibrosis based on a large-scale comprehensive RNA expression analysis of human lung tissue. We subsequently extracted several lncRNAs that are also involved in cellular senescence. Among them, we focused on FENDRR, a lncRNA specifically expressed in mesenchymal cells, functions to regulate the cellular senescence phenotype of fibroblasts induced by stimuli such as TGF-β and oxidative stress, which is assumed to be mediated partly by the regulation of NADPH oxidase.

Academic Significance and Societal Importance of the Research Achievements

肺線維症の肺組織で発現変化する新規エピゲノム因子・長鎖ノンコーディングRNAが肺細胞において病態形成に関係した病的な細胞変化、特に細胞老化の表現型を制御していることが示唆された。本研究の更なる発展により難治の肺疾患において長鎖ノンコーディングRNAを用いた同疾患の新しい治療標的の開発やバイオマーカーの創出が期待される。

Research Products

• [Int'l Joint Research] Yale University(米国)
• [Int'l Joint Research] Yale University(米国)
• [Int'l Joint Research] Yale University(米国)
• [Journal Article] Successful Treatment with High-dose Steroids for Acute Exacerbation of Idiopathic Pulmonary Fibrosis Triggered by COVID-19 (2022)
  • Author(s): Omote Norihito、Kanemitsu Yoshihiro、Inoue Takahiro、Yonezawa Toshiyuki、Ichihashi Takuji、Shindo Yuichiro、Sakamoto Koji、Ando Akira、Suzuki Atsushi、Niimi Akio、Ito Satoru、Imaizumi Kazuyoshi、Hashimoto Naozumi
  • Journal Title: Internal Medicine Volume: 61 Issue: 2 Pages: 233-236
  • DOI: 10.2169/internalmedicine.8163-21
  • NAID: 130008141771
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2022-01-15
  • Peer Reviewed / Open Access
• [Journal Article] COVID-19-Triggered Acute Exacerbation of IPF, an Underdiagnosed Clinical Entity With Two-Peaked Respiratory Failure: A Case Report and Literature Review (2022)
  • Author(s): Goto Yosuke、Sakamoto Koji、Fukihara Jun、Suzuki Atsushi、Omote Norihito、Ando Akira、Shindo Yuichiro、Hashimoto Naozumi
  • Journal Title: Frontiers in Medicine Volume: 9 Pages: 815924-815924
  • DOI: 10.3389/fmed.2022.815924
  • Peer Reviewed / Open Access
• [Journal Article] Overexpression of bone morphogenetic protein receptor type 2 suppresses transforming growth factor β-induced profibrotic responses in lung fibroblasts (2022)
  • Author(s): Fukihara Jun、Maiolo Suzanne、Kovac Jessica、Sakamoto Koji、Wakahara Keiko、Hashimoto Naozumi、Reynolds Paul N.
  • Journal Title: Experimental Lung Research Volume: 48 Issue: 1 Pages: 35-51
  • DOI: 10.1080/01902148.2021.2024301
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A comprehensible machine learning tool to differentially diagnose idiopathic pulmonary fibrosis from other chronic interstitial lung diseases (2022)
  • Author(s): Furukawa T, Oyama S, Yokota H, Kondoh Y, Kataoka K, Johkoh T, Fukuoka J, Hashimoto N,Sakamoto K, Shiratori Y, Hasegawa Y
  • Journal Title: Respirology Volume: 27 Issue: 9 Pages: 739-746
  • DOI: 10.1111/resp.14310
  • Peer Reviewed
• [Journal Article] CINS: Cell Interaction Network inference from Single cell expression data (2022)
  • Author(s): Yuan Ye、Cosme Carlos、Adams Taylor Sterling、Schupp Jonas、Sakamoto Koji、Xylourgidis Nikos、Ruffalo Matthew、Li Jiachen、Kaminski Naftali、Bar-Joseph Ziv
  • Journal Title: PLOS Computational Biology Volume: 18 Issue: 9 Pages: e1010468-e1010468
  • DOI: 10.1371/journal.pcbi.1010468
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] BMP3b Is a Novel Antifibrotic Molecule Regulated by Meflin in Lung Fibroblasts (2022)
  • Author(s): Suzuki Atsushi、Sakamoto Koji、Nakahara Yoshio、Enomoto Atsushi、Hino Jun、Ando Akira、Inoue Masahide、Shiraki Yukihiro、Omote Norihito、Kusaka Masahiro、Fukihara Jun、Hashimoto Naozumi
  • Journal Title: American Journal of Respiratory Cell and Molecular Biology Volume: 67 Issue: 4 Pages: 446-458
  • DOI: 10.1165/rcmb.2021-0484oc
  • Peer Reviewed / Open Access
• [Journal Article] Size and surface modification of silica nanoparticles affect the severity of lung toxicity by modulating endosomal ROS generation in macrophages (2021)
  • Author(s): Masahide Inoue, Koji Sakamoto, Atsushi Suzuki, Shinya Nakai, Akira Ando, Yukihiko Shiraki, Yoshio Nakahara, Mika Omura, Atsushi Enomoto, Ikuhiko Nakase, Makoto Sawada, Naozumi Hashimoto
  • Journal Title: Particle and Fibre Toxicology Volume: 18 Issue: 1 Pages: 21-21
  • DOI: 10.1186/s12989-021-00415-0
  • Peer Reviewed / Open Access
• [Journal Article] Fibroblasts positive for meflin have anti-fibrotic properties in pulmonary fibrosis (2021)
  • Author(s): Nakahara Y, Hashimoto N, Sakamoto K, Enomoto A, Adams TS, Yokoi T, Omote N, Poli S, Ando A, Wakahara K, Suzuki A, Inoue M, Hara A, Mizutani Y, Imaizumi K, Kawabe T, Rosas IO, Takahashi M, Kaminski N, Hasegawa Y.
  • Journal Title: European Respiratory Journal Volume: 58 Issue: 6 Pages: 2003397-2003397
  • DOI: 10.1183/13993003.03397-2020
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Long noncoding RNA TINCR is a novel regulator of human bronchial epithelial cell differentiation state. (2021)
  • Author(s): Omote N, Sakamoto K, Li Q, Schupp JC, Adams T, Ahangari F, Chioccioli M, DeIuliis G, Hashimoto N, Hasegawa Y, Kaminski N.
  • Journal Title: Physiol Rep. Volume: 9 Issue: 3
  • DOI: 10.14814/phy2.14727
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Acute Exacerbation of Pleuroparenchymal Fibroelastosis Secondary to Allogenic Hematopoietic Stem Cell Transplantation (2020)
  • Author(s): Murakami Y, Sakamoto K, Okumura Y, Suzuki A, Mii S, Sato M, Yokoi T, Hashimoto N, Hasegawa Y.
  • Journal Title: Internal Medicine Volume: 59 Issue: 21 Pages: 2737-2743
  • DOI: 10.2169/internalmedicine.4995-20
  • NAID: 130007934213
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2020-11-01
  • Peer Reviewed / Open Access
• [Journal Article] Clinical burden of immune checkpoint inhibitor-induced pneumonitis (2020)
  • Author(s): Sakamoto Koji、Fukihara Jun、Morise Masahiro、Hashimoto Naozumi
  • Journal Title: Respiratory Investigation Volume: 58 Issue: 5 Pages: 305-319
  • DOI: 10.1016/j.resinv.2020.05.008
  • Peer Reviewed
• [Journal Article] Serum mitochondrial DNA predicts the risk of acute exacerbation and progression of idiopathic pulmonary fibrosis (2020)
  • Author(s): Sakamoto Koji、Furukawa Taiki、Yamano Yasuhiko、Kataoka Kensuke、Teramachi Ryo、Walia Anjali、Suzuki Atsushi、Inoue Masahide、Nakahara Yoshio、Ryu Changwan、Hashimoto Naozumi、Kondoh Yasuhiro
  • Journal Title: European Respiratory Journal Volume: 57 Issue: 1 Pages: 2001346-2001346
  • DOI: 10.1183/13993003.01346-2020
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prognostic Impact and Risk Factors of Immune-Related Pneumonitis in Patients With Non?Small-Cell Lung Cancer Who Received Programmed Death 1 Inhibitors (2019)
  • Author(s): Fukihara Jun、Sakamoto Koji、Koyama Junji、Ito Takayasu、Iwano Shingo、Morise Masahiro、Ogawa Masahiro、Kondoh Yasuhiro、Kimura Tomoki、Hashimoto Naozumi、Hasegawa Yoshinori
  • Journal Title: Clinical Lung Cancer Volume: 20 Issue: 6 Pages: 442-450.e4
  • DOI: 10.1016/j.cllc.2019.07.006
  • Peer Reviewed
• [Journal Article] Repressive role of stabilized hypoxia inducible factor 1α expression on transforming growth factor β‐induced extracellular matrix production in lung cancer cells (2019)
  • Author(s): Ando Akira、Hashimoto Naozumi、Sakamoto Koji、Omote Norihito、Miyazaki Shinichi、Nakahara Yoshio、Imaizumi Kazuyoshi、Kawabe Tsutomu、Hasegawa Yoshinori
  • Journal Title: Cancer Science Volume: 110 Issue: 6 Pages: 1959-1973
  • DOI: 10.1111/cas.14027
  • Peer Reviewed
• [Journal Article] Reply to “Prognostic Impact and Risk Factors of Immune-Related Pneumonitis in Patients With Non?Small-Cell Lung Cancer Who Received Programmed Death-1 Inhibitors” (2019)
  • Author(s): Fukihara Jun、Sakamoto Koji、Koyama Junji、Ito Takayasu、Iwano Shingo、Morise Masahiro、Ogawa Masahiro、Kondoh Yasuhiro、Kimura Tomoki、Hashimoto Naozumi、Hasegawa Yoshinori
  • Journal Title: Clinical Lung Cancer Volume: 19 Issue: 3 Pages: 30330-4
  • DOI: 10.1016/j.cllc.2019.11.013
  • Peer Reviewed
• [Presentation] Meflin-BMP3b Axis Is a Novel Anti-Fibrotic Pathway Against TGF-βInduced Lung Fibrogenesis (2022)
  • Author(s): A. Suzuki , K. Sakamoto , Y. Nakahara , A. Enomoto , J. Hino , A. Ando , M. Inoue , N. Omote , M. Kusaka , J. Fukihara , N. Hashimoto
  • Organizer: American Thoracic Society 2022 International Conference
  • Int'l Joint Research
• [Presentation] Increased Circulating Mitochondrial DNA Content Predicts Fatal Complication and Worse Prognosis in Idiopathic Pulmonary Fibrosis (2020)
  • Author(s): K. Sakamoto, T. Furukawa, Y. Yamano, R. Teramachi, A. Suzuki, Y. Nakahara, M. Inoue, K. Kataoka, N. Hashimoto, Y. Kondoh, Y. Hasegawa
  • Organizer: American Thoracic Society 2020 International Conference
  • Int'l Joint Research
• [Presentation] Single-Cell RNAseq of Aging Mouse Lungs Reveals Global and Cell-Specific Inflammatory Aberrations (2020)
  • Author(s): C. Cosme Jr., J.E. McDonough, T. Adams, J.C. Schupp, N. Omote, F. Ahangari, G. DeIuliis, K. Sakamoto, N. Kaminski
  • Organizer: American Thoracic Society 2020 International Conference
  • Int'l Joint Research
• [Presentation] The Role of Meflin Expression in Fibroblasts During Development of Pulmonary Fibrosis (2020)
  • Author(s): N. Hashimoto, Y. Nakahara, K. Sakamoto, A. Enomoto, T. Yokoi, A. Suzuki, M. Inoue, K. Wakahara, Y. Hasegawa
  • Organizer: American Thoracic Society 2020 International Conference
  • Int'l Joint Research
• [Presentation] Long Non-Coding RNA TINCR Is a Novel Regulator of Human Bronchial Epithelial Cell Differentiation (2020)
  • Author(s): N. Omote, K. Sakamoto, Q. Li, J.C. Schupp, T. Adams, F. Ahangari, M. Chioccioli, N. Hashimoto, Y. Hasegawa, N. Kaminski
  • Organizer: American Thoracic Society 2020 International Conference
  • Int'l Joint Research
• [Presentation] Pirfenidone Delays the Prescription of Concomitant Drugs in Patients with Idiopathic Pulmonary Fibrosis: Post-Hoc Analysis of Japanese Phase III Clinical Trial (2020)
  • Author(s): A. Suzuki, H. Sakaguchi, M. Ebina, A. Azuma, T. Ogura, Y. Taguchi, M. Suga, H. Takahashi, Y. Sugiyama, S. Kudoh, T. Nukiwa , S. Miyazawa, K. Sakamoto, Y. Kondoh
  • Organizer: American Thoracic Society 2020 International Conference
  • Int'l Joint Research
• [Presentation] Assessment of circulating mitochondrial DNA as a liquid biomarker in acute exacerbation of idiopathic pulmonary fibrosis (2019)
  • Author(s): Koji Sakamoto, Taiki Furukawa, Kensuke Kataoka, Yasuhiro Kondoh, Yoshinori Hasegawa
  • Organizer: American Thoracic Society 2019 International Conference
  • Int'l Joint Research
• [Presentation] Loss of lncRNA FENDRR Induces Senescence in Adult Mouse Lungs (2019)
  • Author(s): N. Xylourgidis, K. Sakamoto, J. C. Schupp, T. Adams, G. DeIuliis, N. Omote, N. Hashimoto, Y. Hasegawa, N. Kaminski
  • Organizer: American Thoracic Society 2019 International Conference
  • Int'l Joint Research
• [Presentation] TINCR, a Long Intergenic Noncoding RNA Decreased in IPF, Is a Novel Regulator of Airway Epithelial Cell Differentiation (2019)
  • Author(s): N. Omote, K. Sakamoto, Q. Li, J. C. Schupp, T. Adams, F. Ahangari, M. Chioccioli, N. Xylourgidis, G. DeIuliis, N. Hashimoto, Y. Hasegawa, N. Kaminski
  • Organizer: American Thoracic Society 2019 International Conference
  • Int'l Joint Research
• [Presentation] Assessment of Circulating Mitochondrial DNA as a Liquid Biomarker in Acute Exacerbation of Idiopathic Pulmonary Fibrosis (2019)
  • Author(s): Koji Sakamoto
  • Organizer: 2019 ATS International Conference
  • Int'l Joint Research
• [Presentation] Acute exacerbation of pleuroparenchymal fibroelastosis in patient status post hematopoietic stem cell transplantation (2018)
  • Author(s): Koji Sakamoto
  • Organizer: 23th Congress of the Asian Pacific Society of Respirology
  • Int'l Joint Research
• [Remarks] 特発性肺線維症の病気の進行や急性増悪を予測できる 新規の血液指標（ミトコンドリア DNA）を発見！
  • URL: https://research-er.jp/articles/view/91640