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Analysis of the roles and interaction of various cells including myofibroblasts involved in fibrosis after myocardial infarction

Research Project

Project/Area Number 17H01525
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Pharmacology in pharmacy
Research InstitutionKyushu University

Principal Investigator

KUROSE HITOSHI  九州大学, 薬学研究院, 教授 (10183039)

Co-Investigator(Kenkyū-buntansha) 長坂 明臣  九州大学, 薬学研究院, 助教 (10723877)
仲矢 道雄  九州大学, 薬学研究院, 准教授 (80464387)
Project Period (FY) 2017-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥41,600,000 (Direct Cost: ¥32,000,000、Indirect Cost: ¥9,600,000)
Fiscal Year 2020: ¥8,060,000 (Direct Cost: ¥6,200,000、Indirect Cost: ¥1,860,000)
Fiscal Year 2019: ¥9,620,000 (Direct Cost: ¥7,400,000、Indirect Cost: ¥2,220,000)
Fiscal Year 2018: ¥9,620,000 (Direct Cost: ¥7,400,000、Indirect Cost: ¥2,220,000)
Fiscal Year 2017: ¥14,300,000 (Direct Cost: ¥11,000,000、Indirect Cost: ¥3,300,000)
Keywords薬理学 / シグナル伝達 / 循環器・高血圧 / 免疫学 / 細胞外微小環境 / 内皮細胞 / 炎症 / 免疫細胞 / 心筋梗塞 / Gタンパク質選択的受容体 / 阻害薬 / バイアス型阻害作用 / プロトン感知性受容体 / G12ファミリー / 脂質
Outline of Final Research Achievements

Lesion of the heart after myocardial infarction is compensated by collagen. However, excess deposition of collagen is called as fibrosis that is a target of the treatment. Collagen is produced by myofibroblasts. Myocardial infarction results in death of cells at ischemic area, which causes inflammation. Inflammation is induced in parallel to progression of fibrosis that is controlled by myofibroblasts. Then, mechanistic analysis of inflammation is thought to be important to treat fibrosis. In addition to inflammation, concentration of proton is known to increase under the ischemic conditions. However, the physiological meaning has not been analyzed. In this project, importance of infiltration of leukocytes to ischemic area, the roles of proton-sensing receptor in myocardial infarction and receptor-mediated intracellular signaling were studied. Then, the association of these responses with fibrosis was evaluated.

Academic Significance and Societal Importance of the Research Achievements

(1)筋線維芽細胞への分化を制御する因子として、細胞骨格に作用するドレブリンを見出した。ドレブリンの効果はSmad3およびRho/MRTF/SRF経路を介していた。(2)ロイコトリエンB4受容体が梗塞後の白血球の浸潤に大きな役割を持つこと、炎症を抑制すると線維化や心機能の低下が抑制されることを示した。(3)内皮細胞のpH感知性受容体は活性化されると接着因子の発現を増加させ、好中球の浸潤を促進し炎症を誘起させた。炎症が抑制されると線維化も抑制されたことから、炎症の抑制が線維化の進行を阻害すること、梗塞後の炎症にかかわる分子が線維化治療薬のターゲットになることを示した。

Report

(5 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Annual Research Report
  • 2018 Annual Research Report
  • 2017 Annual Research Report
  • Research Products

    (47 results)

All 2021 2020 2019 2018 2017 Other

All Int'l Joint Research (5 results) Journal Article (13 results) (of which Int'l Joint Research: 6 results,  Peer Reviewed: 13 results,  Open Access: 9 results,  Acknowledgement Compliant: 2 results) Presentation (26 results) (of which Int'l Joint Research: 8 results,  Invited: 6 results) Book (1 results) Remarks (2 results)

  • [Int'l Joint Research] Seoul National University(韓国)

    • Related Report
      2020 Annual Research Report
  • [Int'l Joint Research] University of Strasbourg(フランス)

    • Related Report
      2020 Annual Research Report
  • [Int'l Joint Research] Seoul National University(韓国)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] University of Strasbourg(フランス)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] Seoul National University(韓国)

    • Related Report
      2018 Annual Research Report
  • [Journal Article] Efferocytosis during myocardial infarction.2020

    • Author(s)
      Yoshimura C, Nagasaka A, Kurose H, Nakaya M.
    • Journal Title

      J Biochem.

      Volume: 68 Issue: 1 Pages: 1-6

    • DOI

      10.1093/jb/mvaa051

    • NAID

      40022279056

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Gα12/13 signaling in metabolic diseases.2020

    • Author(s)
      Yang YM, Kuen DS, Chung Y, Kurose H, Kim SG.
    • Journal Title

      Exp Mol Med

      Volume: 52 Issue: 6 Pages: 896-910

    • DOI

      10.1038/s12276-020-0454-5

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Leukotriene B4 receptor 1 exacerbates inflammation following myocardial infarction.2020

    • Author(s)
      Horii Y, Nakaya M, Ohara H, Nishihara H, Watari K, Nagasaka A, Nakaya T, Sugiura Y, Okuno T, Koga T, Tanaka A, Yokomizo T, Kurose H.
    • Journal Title

      FASEB Journal

      Volume: 印刷中 Issue: 6 Pages: 8749-8763

    • DOI

      10.1096/fj.202000041r

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Drebrin is induced during myofibroblast differentiation and enhances the production of fibrosis-related genes.2020

    • Author(s)
      Hironaka T, Ueno T, Mae K, Yoshimura C, Morinaga T, Horii Y, Nagasaka A, Kurose H, Nakaya M.
    • Journal Title

      Biochem Biophys Res Commun.

      Volume: 529 Issue: 2 Pages: 224-230

    • DOI

      10.1016/j.bbrc.2020.05.110

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Therapeutic Targets for the Treatment of Cardiac Fibrosis and Cancer: Focusing on TGF-β Signaling2020

    • Author(s)
      Parichatikanond W, Luangmonkong T, Mangmool S, Kurose H.
    • Journal Title

      Frontiers in Cardiovascular Medicine

      Volume: 7 Pages: 34-34

    • DOI

      10.3389/fcvm.2020.00034

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The roles of inhibitory Smads in cancer progression2019

    • Author(s)
      Hironaka T, Ohba Y, Kurose H, Nakaya M.
    • Journal Title

      Nihon Yakurigaku Zasshi

      Volume: 154 Pages: 44-44

    • NAID

      130007678393

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Therapeutic Targets for Treatment of Heart Failure: Focus on GRKs and β-Arrestins Affecting βAR Signaling.2018

    • Author(s)
      Mangmool S, Parichatikanond W, Kurose H.
    • Journal Title

      Front Pharmacol.

      Volume: 9 Pages: 1336-1336

    • DOI

      10.3389/fphar.2018.01336

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Gα12 ablation exacerbates liver steatosis and obesity by suppressing USP22/SIRT1-regulated mitochondrial respiration.2018

    • Author(s)
      Kim TH, Yang YM, Han CY, Koo JH, Oh H, Kim SS, You BH, Choi YH, Park TS, Lee CH, Kurose H, Noureddin M, Seki E, Wan YY, Choi CS, Kim SG.
    • Journal Title

      J Clin Invest.

      Volume: 128 Issue: 12 Pages: 5587-5602

    • DOI

      10.1172/jci97831

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Complex formation between the vasopressin 1b receptor, β-arrestin-2, and the μ-opioid receptor underlies morphine tolerance2018

    • Author(s)
      Koshimizu TA, et al.
    • Journal Title

      Nat Neurosci

      Volume: Epub ahead of print Issue: 6 Pages: 820-833

    • DOI

      10.1038/s41593-018-0144-y

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Cardiac myofibroblast engulfment of dead cells facilitates recovery after myocardial infarction.2017

    • Author(s)
      Michio Nakaya,Kenji Watari,Mitsuru Tajima,Takeo Nakaya,Shoichi Matsuda,Hiroki Ohara,Hiroaki Nishihara,Hiroshi Yamaguchi,Akiko Hashimoto,Mitsuho Nishida,Akiomi Nagasaka,Yuma Horii,Hiroki Ono,Gentaro Iribe,Ryuji Inoue,Makoto Tsuda,Kazuhide Inoue,Akira Tanaka,Masahiko Kuroda,Shigekazu Nagata,Hitoshi Kurose
    • Journal Title

      Journal of Clinical Investigation

      Volume: 127 Issue: 1 Pages: 383-401

    • DOI

      10.1172/jci83822

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Dioxin-induced increase in leukotriene B4 biosynthesis through the aryl hydrocarbon receptor and its relevance to hepatotoxicity owing to neutrophil infiltration2017

    • Author(s)
      Takeda Tomoki、Komiya Yukiko、Koga Takayuki、Ishida Takumi、Ishii Yuji、Kikuta Yasushi、Nakaya Michio、Kurose Hitoshi、Yokomizo Takehiko、Shimizu Takao、Uchi Hiroshi、Furue Masutaka、Yamada Hideyuki
    • Journal Title

      Journal of Biological Chemistry

      Volume: 292 Issue: 25 Pages: 10586-10599

    • DOI

      10.1074/jbc.m116.764332

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The proton-sensing G protein-coupled receptor T-cell death-associated gene 8 (TDAG8) shows cardioprotective effects against myocardial infarction.2017

    • Author(s)
      Nagasaka A, Mogi C, Ono H, Nishi T, Horii Y, Ohba Y, Sato K, Nakaya M, Okajima F, Kurose H.
    • Journal Title

      Sci Rep.

      Volume: 7 Issue: 1 Pages: 7812-7812

    • DOI

      10.1038/s41598-017-07573-2

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] β-Adrenergic Receptor and Insulin Resistance in the Heart.2017

    • Author(s)
      Mangmool S, Denkaew T, Parichatikanond W, Kurose H.
    • Journal Title

      Biomol Ther (Seoul).

      Volume: 25 Issue: 1 Pages: 44-56

    • DOI

      10.4062/biomolther.2016.128

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Presentation] β-Blocker Signaling in Cardiac Myocytes.2021

    • Author(s)
      Hitoshi Kurose
    • Organizer
      第85回日本循環器学会学術集会
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] G protein selectivity of antagonists.2020

    • Author(s)
      Hitoshi Kurose
    • Organizer
      NIPS International Meeting on Cardiovascular Physiology 2020
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] プロトン感知性GPCR(GPR4)に着目した心筋梗塞時におけるpH低下の生理的影響の解析2019

    • Author(s)
      荻野瑠星、伊藤峻太、渡健治、長坂明臣、仲矢道雄、黒瀬等
    • Organizer
      生体機能と創薬シンポジウム2019
    • Related Report
      2019 Annual Research Report
  • [Presentation] Smad6を安定化させ、BMPシグナルを抑制するユビキチンリガーゼの同定2019

    • Author(s)
      廣中貴則、大場悠生、長坂明臣、仲矢道雄、黒瀬等
    • Organizer
      次世代を担う創薬・医療薬理シンポジウム2019
    • Related Report
      2019 Annual Research Report
  • [Presentation] Smad6を安定化し、BMPシグナルを抑制するユビキチンリガーゼの同定2019

    • Author(s)
      廣中貴則、大場悠生、長坂明臣、仲矢道雄、黒瀬等
    • Organizer
      第92回日本生化学会大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 心筋梗塞後の応答におけるGタンパク質共役型受容体の役割2019

    • Author(s)
      黒瀬 等
    • Organizer
      第48回 日本心脈管作動物質学会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] 心筋梗塞時におけるプロトン感知性GPCR(GPR4)の役割解析2019

    • Author(s)
      伊藤峻太、萩原柾、渡健治、長坂明臣、仲矢道雄、黒瀬等
    • Organizer
      第92回 日本薬理学会年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 心筋梗塞時の死細胞除去のメカニズム2018

    • Author(s)
      黒瀬 等
    • Organizer
      第5回 iHFフォーラム
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] 心筋梗塞時におけるプロトン感知性GPCR(GPR4)の役割解析2018

    • Author(s)
      伊藤峻太、萩原柾、渡健治、長坂明臣、仲矢道雄、黒瀬等
    • Organizer
      第71回 日本薬理学会西南部会
    • Related Report
      2018 Annual Research Report
  • [Presentation] BLT1は心筋梗塞時における炎症を悪化させる2018

    • Author(s)
      堀井雄真、仲矢道雄、西原弘朗、大原広貴、渡健治、長坂明臣、黒瀬等
    • Organizer
      次世代を担う創薬・医療薬理シンポジウム2018
    • Related Report
      2018 Annual Research Report
  • [Presentation] Construction of Gα13-selective designer GPCR2018

    • Author(s)
      Masaki Hagiwara, Akiomi Nagasaka, Michio Nakaya, Hitoshi Kurose
    • Organizer
      Translational Research Metabolic and Inflammatory Diseases and Cancer, Seoul
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Role of proton-sensing GPCR (GPR4) in myocardial infarction2018

    • Author(s)
      Shunta Ito, Masaki Hagiwara, Kenji Watari, Toshihide Nishi, Akiomi Nagasaka, Michio Nakaya, Hitoshi Kurose
    • Organizer
      Translational Research Metabolic and Inflammatory Diseases and Cancer, Seoul
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Smad6の安定化を介してBMPシグナルを抑制するubiquitin ligaseの同定2018

    • Author(s)
      大場悠生、仲矢道雄、廣中貴則、小迫英尊、長坂明臣、黒瀬等
    • Organizer
      第17回 次世代を担う若手ファーマ・バイオフォーラム2018
    • Related Report
      2018 Annual Research Report
  • [Presentation] 心筋梗塞時におけるプロトン感知性GPCR(GPR4)の役割解析2018

    • Author(s)
      伊藤竣太、萩原柾、渡健治、長坂明臣、仲矢道雄、黒瀬等
    • Organizer
      生体機能と創薬シンポジウム 2018
    • Related Report
      2018 Annual Research Report
  • [Presentation] BLT1 deteriorates inflammation following myocardial infarction2018

    • Author(s)
      Yuma Horii, Michio Nakaya, Hiroaki Nishihara, Hiroki Ohara, Kenji Watari, Akiomi Nagasaka, Hitoshi Kurose
    • Organizer
      18th World Congress of Basic and Clinical Pharmacology (IUPHAR)
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 心疾患のシグナリング解析2018

    • Author(s)
      黒瀬等
    • Organizer
      第30回 蔵王カンファランス
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] 心筋梗塞後に出現する筋線維芽細胞の起源2017

    • Author(s)
      黒瀬等、仲矢道雄、渡健治
    • Organizer
      第16回生命科学研究会
    • Related Report
      2017 Annual Research Report
  • [Presentation] BLT1は心筋梗塞時における炎症を悪化させる2017

    • Author(s)
      堀井雄真、仲矢道雄、西原弘朗、大原広貴、渡健治、長坂明臣、黒瀬等
    • Organizer
      次世代を担う創薬・医療薬理シンポジウム2017
    • Related Report
      2017 Annual Research Report
  • [Presentation] 心筋梗塞におけるpH低下のin vivoイメージング2017

    • Author(s)
      萩原柾、長坂明臣、伊藤峻太、仲矢道雄、浅沼大祐、廣瀬謙造、黒瀬等
    • Organizer
      生体機能と創薬シンポジウム2017
    • Related Report
      2017 Annual Research Report
  • [Presentation] GRK2は、Smad6を介してBMPによる骨芽細胞の分化を促進する2017

    • Author(s)
      大場悠生、仲矢道雄、小迫英尊、長坂明臣、黒瀬等
    • Organizer
      第16回 次世代を担う若手ファーマ・バイオフォーラム2017
    • Related Report
      2017 Annual Research Report
  • [Presentation] pH imaging at infarct area in myocardial infarction2017

    • Author(s)
      萩原柾、長坂明臣、伊藤峻太、仲矢道雄、浅沼大祐、廣瀬謙造、黒瀬等
    • Organizer
      69th Korean Society of Pharmacology
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Cardiac Fibrosis2017

    • Author(s)
      黒瀬等
    • Organizer
      69th Korean Society of Pharmacology
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] The role of GPR4 in myocardial infarction2017

    • Author(s)
      伊藤峻太、萩原柾、渡健治、長坂明臣、仲矢道雄、黒瀬等
    • Organizer
      69th Korean Society of Pharmacology
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] BLT1は心筋梗塞時における炎症を悪化させる2017

    • Author(s)
      堀井 雄真、仲矢 道雄、西原 弘朗、大原 広貴、渡 健治、長坂 明臣、黒瀬 等
    • Organizer
      第70回日本薬理学会西南部会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 心筋梗塞時におけるプロトン感知性受容体(GPR4)の役割解析2017

    • Author(s)
      伊藤峻太、萩原柾、渡健治、長坂明臣、仲矢道雄、黒瀬等
    • Organizer
      第34回日本薬学会九州支部大会
    • Related Report
      2017 Annual Research Report
  • [Presentation] BLT1は心筋梗塞時における炎症を悪化させる2017

    • Author(s)
      堀井雄真、仲矢道雄、西原弘朗、大原広貴、渡健治、長坂明臣、黒瀬等
    • Organizer
      酸素生物学・ダイイングコード合同若手会議
    • Related Report
      2017 Annual Research Report
  • [Book] 標準薬理学 第8版2021

    • Author(s)
      黒瀬 等
    • Publisher
      医学書院
    • ISBN
      9784260041638
    • Related Report
      2020 Annual Research Report
  • [Remarks]

    • URL

      http://chudoku.phar.kyushu-u.ac.jp/

    • Related Report
      2018 Annual Research Report
  • [Remarks] 九州大学薬学部薬効安全性学分野ホームページ

    • URL

      http://chudoku.phar.kyushu-u.ac.jp/

    • Related Report
      2017 Annual Research Report

URL: 

Published: 2017-04-28   Modified: 2022-01-27  

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