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Elucidation of anti-tumor mechanisms based on innate immune activation by PHD inhibitors and exploration of therapeutic targets

Research Project

Project/Area Number 20K07072
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 47040:Pharmacology-related
Research InstitutionOsaka Metropolitan University (2022)
Osaka City University (2020-2021)

Principal Investigator

Tomita Shuhei  大阪公立大学, 大学院医学研究科, 教授 (00263898)

Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2021: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2020: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
KeywordsHIF-PH阻害薬 / 低酸素 / 腫瘍免疫 / マクロファージ / 自然免疫 / がん微小環境 / PHD阻害薬
Outline of Research at the Start

本研究の目的は,PHD-HIFを基軸とした詳細な分子解析を通して、PHDiにより形質変換した腫瘍内Mφが抗腫瘍効果をもたらす機序を明らかにすることを第一目的とする。また、本研究の遂行は、現在の腫瘍免疫療法では難治性を示すがんに対して,自然免疫の活性化過程を標的とした新しい腫瘍免疫療法を創出する可能性を有しており、新規創薬研究分野にも繋がることが期待される。

Outline of Final Research Achievements

We found that HIF-PH inhibitors, which enhance HIF signaling, inhibit tumor growth and prolong survival by directly acting on the Mφ subpopulation within the tumor in an animal model of tumor transplantation. The aim of this study was to elucidate the mechanism by which PHD-HIF signaling activation promotes phagocytosis of Ly6CloMφ in tumors. As a result, we screened for the key relevant functional molecules and identified HIF-induced Phagocytosis Factor (HiPAF) as a candidate molecule that contributes to the promotion of phagocytosis induced in Ly6CloMφ in tumors by the activation of PHD-HIF signaling.

Academic Significance and Societal Importance of the Research Achievements

本研究の遂行は、現在の腫瘍免疫療法では難治性を示すがんに対して,自然免疫の活性化過程を標的とした新しい腫瘍免疫療法を創出する可能性を有しており、新規創薬研究分野にも繋がることが期待される。

Report

(4 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (16 results)

All 2022 2021 2020

All Journal Article (10 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 7 results,  Open Access: 5 results) Presentation (5 results) (of which Invited: 5 results) Book (1 results)

  • [Journal Article] An efficient CRISPR interference-based prediction method for synergistic/additive effects of novel combinations of anti-tuberculosis drugs2022

    • Author(s)
      Samukawa Noriaki、Yamaguchi Takehiro、Ozeki Yuriko、Matsumoto Sohkichi、Igarashi Masayuki、Kinoshita Naoko、Hatano Masaki、Tokudome Kentaro、Matsunaga Shinji、Tomita Shuhei
    • Journal Title

      Microbiology

      Volume: 168 Issue: 12 Pages: 1-11

    • DOI

      10.1099/mic.0.001285

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Partial endothelial-to-mesenchymal transition mediated by HIF-induced CD45 in neointima formation upon carotid artery ligation2022

    • Author(s)
      Yamashiro Yoshito、Ramirez Karina、Nagayama Kazuaki、Hattori Naoko、Liu Yu-Yu、Matsunaga Shinji、Tomita Shuhei、Kubota Yoshiaki、Yanagisawa Hiromi
    • Journal Title

      Cardiovascular Research

      Volume: 12 Issue: 7 Pages: 1606-1618

    • DOI

      10.1093/cvr/cvac190

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] HIF-PH阻害薬の使用における悪性腫瘍リスクについて2022

    • Author(s)
      松永慎司,冨田修平
    • Journal Title

      腎と透析

      Volume: 93 Pages: 236-239

    • Related Report
      2022 Annual Research Report
  • [Journal Article] 腫瘍血管形成から見た腫瘍組織微小環境2022

    • Author(s)
      松永慎司,冨田修平
    • Journal Title

      血管

      Volume: 45 Pages: 17-23

    • Related Report
      2022 Annual Research Report
  • [Journal Article] HIF‐1α controls palatal wound healing by regulating macrophage motility via S1P/S1P 1 signaling axis2021

    • Author(s)
      Hutami Islamy Rahma、Izawa Takashi、Khurel‐Ochir Tsendsuren、Sakamaki Takuma、Iwasa Akihiko、Tomita Shuhei、Tanaka Eiji
    • Journal Title

      Oral Diseases

      Volume: - Issue: 4 Pages: 1157-1169

    • DOI

      10.1111/odi.13856

    • Related Report
      2022 Annual Research Report 2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Partial endothelial-to-mesenchymal transition (EndMT) contributes to lumen re-organization after carotid artery ligation2021

    • Author(s)
      Yamashiro Yoshito、Ramirez Karina、Nagayama Kazuaki、Tomita Shuhei、Kubota Yoshiaki、Yanagisawa Hiromi
    • Journal Title

      bioRxiv

      Volume: -

    • DOI

      10.1101/2021.08.13.456319

    • Related Report
      2021 Research-status Report
  • [Journal Article] Effects of orally active hypoxia inducible factor alpha prolyl hydroxylase inhibitor, FG4592 on renal fibrogenic potential in mouse unilateral ureteral obstruction model2020

    • Author(s)
      Kabei Kazuya、Tateishi Yu、Shiota Masayuki、Osada-Oka Mayuko、Nishide Shunji、Uchida Junji、Nakatani Tatsuya、Matsunaga Shinji、Yamaguchi Takehiro、Tomita Shuhei、Miura Katsuyuki
    • Journal Title

      Journal of Pharmacological Sciences

      Volume: 142 Issue: 3 Pages: 93-100

    • DOI

      10.1016/j.jphs.2019.12.002

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Yohimbine ameliorates lipopolysaccharide-induced acute kidney injury in rats2020

    • Author(s)
      Shimokawa Takaomi、Yoneda Kozo、Yamagata Masayo、Hayashi Kohei、Tomita Shuhei
    • Journal Title

      European Journal of Pharmacology

      Volume: 871 Pages: 172917-172917

    • DOI

      10.1016/j.ejphar.2020.172917

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Prolyl-hydroxylase inhibitors reconstitute tumor blood vessels in mice2020

    • Author(s)
      Nishide Shunji、Uchida Junji、Matsunaga Shinji、Tokudome Kentaro、Yamaguchi Takehiro、Kabei Kazuya、Moriya Taiki、Miura Katsuyuki、Nakatani Tatsuya、Tomita Shuhei
    • Journal Title

      Journal of Pharmacological Sciences

      Volume: 143 Issue: 2 Pages: 122-126

    • DOI

      10.1016/j.jphs.2020.02.010

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Hypoxia inducible factor1α regulates Lipin1 differently in pre adipocytes and mature adipocytes2020

    • Author(s)
      Kihira Yoshitaka、Fujimura Yoshino、Tomita Shuhei、Tamaki Toshiaki、Sato Eiji
    • Journal Title

      Molecular Medicine Reports

      Volume: 22 Pages: 559-565

    • DOI

      10.3892/mmr.2020.11076

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Presentation] 酸素シグナルによる血管調節機構2022

    • Author(s)
      冨田修平
    • Organizer
      第51回日本心脈管作動物質学会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] eReviewシステムを用いた水平・垂直統合の取り組み2022

    • Author(s)
      冨田修平
    • Organizer
      第96回日本薬理学会年会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] HIF-PH阻害薬の悪性腫瘍への潜在的影響2021

    • Author(s)
      冨田修平
    • Organizer
      第64回日本腎臓学会
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] 低酸素シグナル制御ががん微小環境に及ぼす影響2021

    • Author(s)
      冨田修平
    • Organizer
      第94回日本生化学会
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] 低酸素シグナルのがん微小環境に及ぼす影響2020

    • Author(s)
      冨田修平
    • Organizer
      第20回日本抗加齢医学会
    • Related Report
      2020 Research-status Report
    • Invited
  • [Book] エース薬理学2020

    • Author(s)
      金井好克、安西尚彦、安藤 仁、浅井 聰、冨田修平
    • Total Pages
      303
    • Publisher
      南山堂
    • ISBN
      9784525140717
    • Related Report
      2020 Research-status Report

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Published: 2020-04-28   Modified: 2024-01-30  

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