Comprehensive screening of miviroenvirinmental factors that affect liver fibrosis

• Project/Area Number: 19H03630
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• 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) ; 森川 賢一 北海道大学, 医学研究院, 准教授 (60384377) ; 大西 俊介 北海道大学, 医学研究院, 准教授 (10443475)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2021: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2020: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2019: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
• Keywords: 肝線維化 / 糖鎖修飾 / 内科

Outline of Research at the Start

本研究では、従来非可逆的とされていた肝硬変症の組織病態を積極的に修復する手法を開発するため、以下の研究を行う。(1)NAFLD/NASH, 肝硬変患者血清・組織検体を対象に、独自に構築した高速解析系による糖鎖修飾構造の網羅的解析、およびmicroRNAの網羅的探索、(2)同定された糖鎖構造に結合する抗体、小分子のハイ・スループットスクリーニング、(3)培養星細胞、間葉系幹細胞をもちいた肝線維化・修復に関連する成分分析、および(4)肝星細胞活性化により再構築される宿主因子と肝線維化、肝脂肪化機構の解析である。本研究の成果により肝硬変の組織病態を回復させる新規クラスの薬物・細胞療法が創出される。

Outline of Final Research Achievements

1. Comprehensive analysis of serum glycan modification structures revealed that the expression of A2F bisect glycans is upregulated in patients with advanced liver fibrosis in NASH. 2. We identified several carrier proteins of A2F bisect glycans including IgA. We identified several carrier proteins of A2F bisect glycans, including IgA. 3. Comprehensive analysis of micro RNAs associated with the activation of cultured hepatic astrocytes revealed that miR-29a, miR-449a, and other specific miRNAs were highly expressed in activated astrocytes and regulated the expression of proteins in the cytoskeleton, extracellular matrix, and chemotaxis-related pathways by pathway analysis. 4. serum Ang2 was significantly elevated in hepatitis C post-SVR carcinoma cases.

Academic Significance and Societal Importance of the Research Achievements

本研究の成果は、肝星細胞を標的とした細胞・薬物療法による肝線維化の組織修復を促進する治療法開発の基盤となる。肝疾患と糖鎖発現変動に関する研究は多数報告があるが、主要な全てのクラスの糖鎖の包括的な解析例はない。包括的糖鎖修飾解析の結果同定された特異修飾糖鎖は、非侵襲的診断マーカーとしてのみならず、糖鎖構造に対する抗体、結合小分子を大規模探索し、糖鎖修飾構造を標的とした分子標的治療が構築される可能性がある。

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] Tenofovir-disoproxil-fumarate modulates lipid metabolism via hepatic CD36/PPAR-alpha activation in hepatitis B virus infection (2021)
  • Author(s): Suzuki K, Suda G, Yamamoto Y, Furuya K, Baba M, Nakamura A, Miyoshi H, Kimura M, Maehara O, Yamada R, Kitagataya T, Yamamoto K, Shigesawa T, Nakamura A, Ohara M, Kawagishi N, Nakai M, Sho T, Natsuizaka M, Morikawa K, Ogawa K, Ohnishi S, Sakamoto N
  • Journal Title: J Gastroenterol. Volume: 56 Issue: 2 Pages: 168-180
  • DOI: 10.1007/s00535-020-01750-3
  • Peer Reviewed
• [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
• [Journal Article] Lenvatinib suppresses cancer stem-like cells in HCC by inhibiting FGFR1-3 signaling, but not FGFR4 signaling (2020)
  • Author(s): Shigesawa Taku、Morikawa Kenichi et al.
  • Journal Title: Carcinogenesis Volume: 42 Issue: 1 Pages: 58-69
  • DOI: 10.1093/carcin/bgaa049
  • Peer Reviewed / Open Access
• [Journal Article] Baseline angiopoietin‐2 and FGF19 levels predict treatment response in patients receiving multikinase inhibitors for hepatocellular carcinoma (2020)
  • Author(s): Shigesawa Taku、Suda Goki、Kimura Megumi、Shimazaki Tomoe、Maehara Osamu、Yamada Ren、Kitagataya Takashi、Suzuki Kazuharu、Nakamura Akihisa、Ohara Masatsugu、Umemura Machiko、Kawagishi Naoki、Nakai Masato、Sho Takuya、Natsuizaka Mitsuteru、Morikawa Kenichi、Ogawa Koji、Sakamoto Naoya
  • Journal Title: JGH Open Volume: 4 Issue: 5 Pages: 880-888
  • DOI: 10.1002/jgh3.12339
  • Peer Reviewed / Open Access
• [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] Quantifying Protein-Specific N-Glycome Profiles by Focused Protein and Immunoprecipitation Glycomics (2019)
  • Author(s): Kobayashi Takashi、Ogawa Koji、Furukawa Jun-ichi、Hanamatsu Hisatoshi、Hato Megumi、Yoshinaga Tomoyo、Morikawa Kenichi、Suda Goki、Sho Takuya、Nakai Masato、Higashino Kenichi、Numata Yoshito、Shinohara Yasuro、Sakamoto Naoya
  • Journal Title: Journal of Proteome Research Volume: 18 Issue: 8 Pages: 3133-3141
  • DOI: 10.1021/acs.jproteome.9b00232
  • NAID: 120006876288
  • Peer Reviewed