Application of anti-HMGB1 m Ab in intracerebral hemorrhage-induced brain injury in common marmoset and elucidation of HMGB1 translocation mechanism

• Project/Area Number: 20K17930
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56010:Neurosurgery-related
• Research Institution: Okayama University
• Principal Investigator: 王 登莉 岡山大学, 医歯薬学域, 助教 (40815693)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2023: ¥390,000 (Direct Cost: ¥300,000、Indirect Cost: ¥90,000); Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: 抗体治療 / 脳出血 / マーモセットモデル / HMGB1 / コラゲナーゼ / 炎症

Outline of Research at the Start

脳出血は、有効な治療法がない重症疾病である。このため、脳出血は患者と介護者のQOLに大きな影響を与える。HMGB1は細胞核由来の活性物質であり、細胞外空間で炎症性サイトカイン様活性を示す。我々はこれまでに、ラット抗HMGB1 抗体の末梢投与がラット脳出血によって引き起こされる脳障害を顕著に改善することを示した。しかしながら、脳出血過程におけるHMGB1の核から細胞外へのトランスロケ ーション機構は、未だ明らかではない。本研究では、その過程を明らかにし、さらに、ヒト化 抗HMGB1抗体のマーモセット出血脳障害モデルにおける有効性を検証する。その結果は、前臨床POCレベルを上昇させると期待できる。

Outline of Annual Research Achievements

本研究では、霊長類マーモセットを用いた脳出血モデルで、ヒト化抗HMGB1抗体の効果を確認し、血腫吸収メカニズムの解明を目指しました。研究成果は既に論文として出版されています。また、in vitro実験により、血液成分が血管内皮細胞および神経細胞におけるHMGB1のtranslocationを誘発し、抗HMGB1抗体がこのtranslocationを抑制する効果が確認されました。第二の論文はすでに投稿済みです。

Research Products

• [Journal Article] Perineural Treatment with High Mobility Group Box-1 Monoclonal Antibody Prevents Initiation of Pain-Like Behaviors in Female Mice with Trigeminal Neuropathy (2024)
  • Author(s): Ma Simeng、Nakamura Yoki、Kochi Takahiro、Uemoto Suzuna、Hisaoka-Nakashima Kazue、Wang Dengli、Liu Keyue、Wake Hidenori、Nishibori Masahiro、Morioka Norimitsu
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 47 Issue: 1 Pages: 221-226
  • DOI: 10.1248/bpb.b23-00729
  • ISSN: 0918-6158, 1347-5215
  • Year and Date: 2024-01-20
  • Peer Reviewed
• [Journal Article] Protective effects of an anti-4-HNE monoclonal antibody against liver injury and lethality of endotoxemia in mice (2023)
  • Author(s): Qiao Handong、Morioka Yuta、Wang Dengli、Liu Keyue、Gao Shangze、Wake Hidenori、Ousaka Daiki、Teshigawara Kiyoshi、Mori Shuji、Nishibori Masahiro
  • Journal Title: European Journal of Pharmacology Volume: 950 Pages: 175702-175702
  • DOI: 10.1016/j.ejphar.2023.175702
  • Peer Reviewed
• [Journal Article] Treatment of Marmoset Intracerebral Hemorrhage with Humanized Anti-HMGB1 mAb (2022)
  • Author(s): Dengli Wang, Daiki Ousaka, Handong Qiao, Ziyi Wang, Kun Zhao, Shangze Gao, Keyue Liu, Kiyoshi Teshigawara, Kenzo Takada, Masahiro Nishibori
  • Journal Title: Cells Volume: 11 Issue: 19 Pages: 1-22
  • DOI: 10.3390/cells11192970
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Histamine induced high mobility group box-1 release from vascular endothelial cells through H1 receptor (2022)
  • Author(s): Shangze Gao, Keyue Liu, Wenhan Ku, Dengli Wang, Hidenori Wake, Handong Qiao, Kiyoshi Teshigawara, Masahiro Nishibori
  • Journal Title: Front Immunol . Volume: 13 Pages: 1-15
  • DOI: 10.3389/fimmu.2022.930683
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] High-mobility group box 1-mediated hippocampal microglial activation induces cognitive impairment in mice with neuropathic pain (2022)
  • Author(s): Kazue Hisaoka-Nakashima, Kazuto Ohata, Natsuki Yoshimoto, Shintarou Tokuda, Nanako Yoshii, Yoki Nakamura, Dengli Wang, Keyue Liu, Hidenori Wake, Takayuki Yoshida, Yukio Ago, Kouichi Hashimoto, Masahiro Nishibori, Norimitsu Morioka
  • Journal Title: Exp Neurol . Volume: 355 Pages: 114146-114146
  • DOI: 10.1016/j.expneurol.2022.114146
  • Peer Reviewed
• [Journal Article] High Mobility Group Box-1 and Blood Brain Barrier Disruption (2020)
  • Author(s): Nishibori Masahiro、Wang Dengli、Ousaka Daiki、Wake Hidenori
  • Journal Title: Cells Volume: 9 Issue: 12 Pages: 2650-2650
  • DOI: 10.3390/cells9122650
  • Peer Reviewed / Open Access
• [Journal Article] Corticosterone Induces HMGB1 Release in Primary Cultured Rat Cortical Astrocytes: Involvement of Pannexin-1 and P2X7 Receptor-Dependent Mechanisms (2020)
  • Author(s): Hisaoka-Nakashima Kazue、Azuma Honami、Ishikawa Fumina、Nakamura Yoki、Wang Dengli、Liu Keyue、Wake Hidenori、Nishibori Masahiro、Nakata Yoshihiro、Morioka Norimitsu
  • Journal Title: Cells Volume: 9 Issue: 5 Pages: 1068-1068
  • DOI: 10.3390/cells9051068
  • Peer Reviewed / Open Access
• [Journal Article] Histidine-Rich Glycoprotein Inhibits High-Mobility Group Box-1-Mediated Pathways in Vascular Endothelial Cells through CLEC-1A (2020)
  • Author(s): Gao Shangze、Wake Hidenori、Sakaguchi Masakiyo、Wang Dengli、Takahashi Youhei、Teshigawara Kiyoshi、Zhong Hui、Mori Shuji、Liu Keyue、Takahashi Hideo、Nishibori Masahiro
  • Journal Title: iScience Volume: 23 Issue: 6 Pages: 101180-101180
  • DOI: 10.1016/j.isci.2020.101180
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Treatment of intracerebral hemorrhage with humanized a-HMGB1 mAb in non-human primate brain (2021)
  • Author(s): 王登莉
  • Organizer: 第139回日本薬理学会近畿部会
• [Presentation] The therapeutic effects of humanized anti-HMGB1 mAb on intracerebral hemorrhage-induced brain injury in marmoset. (2021)
  • Author(s): 王登莉
  • Organizer: 第44回日本神経科学学会
• [Presentation] 抗HMGB1抗体による脳内出血の治療: 霊長類マーモセットを用いた検討 (2021)
  • Author(s): 王登莉
  • Organizer: 第36回創薬・薬理フォーラム（岡山）
• [Presentation] Treatment of intracerebral hemorrhage with humanized a-HMGB1 mAb in non-human primate brain (2021)
  • Author(s): 王登莉
  • Organizer: 第95回日本薬理学会年会
• [Presentation] 脳出血時のミクログリアにおけるHMGB1トランスロケーションに関する検討 (2020)
  • Author(s): 小橋和馬、長谷川玲央、松川力嗣, 劉克約, 喬寒棟, 和氣秀徳，逢坂大樹，王登莉，西堀正洋
  • Organizer: 創薬・薬理フォーラム岡山
• [Presentation] HMGB1 Translocation in Neurons after Ischemic Insult: Subcellular Localization in Mitochondria and Peroxisomes (2020)
  • Author(s): Dengli Wang, Keyue Liu, Kiyoshi Teshigawara, Hidenori Wake, and Masahiro Nishibori
  • Organizer: 第137回日本薬理学会近畿部会
• [Presentation] The therapeutic effects of anti-HMGB1 mAb on subdural hematoma-induced brain injury in rats (2020)
  • Author(s): Dengli Wang, Shangze Gao, Keyue Liu, Hidenori Wake,Kiyoshi Teshigawara, Shuji Mori and Masahiro Nishibori
  • Organizer: 第43回日本神経科学学会
• [Remarks] Research Map (王 登莉)
  • URL: https://researchmap.jp/okayaku2017