Targeting the glycosylated structure of liver tissue stromal proteins to form the basis for glycosylation drug discovery for liver fibrosis.

• Project/Area Number: 20K21592
• 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: Hokkaido University
• Principal Investigator: Sakamoto Naoya 北海道大学, 医学研究院, 教授 (10334418)
• Co-Investigator(Kenkyū-buntansha): 須田 剛生 北海道大学, 大学病院, 特任助教 (20447460) ; 古川 潤一 北海道大学, 医学研究院, 特任准教授 (30374193)
• Project Period (FY): 2020-07-30 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2021: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2020: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
• Keywords: 肝線維化

Outline of Research at the Start

本研究で申請者らは、肝線維化の組織病態に関連する間質蛋白と糖鎖修飾構造の解析を進め、分子標的治療薬開発の開発を目指す。本研究の遂行により、従来対症療法に留まっていた肝硬変、さらにNASHに対し、組織病態を積極的に改善させ、肝発癌リスクを低下させる新規クラスの薬物，核酸、細胞療法が創出される可能性がある。本研究では、肝線維化、肝発癌やC型ウイルス肝炎患者のDAA治療後症例の血清を対象とした糖鎖修飾構造の包括解析を行い、病態の進行、軽快に関連する蛋白、分子を探索する。同定された候補分子については、化合物ライブラリー等を用いた阻害活性物質の探索を進め、治療標的としての解析も進める。

Outline of Final Research Achievements

We performed a comprehensive analysis of serum and cellular glycosylation in order to develop cellular and pharmacological therapies targeting hepatic astrocytes to promote tissue repair of liver fibrosis, and obtained the following results: 1. Comprehensive analysis of micro RNAs associated with the activation of cultured hepatic astrocytes showed that miR-29a, miR-449a, and other specific miRNAs were associated.

Academic Significance and Societal Importance of the Research Achievements

肝線維化に関連する患者血清中の複合糖鎖解析とその機能解析から抗体薬等の開発の可能性を見いだした。また、血清分泌型microRNAの網羅的探索、MSC培養液から肝線維化抑制効果を担う蛋白、小分子の探索など、多くの治療標的を同定し、創薬につながる基盤を形成することができた。
今後、同定された候補miRNAの制御遺伝子のpashway解析、さらにanti-miRNAによる発現抑制が星細胞活性化抑制、肝線維化抑制効果をもたらすか否かを検証する。

Research Products

• [Journal Article] The potential of soluble CD14 in discriminating nonalcoholic steatohepatitis from nonalcoholic fatty liver disease (2022)
  • Author(s): Nakamura Akihisa、Yamamoto Koji、Sakamoto Naoya et al.
  • Journal Title: Hepatology Research Volume: - Issue: 6 Pages: 508-521
  • DOI: 10.1111/hepr.13757
  • Peer Reviewed
• [Journal Article] Baseline serum angiopoietin-2 and VEGF levels predict the deterioration of the liver functional reserve during lenvatinib treatment for hepatocellular carcinoma (2021)
  • Author(s): Shigesawa T, Suda G, Kimura M, Maehara O, Tokuchi Y, Kubo A, Yamada R, Furuya K, Baba M, Kitagataya T, Suzuki K, Ohara M, Kawagishi N, Nakai M, Sho T, Natsuizaka M, Morikawa K, Ogawa K, Sakamoto N.
  • Journal Title: PLoS One Volume: 16(3) Issue: 3 Pages: e0247728-e0247728
  • DOI: 10.1371/journal.pone.0247728
  • Peer Reviewed / Open Access
• [Journal Article] Baseline elevated serum angiopoietin-2 predicts long-term non-regression of liver fibrosis after direct-acting antiviral therapy for hepatitis C (2021)
  • Author(s): Kawagishi Naoki、Suda Goki、Kimura Megumi、Maehara Osamu、Yamada Ren、Tokuchi Yoshimasa、Kubo Akinori、Kitagataya Takashi、Shigesawa Taku、Suzuki Kazuharu、Ohara Masatsugu、Nakai Masato、Sho Takuya、Natsuizaka Mitsuteru、Morikawa Kenichi、Ogawa Koji、Kudo Yusuke、Nishida Mutsumi、Sakamoto Naoya
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 9207-9207
  • DOI: 10.1038/s41598-021-88632-7
  • Peer Reviewed / Open Access
• [Journal Article] Possible correlation between increased serum free carnitine levels and increased skeletal muscle mass following HCV eradication by direct acting antivirals (2021)
  • Author(s): Tokuchi Yoshimasa、Suda Goki、et al.,
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 16616-16616
  • DOI: 10.1038/s41598-021-96203-z
  • Peer Reviewed / Open Access
• [Journal Article] Frequency and Characteristics of Overestimated Renal Function in Japanese Patients with Chronic Liver Disease and Its Relation to Sarcopenia (2021)
  • Author(s): Yoshida Sonoe、Suda Goki、et al.,
  • Journal Title: Nutrients Volume: 13 Issue: 7 Pages: 2415-2415
  • DOI: 10.3390/nu13072415
  • Peer Reviewed / Open Access
• [Journal Article] FGFR2 maintains cancer cell differentiation via AKT signaling in esophageal squamous cell carcinoma (2021)
  • Author(s): Maehara Osamu、Suda Goki、Natsuizaka Mitsuteru、Shigesawa Taku、Kanbe Gouki、Kimura Megumi、Sugiyama Masaya、Mizokami Masashi、Nakai Masato、Sho Takuya、Morikawa Kenichi、Ogawa Koji、Ohashi Shinya、Kagawa Shingo、Kinugasa Hideaki、Naganuma Seiji、Okubo Naoto、Ohnishi Shunsuke、Takeda Hiroshi、Sakamoto Naoya
  • Journal Title: Cancer Biology & Therapy Volume: 22 Issue: 5-6 Pages: 372-380
  • DOI: 10.1080/15384047.2021.1939638
  • Peer Reviewed
• [Journal Article] Tri-antennary tri-sialylated mono-fucosylated glycan of alpha-1 antitrypsin as a non-invasive biomarker for non-alcoholic steatohepatitis: a novel glycobiomarker for non-alcoholic steatohepatitis (2020)
  • Author(s): Ogawa Koji、Kobayashi Takashi、Furukawa Jun-ichi、Hanamatsu Hisatoshi、Nakamura Akihisa、Suzuki Kazuharu、Kawagishi Naoki、Ohara Masatsugu、Umemura Machiko、Nakai Masato、Sho Takuya、Suda Goki、Morikawa Kenichi、Sakamoto Naoya et al.
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 321-321
  • DOI: 10.1038/s41598-019-56947-1
  • Peer Reviewed / Open Access
• [Journal Article] High serum angiopoietin‐2 level predicts non‐regression of liver stiffness measurement‐based liver fibrosis stage after direct‐acting antiviral therapy for hepatitis C (2020)
  • Author(s): Kawagishi Naoki、Suda Goki、Kimura Megumi、Maehara Osamu、Shimazaki Tomoe、Yamada Ren、Kitagataya Takashi、Shigesawa Taku、Suzuki Kazuharu、Nakamura Akihisa、Ohara Masatsugu、Umemura Machiko、Nakai Masato、Sho Takuya、Natsuizaka Mitsuteru、Morikawa Kenichi、Ogawa Koji、Kudo Yusuke、Nishida Mutsumi、Sakamoto Naoya
  • Journal Title: Hepatology Research Volume: in press Issue: 6 Pages: 671-681
  • DOI: 10.1111/hepr.13490
  • Peer Reviewed