Targeting HSP47 for the treatment of pulmonary fibrosis

• Project/Area Number: 20K08520
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: Nagasaki University
• Principal Investigator: Mukae Hiroshi 長崎大学, 医歯薬学総合研究科(医学系), 教授 (80253821)
• Co-Investigator(Kenkyū-buntansha): 田中 義正 長崎大学, 先端創薬イノベーションセンター, 教授 (90280700)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2022: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: HSP47 / 肺線維症 / 肺線維芽細胞 / コラーゲン

Outline of Research at the Start

特発性肺線維症は予後不良の難治性疾患であり、コラーゲンの過剰な集積が病態形成において重要である。コラーゲンの合成において必要不可欠な分子シャペロンであるHeat Shock Protein 47 (HSP47) が肺線維化の機序と病態形成に密接に関与しており、治療ターゲットとして注目されている。しかし、HSP47をターゲットとするための有用なバイオマーカーや、HSP47の発現や機能を抑制する低中分子化合物に着目した薬剤の開発は進んでおらず、本研究ではHSP47抑制効果をもつ薬剤のスクリーニングおよびバイオマーカーの研究により新規肺線維化抑制薬の開発を目指している。

Outline of Final Research Achievements

In this study, we conducted basic research on the development of drugs for pulmonary fibrosis targeting Heat Shock Protein 47 (HSP47), and constructed a screening system to evaluate the interaction between HSP47 and collagen molecules. The screening was conducted using a library of original compounds and marine microorganism extracts from Nagasaki University. In this process, we succeeded in obtaining hit compounds from the synthetic compound library, but no fibrosis inhibitory effect at the cellular level was observed. On the other hand, some hit extracts were obtained in the screening of the marine microorganism extract library, and we are still synthesizing and optimizing the hit compounds.

Academic Significance and Societal Importance of the Research Achievements

本研究では、Heat Shock Protein 47 (HSP47) をターゲットとして、肺線維症治療薬開発の基盤研究を行った。現在新規治療薬の開発が求められている肺線維症において、独自のスクリーニング系を用いて、大学独自の化合物、海洋微生物抽出物から治療薬として有望な新規化合物が得られた。今回の研究の結果は、難治で知られる肺線維症に対してHSP47をターゲットとした画期的な治療法の開発に繋がる社会的意義がある。

Research Products

• [Journal Article] Two Distinct Mechanisms Underlying γδ T Cell-Mediated Regulation of Collagen Type I in Lung Fibroblasts (2022)
  • Author(s): Okuno Daisuke、Sakamoto Noriho、Akiyama Yoshiko、Tokito Takatomo、Hara Atsuko、Kido Takashi、Ishimoto Hiroshi、Ishimatsu Yuji、Tagod Mohammed S. O.、Okamura Haruki、Tanaka Yoshimasa、Mukae Hiroshi
  • Journal Title: Cells Volume: 11 Issue: 18 Pages: 2816-2816
  • DOI: 10.3390/cells11182816
  • Peer Reviewed / Open Access
• [Journal Article] Clinical characteristics of idiopathic interstitial pneumonias with anti-Ro52/tripartite motif-containing 21 antibodies (2022)
  • Author(s): Tahara Masahiro、Sakamoto Noriho、Satoh Minoru、Ishimoto Hiroshi、Yura Hirokazu、Yamasaki Kei、Kido Takashi、Fujino Yoshihisa、Hasegawa Tomoko、Tanaka Shin、Yatera Kazuhiro、Mukae Hiroshi
  • Journal Title: Scientific Reports Volume: 12 Issue: 1 Pages: 11122-11122
  • DOI: 10.1038/s41598-022-15321-4
  • Peer Reviewed / Open Access
• [Journal Article] Sensitivity of transbronchial lung cryobiopsy in the diagnosis of different interstitial lung diseases (2022)
  • Author(s): Zaizen Y, Tachibana Y, Ozasa M, Yamano Y, Takei R, Kohashi Y, Kataoka K, Saito Y, Tabata K, Okamoto M, Tominaga M, Fujimoto K, Sakamoto N, Ashizawa K, Mukae H, Bychkov A, Johkoh T, Hoshino T, Kondoh Y, Fukuoka J.
  • Journal Title: Sci Rep Volume: 21 Issue: 1 Pages: 22037-22037
  • DOI: 10.1038/s41598-022-26510-6
  • Peer Reviewed / Open Access
• [Journal Article] Associations between chest CT abnormalities and clinical features in patients with the severe fever with thrombocytopenia syndrome. (2022)
  • Author(s): Ashizawa H, Yamamoto K, Ashizawa N, Takeda K, Iwanaga N, Takazono T, Sakamoto N, Sumiyoshi M, Ide S, Umemura A, Yoshida M, Fukuda Y, Kobayashi T, Tashiro M, Tanaka T, Katoh S, Morimoto K, Ariyoshi K, Morimoto S, Tun MMN, Inoue S, Morita K, Kurihara S, Izumikawa K, Yanagihara K, Mukae H.
  • Journal Title: Viruses Volume: 14 Issue: 2 Pages: 279-279
  • DOI: 10.3390/v14020279
  • Peer Reviewed / Open Access
• [Journal Article] A comparative study of the sarcopenia screening in older patients with interstitial lung disease. (2022)
  • Author(s): Hanada M, Sakamoto N, Ishimoto H, Kido T, Miyamura T, Oikawa M, Nagura H, Takeuchi R, Kawazoe Y, Sato S, Hassan SA, Ishimatsu Y, Takahata H, Mukae H, Kozu R.
  • Journal Title: BMC Pulm Med. Volume: 25 Issue: 1 Pages: 45-45
  • DOI: 10.1186/s12890-022-01840-3
  • Peer Reviewed / Open Access
• [Journal Article] HLA-B54 is an independent risk factor for pneumonia in Japanese patients with interstitial lung disease: A multicenter retrospective cohort study (2021)
  • Author(s): Sakamoto Noriho、Ishimoto Hiroshi、Tahara Masahiro、Kido Takashi、Hara Atsuko、Miyamura Takuto、Okuno Daisuke、Tokito Takatomo、Yoshioka Sumako、Morimoto Shimpei、Takazono Takahiro、Yamamoto Kazuko、Yamaguchi Hiroyuki、Obase Yasushi、Ishimatsu Yuji、Yatera Kazuhiro、Mukae Hiroshi
  • Journal Title: Respiratory Medicine Volume: 188 Pages: 106612-106612
  • DOI: 10.1016/j.rmed.2021.106612
  • Peer Reviewed
• [Journal Article] Recognition of Connective Tissue Disease-Related Interstitial Pneumonia Based on Histological Score-A Validation Study of an Online Diagnostic Decision Support Tool (2021)
  • Author(s): Ozasa Mutsumi、Zaizen Yoshiaki、Tabata Kazuhiro、Kataoka Kensuke、Sato Shuntaro、Bychkov Andrey、Sakamoto Noriho、Mukae Hiroshi、Kondoh Yasuhiro、Fukuoka Junya
  • Journal Title: Diagnostics Volume: 11 Issue: 8 Pages: 1359-1359
  • DOI: 10.3390/diagnostics11081359
  • NAID: 120007172267
  • Peer Reviewed
• [Journal Article] Prospective nationwide multicentre cohort study of the clinical significance of autoimmune features in idiopathic interstitial pneumonias (2021)
  • Author(s): Enomoto Noriyuki、Homma Sakae、Inase Naohiko、Kondoh Yasuhiro、Saraya Takeshi et al.
  • Journal Title: Thorax Volume: 77 Issue: 2 Pages: 143-153
  • DOI: 10.1136/thoraxjnl-2020-216263
  • Peer Reviewed
• [Journal Article] Efficacy and safety of nintedanib in Japanese patients with early-stage idiopathic pulmonary fibrosis: a study protocol for an observational study (2021)
  • Author(s): Sakamoto Noriho、Hamada Naoki、Okamoto Masaki、Tobino Kazunori、Ichiyasu Hidenori、Ishii Hiroshi、Ichikado Kazuya、Morimoto Shimpei、Hosogaya Naoki、Mukae Hiroshi
  • Journal Title: BMJ Open Volume: 11 Issue: 6 Pages: e047249-e047249
  • DOI: 10.1136/bmjopen-2020-047249
  • NAID: 120007172283
  • Peer Reviewed / Open Access
• [Journal Article] Safety and tolerability of combination therapy with pirfenidone and nintedanib for idiopathic pulmonary fibrosis: a multicenter retrospective observational study in Japan (2021)
  • Author(s): Shu Hisata, Masashi Bando, Sakae Homma, Kensuke Kataoka, Takashi Ogura, Shinyu Izumi, Susumu Sakamoto, Kizuku Watanabe, Yoshinobu Saito, Yasuo Shimizu, Motoyasu Kato, Yasuhiro Nishioka, Hiromichi Hara, Yuko Waseda, Yoshinori Tanino, et al.
  • Journal Title: Respir Investig Volume: 59 Issue: 6 Pages: 819-826
  • DOI: 10.1016/j.resinv.2021.04.005
  • Peer Reviewed
• [Journal Article] Screening of Inhibitors Targeting Heat Shock Protein 47 Involved in the Development of Idiopathic Pulmonary Fibrosis (2021)
  • Author(s): Okuno Daisuke、Sakamoto Noriho、Tagod Mohammed S. O.、Akiyama Yoshiko、Moriyama Sakiko、Miyamura Takuto、Hara Atsuko、Kido Takashi、Ishimoto Hiroshi、Ishimatsu Yuji、Tanaka Takashi、Ishihara Jun、Takeda Kohsuke、Tanaka Yoshimasa、Mukae Hiroshi
  • Journal Title: ChemMedChem Volume: 16 Issue: 16 Pages: 2515-2523
  • DOI: 10.1002/cmdc.202100064
  • Peer Reviewed
• [Journal Article] Exposure to PM2.5 is a risk factor for acute exacerbation of surgically diagnosed idiopathic pulmonary fibrosis: a case?control study (2021)
  • Author(s): Tahara Masahiro、Fujino Yoshihisa、Yamasaki Kei、Oda Keishi、Kido Takashi、Sakamoto Noriho、Kawanami Toshinori、Kataoka Kensuke、Egashira Ryoko、Hashisako Mikiko、Suzuki Yuzo、Fujisawa Tomoyuki、Mukae Hiroshi、Suda Takafumi、Yatera Kazuhiro
  • Journal Title: Respiratory Research Volume: 22 Issue: 1 Pages: 80-80
  • DOI: 10.1186/s12931-021-01671-6
  • Peer Reviewed / Open Access
• [Journal Article] Pirfenidone plus inhaled N-acetylcysteine for idiopathic pulmonary fibrosis: a randomized trial (2021)
  • Author(s): Susumu Sakamoto, Kensuke Kataoka, Yasuhiro Kondo, Motoyasu Kato, Tomoaki Hoshino, Hiroshi Mukae, Masashi Bando, Takafumi Suda, Takashi Kido, Yoshinori Tanino, et al.
  • Journal Title: Eur Respir J Volume: 57 Issue: 1 Pages: 200348-200348
  • DOI: 10.1183/13993003.00348-2020
  • Peer Reviewed
• [Journal Article] Corticosteroids are associated with reduced skeletal muscle function in interstitial lung disease patients with mild dyspnea (2020)
  • Author(s): Masatoshi Hanada, Yuji Ishimatsu, Noriho Sakamoto, Hiroki Nagura, Masato Oikawa, Yosuke Morimoto, Shuntaro Sato, Hiroshi Mukae, Ryo Kozu
  • Journal Title: Respiratory Medicine Volume: 174 Pages: 106184-106184
  • DOI: 10.1016/j.rmed.2020.106184
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] IL‐15 is a biomarker involved in the development of rapidly progressive interstitial lung disease complicated with polymyositis/dermatomyositis (2020)
  • Author(s): Shimizu T.、Koga T.、Furukawa K.、Horai Y.、Fujikawa K.、Okada A.、Okamoto M.、Endo Y.、Tsuji S.、Takatani A.、Umeda M.、Fukui S.、Sumiyoshi R.、Kawashiri S.‐y.、Iwamoto N.、Igawa T.、Ichinose K.、Tamai M.、Sakamoto N.、Nakamura H.、Origuchi T.、Mukae H.、Kuwana M.、Kawakami A.
  • Journal Title: Journal of Internal Medicine Volume: 289 Issue: 2 Pages: 206-220
  • DOI: 10.1111/joim.13154
  • Peer Reviewed
• [Journal Article] Comparison of lung microbiota between antineutrophil cytoplasmic antibody-associated vasculitis and sarcoidosis. (2020)
  • Author(s): Shoichi Fukui, Shimpei Morimoto, Kunihiro Ichinose, Shota Nakashima, Hiroshi Ishimoto, Atsuko Hara, Tomoyuki Kakugawa, et al.
  • Journal Title: Sci Rep Volume: 10(1) Issue: 1 Pages: 9466-9466
  • DOI: 10.1038/s41598-020-66178-4
  • NAID: 120006988158
  • Peer Reviewed / Open Access
• [Journal Article] Prediction of Anti-Cancer Drug-Induced Pneumonia in Lung Cancer Patients: Novel High-Resolution Computed Tomography Fibrosis Scoring. (2020)
  • Author(s): Hiroshi Gyotoku, Hiroyuki Yamaguchi, Hiroshi Ishimoto, Shuntaro Sato, Hirokazu Taniguchi, Hiroaki Senju, Tomoyuki Kakugawa, Katsumi Nakatomi, Noriho Sakamoto, Minoru Fukuda, Yasushi Obase, Hiroshi Soda, Kazuto Ashizawa, Hiroshi Mukae
  • Journal Title: J Clin Med Volume: 9(4) Issue: 4 Pages: 1045-1045
  • DOI: 10.3390/jcm9041045
  • Peer Reviewed / Open Access
• [Journal Article] Presence of heat shock protein 47-positive fibroblasts in cancer stroma is associated with increased risk of postoperative recurrence in patients with lung cancer (2020)
  • Author(s): Takuto Miyamura, Noriho Sakamoto, Kaori Ishida, Tomoyuki Kakugawa, Hirokazu Taniguchi , Yoshiko Akiyama, Daisuke Okuno, Atsuko Hara, Takashi Kido, Hiroshi Ishimoto, Takuro Miyazaki, Keitaro Matsumoto, Tomoshi Tsuchiya, Hiroyuki Yamaguchi, Taiga Miyazaki, Yasushi Obase, Yuji Ishimatsu, Takeshi Nagayasu, Hiroshi Mukae
  • Journal Title: Respiratory Research Volume: 21(1) Issue: 1 Pages: 234-234
  • DOI: 10.1186/s12931-020-01490-1
  • Peer Reviewed / Open Access
• [Journal Article] Small molecule inhibitor of HSP47 prevents pro-fibrotic mechanisms of fibroblasts in vitro. (2020)
  • Author(s): Takuto Miyamura, Noriho Sakamoto, Tomoyuki Kakugawa, Hirokazu Taniguchi, Yoshiko Akiyama, Daisuke Okuno, Sakiko Moriyama, Atsuko Hara, Takashi Kido, Hiroshi Ishimoto, Hiroyuki Yamaguchi, Taiga Miyazaki, Yasushi Obase, Yuji Ishimatsu, Yoshimasa Tanaka, Hiroshi Mukae
  • Journal Title: Biochem Biophys Res Commun Volume: 530(3) Issue: 3 Pages: 561-565
  • DOI: 10.1016/j.bbrc.2020.07.085
  • Peer Reviewed
• [Journal Article] Coinfection With Multiple Nontuberculous Mycobacteria as a Possible Exacerbating Factor in Pulmonary Nontuberculous Mycobacteriosis (2020)
  • Author(s): Naito Keisuke、Noguchi Shingo、Yatera Kazuhiro、Kawanami Toshinori、Yamasaki Kei、Fukuda Kazumasa、Ikegami Hiroaki、Akata Kentaro、Kido Takashi、Sakamoto Noriho、Saito Mitsumasa、Mukae Hiroshi
  • Journal Title: Chest Volume: 158 Issue: 6 Pages: 2304-2313
  • DOI: 10.1016/j.chest.2020.06.027
  • Peer Reviewed
• [Journal Article] Acute exacerbation of idiopathic interstitial pneumonias related to chemotherapy for lung cancer: A nationwide surveillance in Japan (2020)
  • Author(s): Minegishi Y, Gemma A, Homma S, Kishi K, Azuma A, Ogura T, Hamada N, Taniguchi H, Hattori N, Nishioka Y, Tanizawa K, Johkoh T, Yokoyama T, Mori K, Taguchi Y, Ebina M, Inase N, Hagiwara K, Ohnishi H, Mukae H, Inoue Y, Kuwano K, Chiba H, Ohta K, Tanino Y, Sakai F, Sugiyama Y, for the Diffuse Lung Diseases Research Group
  • Journal Title: ERJ OPEN RES Volume: 6 Issue: 2 Pages: 00142-202
  • DOI: 10.1183/23120541.00184-2019
  • Peer Reviewed / Open Access
• [Journal Article] Characteristics of tobacco-related lung diseases in Fukuoka Prefecture, Japan: A prospective, multi-institutional, observational study (2020)
  • Author(s): Ogata-Suetsugu Saiko、Hamada Naoki、Tsuda Toru、Takata Shohei、Kitasato Yasuhiko、Inoue Naoyuki、Nagata Nobuhiko、Yatera Kazuhiro、Mukae Hiroshi、Yoshii Chiharu、Hoshino Tomoaki、Fujita Masaki、Watanabe Kentaro、Tokunaga Shoji、Nakanishi Yoichi
  • Journal Title: Respiratory Investigation Volume: 58 Issue: 1 Pages: 74-80
  • DOI: 10.1016/j.resinv.2019.10.002
  • Peer Reviewed / Open Access
• [Presentation] ヒトγδT細胞を用いた肺線維症治療薬の開発 (2022)
  • Author(s): 奥野大輔, 坂本憲穂, 時任高諄, 由良博一, 城戸貴志, 石本裕士, 田中義正, 迎 寛
  • Organizer: 第2回日本びまん性肺疾患研究会
• [Presentation] Identification of inhibitors targeting heat shock protein 47 for the development of anti-fibrotic therapeutics (2021)
  • Author(s): Daisuke Okuno, Noriho Sakamoto, Takatomo Tokito, Atsuko Hara, Takashi Kido, Hiroshi Ishimoto, Yuji Ishimatsu, Yoshimasa Tanaka, Hiroshi Mukae
  • Organizer: Asian Pacific Society of Respirology 2021
  • Int'l Joint Research
• [Presentation] The Role of Epstein-Barr Virus-Encoded microRNAs in Pulmonary Fibrosis (2020)
  • Author(s): N. Sakamoto, H. Yura, D. Okuno, T. Miyamura, A. Hara, T. Kido, H. Ishimoto, Y. Ishimatsu, H. Mukae
  • Organizer: ATS 2020－American Thoracic Society International Conference
  • Int'l Joint Research
• [Presentation] Immune Complexome Analysis Detects Apolipoprotein E as a Disease-Specific Immune Complex Antigen in Bronchoalveolar Fluids from Patients with Summer-Type Hypersensitivity Pneumonitis (2020)
  • Author(s): Y. Ishimatsu, A. Hara, N. Aibara, K. Ohyama, Y. Akiyama, D. Okuno, T. Miyamura, T. Kido, H. Ishimoto, N. Sakamoto, H. Mukae
  • Organizer: ATS 2020－American Thoracic Society International Conference
  • Int'l Joint Research
• [Presentation] The Utility Of Combinate Detection Of Igh And Tcr Gene Rearrangement, And Malt1 Gene Translocation In Balf For The Diagnosis (2020)
  • Author(s): T. Kido, H. Ishimoto, H. Ishii, K. Hara, H. Kawabata, T. Kawanami, Y. Suzuki, H. Yoshikawa, A. Hara, N. Sakamoto, N. Matsumoto, C. Yoshii, M. Fujita, M. Nakazato, J. Kadota, H. Mukae, K. Yatera
  • Organizer: ATS 2020－American Thoracic Society International Conference
  • Int'l Joint Research
• [Presentation] Effect of Zoledronic Acid and a Bisphosphonate Prodrug on γδ T Cell-Mediated Cytotoxicity Against Lung Cancer Cells (2020)
  • Author(s): D. Okuno, N. Sakamoto, T. Miyamura, A. Hara, T. Kido, H. Ishimoto, H. Yamaguchi, Y. Ishimatsu, Y. Tanaka, H. Mukae
  • Organizer: ATS 2020－American Thoracic Society International Conference
  • Int'l Joint Research
• [Presentation] Heat Shock Protein 47 (HSP47) Positive Fibroblasts in Cancer Stroma Are Associated with Increased Risk of Postoperative Recurrence in Patients with Lung Cancer (2020)
  • Author(s): T. Miyamura, N. Sakamoto, T. Kakugawa, K. Ishida, H. Taniguchi, D. Okuno, A. Hara, T. Kido, H. Ishimoto, T. Miyazaki, K. Matsumoto, T. Tsuchiya, H. Yamaguchi, Y. Obase, Y. Ishimatsu, T. Nagayasu, H. Mukae
  • Organizer: ATS 2020－American Thoracic Society International Conference
  • Int'l Joint Research
• [Presentation] 膵癌化学療法中に生じた薬剤性肺障害の検討 (2020)
  • Author(s): 宮下 律子、石本裕士、奥野大輔、宮村 拓人、由良 博一、高園 貴弘、 原 敦子、 坂本 憲穂、石松 祐二、 尾長谷 靖 、 迎 寛
  • Organizer: 第60回日本呼吸器学会学術講演会
• [Presentation] 肺癌手術検体における，Heat shock protein 47発現の検討 (2020)
  • Author(s): 宮村 拓人、坂本 憲穂、角川 智之、石田 佳央理、奥野 大輔、 原 敦子、 宮崎 拓郎、 城戸 貴志、石本 裕士、 松本 桂太郎、土屋 智 史、石松 祐二、永安 武、迎 寛
  • Organizer: 第60回日本呼吸器学会学術講演会