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Functional analysis of fibrosis-promoting molecules specifically expressed in myofibroblasts and laying the foundations for their drug discovery applications.

Research Project

Project/Area Number 20H03383
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
Research InstitutionKyushu University

Principal Investigator

Michio Nakaya  九州大学, 薬学研究院, 准教授 (80464387)

Co-Investigator(Kenkyū-buntansha) 小迫 英尊  徳島大学, 先端酵素学研究所, 教授 (10291171)
Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000)
Fiscal Year 2022: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000)
Fiscal Year 2021: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000)
Fiscal Year 2020: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
Keywords筋線維芽細胞 / 線維化
Outline of Research at the Start

線維化とは、コラーゲン等の細胞外マトリックスが過剰に産生された状態である。この線維化は、炎症を契機にして、常在性の線維芽細胞等が分化した、『筋線維芽細胞』という細胞群によって実行される。線維化は様々な臓器の病態を悪化させるが、未だ決定的な線維化治療薬はなく、革新的な線維化治療法、薬の開発が望まれている。
我々は、筋線維芽細胞に特異的に発現し、筋線維芽細胞によるコラーゲン等の線維化関連因子の産生を促進する分子を見出した。そこで本研究では、この分子による線維化促進機序を解明し、新規線維化治療法の開発基盤を構築することを目指す。

Outline of Final Research Achievements

Non-alcoholic steatohepatitis (NASH), which has been on the rise in recent years, is a condition of increased fibrosis resulting from inflammation caused by excessive fat accumulation. Fibrosis leads to loss of function due to hardening and eventually to serious conditions such as cirrhosis and liver cancer. However, there is currently no definitive treatment for NASH. We therefore looked for targets that could lead to the development of fibrosis-targeted NASH therapies.
We found a protein that promote fibrosis is only expressed during fibrosis and is specifically expressed in myofibroblasts, the cells responsible for fibrosis.In addition, fibrosis of the liver during NASH was significantly reduced in knockout mice of this protein.

Academic Significance and Societal Importance of the Research Achievements

今回、新たに肝臓の線維化を促進するタンパク質を同定することができた。同定したタンパク質は、マウスおよびヒト共に線維化した肝臓において、活性化した肝星細胞に特異的に発現する。また、正常時の肝臓にはほとんど発現しない。従って、このタンパク質は、非アルコール性脂肪肝炎時やウイルス感染時などの肝臓の線維化治療の標的分子になる可能性が考えられる。今後はこのタンパク質がコラーゲンなどの産生を促進するメカニズムを詳細に解析する予定である。

Report

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

    (27 results)

All 2023 2022 2021 2020 Other

All Journal Article (10 results) (of which Peer Reviewed: 10 results,  Open Access: 9 results) Presentation (9 results) (of which Int'l Joint Research: 1 results,  Invited: 7 results) Book (4 results) Remarks (3 results) Patent(Industrial Property Rights) (1 results) (of which Overseas: 1 results)

  • [Journal Article] VGLL3 is a mechanosensitive protein that promotes cardiac fibrosis through liquid-liquid phase separation2023

    • Author(s)
      Horii Yuma、Matsuda Shoichi、Toyota Chikashi、Morinaga Takumi、Nakaya Takeo、Tsuchiya Soken、Ohmuraya Masaki、Hironaka Takanori、Yoshiki Ryo、Kasai Kotaro、Yamauchi Yuto、Takizawa Noburo、Nagasaka Akiomi、Tanaka Akira、Kosako Hidetaka、Nakaya Michio
    • Journal Title

      Nature Communications

      Volume: 14 Issue: 1 Pages: 1-19

    • DOI

      10.1038/s41467-023-36189-6

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The well-developed actin cytoskeleton and Cthrc1 expression by actin-binding protein drebrin in myofibroblasts promote cardiac and hepatic fibrosis.2023

    • Author(s)
      Takanori Hironaka, Noburo Takizawa, Yuto Yamauchi, Yuma Horii, and Michio Nakaya
    • Journal Title

      J. Biol. Chem.

      Volume: 299(3) Issue: 3 Pages: 102934-102934

    • DOI

      10.1016/j.jbc.2023.102934

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] GRK5‐mediated inflammation and fibrosis exert cardioprotective effects during the acute phase of myocardial infarction2023

    • Author(s)
      Nagasaka Akiomi、Terawaki Tsuyoshi、Noda Makoto、Takashima Miyuki、Fujino Mika、Yamauchi Yuto、Arawaka Shigeki、Kato Takeo、Nakaya Michio
    • Journal Title

      FEBS Open Bio

      Volume: 13 Issue: 2 Pages: 380-391

    • DOI

      10.1002/2211-5463.13551

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] GPRC5B promotes collagen production in myofibroblasts2021

    • Author(s)
      Takizawa Noburo、Hironaka Takanori、Mae Kyosuke、Ueno Tomoyuki、Horii Yuma、Nagasaka Akiomi、Nakaya Michio
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 561 Pages: 180-186

    • DOI

      10.1016/j.bbrc.2021.05.035

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Increased Expression of Heparan Sulfate 6-O-Sulfotransferase-2 Promotes Collagen Production in Cardiac Myofibroblasts2021

    • Author(s)
      Kasai Kotaro、Horii Yuma、Hironaka Takanori、Mae Kyosuke、Ueno Tomoyuki、Nagasaka Akiomi、Nakaya Michio
    • Journal Title

      BPB Reports

      Volume: 4 Issue: 3 Pages: 85-91

    • DOI

      10.1248/bpbreports.4.3_85

    • NAID

      130008049615

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Alteration of circadian machinery in monocytes underlies chronic kidney disease-associated cardiac inflammation and fibrosis2021

    • Author(s)
      Yoshida Yuya、Matsunaga Naoya、Nakao Takaharu、Hamamura Kengo、Kondo Hideaki、Ide Tomomi、Tsutsui Hiroyuki、Tsuruta Akito、Kurogi Masayuki、Nakaya Michio、Kurose Hitoshi、Koyanagi Satoru、Ohdo Shigehiro
    • Journal Title

      Nature Communications

      Volume: 12 Issue: 1 Pages: 2783-2783

    • DOI

      10.1038/s41467-021-23050-x

    • Related Report
      2021 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] Myofibroblast phagocytic cutaneous mucinosis: phagocytosis of mucinous substances by myofibroblasts in a distinctive cutaneous mucinosis: A case report2020

    • Author(s)
      Nakaya T, Kamiya K, Nakaya M, Tsuji K, Niki T, Ohtsuki M, Tanaka A
    • Journal Title

      Medicine (Baltimore).

      Volume: 99(29) Issue: 29 Pages: e20867-e20867

    • DOI

      10.1097/md.0000000000020867

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [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] 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
  • [Presentation] Identification of a mechanosensitive protein that promotes cardiac fibrosis2023

    • Author(s)
      Michio Nakaya
    • Organizer
      International symposium on mechanobiology for Human Health
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 機械的刺激を感知する新規線維化促進分子の同定2023

    • Author(s)
      仲矢道雄
    • Organizer
      2022年度徳島大学先端酵素学研究所共同利用・共同研究拠点成果報告会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] 新規線維化促進因子の同定2022

    • Author(s)
      仲矢道雄
    • Organizer
      第95回日本生化学会大会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] 機械的刺激による組織の線維化2022

    • Author(s)
      仲矢道雄
    • Organizer
      日本機械学会第34回バイオエンジニアリング講演会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] 新規線維化促進因子の同定2022

    • Author(s)
      仲矢道雄
    • Organizer
      第54回日本結合組織学会学術大会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] 新規線維化因子の探索2021

    • Author(s)
      仲矢道雄
    • Organizer
      第二回細胞死コロキウム
    • Related Report
      2021 Annual Research Report
  • [Presentation] 細胞死を起点とした線維化研究2021

    • Author(s)
      仲矢道雄
    • Organizer
      日本Cell Death学会第29回学術集会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] 細胞死を起点とした組織線維化研究2020

    • Author(s)
      仲矢道雄
    • Organizer
      第一回細胞死コロキウム
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] 筋線維芽細胞のマーカー受容体の探索2020

    • Author(s)
      仲矢道雄 、黒瀬等
    • Organizer
      第52回日本結合組織学会
    • Related Report
      2020 Annual Research Report
  • [Book] 臨床免疫・アレルギー科 Vol.77(2)2022

    • Author(s)
      山内佑斗,堀井雄真,仲矢道雄
    • Total Pages
      7
    • Publisher
      科学評論社
    • Related Report
      2022 Annual Research Report
  • [Book] 「筋線維芽細胞と線維化」 臨床免疫・アレルギー科2022

    • Author(s)
      山内佑斗, 堀井雄真, 仲矢道雄
    • Publisher
      科学評論社
    • Related Report
      2021 Annual Research Report
  • [Book] 実験医学 増刊号「Fibrosis」「死細胞貪食と線維化」p88-932020

    • Author(s)
      仲矢道雄,堀井雄真,黒瀬等
    • Total Pages
      6
    • Publisher
      羊土社
    • Related Report
      2020 Annual Research Report
  • [Book] 脳神経内科 「G蛋白質共役受容体キナーゼの生理機能」2020

    • Author(s)
      廣中貴則, 瀧澤宣郎,黒瀬等,仲矢道雄
    • Total Pages
      7
    • Publisher
      科学評論社
    • Related Report
      2020 Annual Research Report
  • [Remarks] 九州大学大学院薬学研究院 疾患制御学分野

    • URL

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

    • Related Report
      2022 Annual Research Report
  • [Remarks] 九州大学薬学研究院疾患制御学分野

    • URL

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

    • Related Report
      2021 Annual Research Report
  • [Remarks] 九州大学薬学研究院薬効安全性学分野

    • URL

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

    • Related Report
      2020 Annual Research Report
  • [Patent(Industrial Property Rights)] 線維化疾患の治療又は予防のための医薬組成物2023

    • Inventor(s)
      仲矢道雄
    • Industrial Property Rights Holder
      九州大学
    • Industrial Property Rights Type
      特許
    • Filing Date
      2023
    • Related Report
      2022 Annual Research Report
    • Overseas

URL: 

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

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