Immune-pathological diagnostic artificial intelligence development research for pulmonary fibrosis using fibrotic foci-specific enhanced micro-CT

• Project/Area Number: 20K21599
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 53:Organ-based internal medicine and related fields
• Research Institution: Fujita Health University (2022); Nagoya University (2020-2021)
• Principal Investigator: Hashimoto Naozumi 藤田医科大学, 医学部, 教授 (30378020)
• Co-Investigator(Kenkyū-buntansha): 若原 恵子 名古屋大学, 医学部附属病院, 講師 (00631433) ; 阪本 考司 名古屋大学, 医学部附属病院, 病院講師 (00635633) ; 中村 彰太 名古屋大学, 医学部附属病院, 講師 (20612849) ; 古川 大記 名古屋大学, 医学部附属病院, 特任助教 (30837654)
• Project Period (FY): 2020-07-30 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2020: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
• Keywords: 肺線維症 / 線維芽細胞 / 金ナノ粒子 / マイクロCT / 血管内皮細胞 / 人工知能 / 診断

Outline of Research at the Start

本研究課題は、病理診断が極めて重要な特発性肺線維症の肺に対して線維芽細胞巣特異的分子meflinに対するX線造影物質の金ナノ粒子標識抗体を用いた造影マイクロCTスキャンを行い線維芽細胞巣に特異的な形態学的所見と分子学的所見を放射線画像として同時に捉えることにチャレンジして、マイクロCTに免疫病理学的診断能を付与する線維芽細胞巣の画像診断アルゴリズムを確立して非侵襲的で高精度な【造影マイクロCTによる特発性肺線維症の診断と治療予測人工知能（AI）開発】につなげる革新的技術基盤の構築を行い、患者のunmetニーズを解決する挑戦的研究目的を持つものである。

Outline of Final Research Achievements

Although evaluation by conventional contrast-enhanced CT with X-ray contrast agents provides useful diagnostic information in clinical setting, the aim of this study is to identify lung disease-specific molecules using high-resolution and high-resolution radiographic images derived from contrast-enhanced micro-CT scans with gold nanoparticles as X-ray contrast agents. In this study, we were able to set micro-CT imaging to detect gold nanoparticle-bound lung-specific antibodies in the lung tissue by producing gold nanoparticle-bound lung-specific antibodies and intravenously administering them to living mice. In the future, administration of adjusted dose of gold nanoparticle-bound lung-specific antibody and adequate detection setting of gold nanoparticles bound to lung tissue by micro-CT might give micro-CT immunopathological diagnostic ability.

Academic Significance and Societal Importance of the Research Achievements

マイクロCTスキャンの臨床応用が期待される中、X線造影物質である金ナノ粒子標識抗原特異的抗体により組織内での標的抗原検出を可能にすることはマイクロCTスキャンに免疫病理学的診断能を付与することができ、侵襲的な検査を最小限にするという患者のアンメットニーズニーズの解消につながることが期待される。5~10年後の実臨床への応用を見据えた患者のunmetニーズを解消する挑戦的研究であり、本研究が得た研究基盤は、対象疾患に疾患特異的病理所見・疾患特異的抗原・その特異的抗体がある場合に応用でき、既存の学術の体系や方向を大きく変革・転換させる潜在性を有する。

Research Products

• [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] 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] Protective role of Nrf2 in zinc oxide nanoparticles-induced lung inflammation in female mice and sexual dimorphism in susceptibility (2022)
  • Author(s): Sehsah Radwa、Wu Wenting、Ichihara Sahoko、Hashimoto Naozumi、Zong Cai、Yamazaki Kyoka、Sato Harue、Itoh Ken、Yamamoto Masayuki、Elsayed Ahmed Ali、El-Bestar Soheir、Kamel Emily、Ichihara Gaku
  • Journal Title: Toxicology Letters Volume: 370 Pages: 24-34
  • DOI: 10.1016/j.toxlet.2022.09.004
  • Peer Reviewed / Int'l Joint Research
• [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] 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] 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] Oxytocin receptor is a promising therapeutic target of malignant mesothelioma (2021)
  • Author(s): Oxytocin receptor is a promising therapeutic target of malignant mesothelioma. Kodama Y, Tanaka I, Sato T, Hori K, Gen S, Morise M, Matsubara D, Sato M, Sekido Y, Hashimoto N.
  • Journal Title: Cancer science Volume: 112 Issue: 9 Pages: 3520-3532
  • DOI: 10.1111/cas.15025
  • Peer Reviewed / Open Access
• [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] Probable usual interstitial pneumonia pattern on chest CT: is it sufficient for a diagnosis of idiopathic pulmonary fibrosis? (2020)
  • Author(s): Fukihara Jun、Kondoh Yasuhiro、Brown Kevin K.、Kimura Tomoki、Kataoka Kensuke、Matsuda Toshiaki、Yamano Yasuhiko、Suzuki Atsushi、Furukawa Taiki、Sumikawa Hiromitsu、Takahashi Osamu、Johkoh Takeshi、Tanaka Tomonori、Fukuoka Junya、Hashimoto Naozumi、Hasegawa Yoshinori
  • Journal Title: European Respiratory Journal Volume: 55 Issue: 4 Pages: 1802465-1802465
  • DOI: 10.1183/13993003.02465-2018
  • Peer Reviewed / Int'l Joint Research
• [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
• [Book] 最新ガイドラインに基づく 呼吸器疾患 診療指針 2023-’24 第2章 「閉塞性肺疾患」閉塞性細気管支炎 (2022)
  • Author(s): 橋本 直純、長谷川好規
  • Total Pages: 472
  • Publisher: 総合医学社
  • ISBN: 4883789365