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Versican Is Crucial for the Initiation of Cardiovascular Lumen Development

Research Project

Project/Area Number 16H05305
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Cardiovascular medicine
Research InstitutionKeio University

Principal Investigator

Makino Shinji  慶應義塾大学, 保健管理センター(日吉), 准教授 (20306707)

Co-Investigator(Kenkyū-buntansha) 藤田 深里  神奈川大学, 理学部, 助教 (60633550)
渡辺 秀人  愛知医科大学, 付置研究所, 教授 (90240514)
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000)
Fiscal Year 2018: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2017: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2016: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
Keywords心臓・血管腔形成 / 先天性心疾患 / 小型魚類 / 血管形成 / 心臓奇形 / 順遺伝学 / 血管腔形成 / 循環器・高血圧 / 再生医学 / 発生・分化 / 心室腔形成
Outline of Final Research Achievements

Versican is an evolutionary conserved extracellular matrix proteoglycan. We performed ENU mutagenesis screening to identify medaka mutants with defects in embryonic cardiovascular development. In this study, we described a recessive point mutation in the versican resulting in reduced versican protein expression. The homozygous mutant showed termination of cardiac development at the linear heart tube stage and exhibited absence of cardiac looping, a constricted outflow tract, and no cardiac jelly. Additionally, progenitor cells did not migrate from the secondary source towards the arterial pole of the linear heart tube, resulting in a constricted outflow tract. Furthermore, mutants lacked blood flow and vascular lumen despite continuous peristaltic heartbeats. These results enhance our understanding of the mechanistic basis of versican, and this mutant represents a novel genetic model to investigate the mechanisms of vascular tubulogenesis.

Academic Significance and Societal Importance of the Research Achievements

心筋・血管系を構成する遺伝子では95%以上のDNA配列がメダカとヒトとの間で保存されていることより、メダカを用いて得られた心室・血管形成の知見は、ヒトでも共通することが予想された。心血管系の複雑な三次元構造は、異なる前駆細胞の移動によって達成されることが確認され、これらの異常により先天性の心血管障害が発症することが証明された。メダカ変異体を用いて可視化した観察によって、中隔欠損症と肺高血圧症が合併する機序を前駆細胞の移動の点から解明した。この機序は、動脈硬化やがんの転移時の血管形成に対する創薬のターゲットにもなる可能性が高く、新しい概念からの有効な薬の開発への成果も今後期待できる。

Report

(4 results)
  • 2019 Final Research Report ( PDF )
  • 2018 Annual Research Report
  • 2017 Annual Research Report
  • 2016 Annual Research Report
  • Research Products

    (19 results)

All 2019 2018 2017 2015

All Journal Article (10 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 10 results,  Open Access: 7 results) Presentation (7 results) (of which Int'l Joint Research: 3 results) Book (2 results)

  • [Journal Article] A tale of two sisters with hypertrophic cardiomyopathy and recurrent embolism: When is the optimal timing of the intervention for left atrial appendage?2019

    • Author(s)
      Kimura Mai、Kohno Takashi、Makino Shinji、Okuda Shigeo、Nawata Kan、Yanagisawa Ryo、Kojima Hidenori、Nishiyama Takahiko、Aizawa Yoshiyasu、Yuasa Shinsuke、Murata Mitsushige、Maekawa Yuichiro、Okamoto Kazuma、Shimizu Hideyuki、Fukuda Keiichi
    • Journal Title

      Heart & Lung

      Volume: 48 Issue: 3 Pages: 198-200

    • DOI

      10.1016/j.hrtlng.2018.08.010

    • Related Report
      2018 Annual Research Report 2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Versican is crucial for the initiation of cardiovascular lumen development in medaka (Oryzias latipes)2019

    • Author(s)
      Mittal Nishant、Yoon Sung Han、Enomoto Hirokazu、Hiroshi Miyama、Shimizu Atsushi、Kawakami Atsushi、Fujita Misato、Watanabe Hideto、Fukuda Keiichi、Makino Shinji
    • Journal Title

      Scientific Reports

      Volume: 9 Issue: 1

    • DOI

      10.1038/s41598-019-45851-3

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Perturbation of the titin/MURF1 signaling complex is associated with hypertrophic cardiomyopathy in a fish model and in human patients2019

    • Author(s)
      Higashikuse Yuta、Mittal Nishant、Arimura Takuro、Yoon Sung Han、Oda Mayumi、Enomoto Hirokazu、Kaneda Ruri、Hattori Fumiyuki、Suzuki Takeshi、Kawakami Atsushi、Gasch Alexander、Furukawa Tetsushi、Labeit Siegfried、Fukuda Keiichi、Kimura Akinori、Makino Shinji
    • Journal Title

      Disease Models & Mechanisms

      Volume: 12 Pages: 041103-041103

    • DOI

      10.1242/dmm.041103

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Mice lacking fat storage-inducing transmembrane protein 2 show improved profiles upon pressure overload-induced heart failure2019

    • Author(s)
      Nishihama Natsumi、Nagayama Takahiro、Makino Shinji、Koishi Ryuta
    • Journal Title

      Heliyon

      Volume: 5 Issue: 3 Pages: e01292-e01292

    • DOI

      10.1016/j.heliyon.2019.e01292

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Selective modulation of local linkages between active transcription and oxidative demethylation activity shapes cardiomyocyte-specific gene-body epigenetic status in mice.2018

    • Author(s)
      Oda M, Wakabayashi S, Ari Wijetunga N, Yuasa S, Enomoto H, Kaneda R, Yoon SH, Mittal N, Jing Q, Suzuki M, Greally JM, Fukuda K, Makino S
    • Journal Title

      BMC genomics

      Volume: 19 Issue: 1 Pages: 349-349

    • DOI

      10.1186/s12864-018-4752-4

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Identification of Fat Storage-Inducing Transmembrane Proteins 1 and 2 as Putative Therapeutic Targets for Heart Failure by Integrated Analysis of Proteome and Transcriptome2018

    • Author(s)
      Nishihama Natsumi
    • Journal Title

      Journal of Proteomics & Bioinformatics

      Volume: 11 Issue: 09 Pages: 173-182

    • DOI

      10.4172/jpb.1000484

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 13年間における当大学での自動体外式除細動器の使用経験2018

    • Author(s)
      清奈帆美、和井内由充子、牧野伸司、河邊博史
    • Journal Title

      CAMPUS HEALTH

      Volume: 55(1) Pages: 195-197

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 心臓震盪(しんぞうしんとう)とは2017

    • Author(s)
      牧野伸司、和井内由充子
    • Journal Title

      慶應保健研究

      Volume: 35 Pages: 7-11

    • NAID

      40021385146

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] 大学生における先天性心疾患の管理状況2017

    • Author(s)
      和井内由充子、牧野伸司
    • Journal Title

      慶應保健研究

      Volume: 35 Pages: 29-35

    • NAID

      40021385184

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Host stromal versican is essential for cancer-associated fibroblast function to inhibit cancer growth.2015

    • Author(s)
      Fanhchaksai K, Okada F, Nagai N, Pothacharoen P, Kongtawelert P, Hatano S, Makino S, Nakamura T and Watanabe H
    • Journal Title

      International Journal of Cancer

      Volume: 138 Issue: 3 Pages: 630-641

    • DOI

      10.1002/ijc.29804

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Perturbation of the titin/MURF1 signaling complex is associated with hypertrophic cardiomyopathy in a fish model2019

    • Author(s)
      Higashikuse Y, Mittal N, Arimura T, Yoon SH, Oda M, Enomoto H, Kaneda R, Hattori F, Suzuki T, Kawakami A, Gasch A, Furukawa T, Labeit S, Fukuda K, Kimura A, Makino S.
    • Organizer
      International Zebrafish Conference
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Usefulness of School Cardiac Checkup in University Students2019

    • Author(s)
      Yumiko Wainai, Shinji Makino
    • Organizer
      日本循環器学会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 大学生における先天性心疾患の管理状況2018

    • Author(s)
      牧野伸司、和井内由充子、武田彩乃、畔上達彦、広瀬寛、西村知泰、横山裕一、河邊博史、森正明
    • Organizer
      日本内科学会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Versican is crucial for the initiation of cardiovascular lumen development in Medaka fish2018

    • Author(s)
      Shinji Makino, Nishant Mittal
    • Organizer
      Weinstein Cardiovascular Development and Regeneration Conference
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Dilated Cardiomyopathy (DCM)-linked Heat shock protein 60 (HSP60) mutations cause upregulation of ROS and autophagy through mitochondrial dysfunction.2017

    • Author(s)
      Shinji Makino
    • Organizer
      日本循環器学会
    • Related Report
      2016 Annual Research Report
  • [Presentation] 若年女子の軽度腎機能低下と出生時体重の関連2017

    • Author(s)
      武田彩乃、神田武志、広瀬寛、西村知泰、牧野伸司、森正明
    • Organizer
      日本内科学会
    • Related Report
      2016 Annual Research Report
  • [Presentation] DCM-linked HSP60 mutations cause upregulation of ROS and autophagy through mitochondrial dysfunction.2017

    • Author(s)
      Shinji Makino
    • Organizer
      Weinstein cardiovascular development meeting
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Book] 保健衛生(遺伝と疾病)2018

    • Author(s)
      牧野伸司
    • Total Pages
      228
    • Publisher
      慶應義塾大学出版会株式会社
    • Related Report
      2017 Annual Research Report
  • [Book] 保健衛生(遺伝と疾病)2018

    • Author(s)
      牧野伸司
    • Total Pages
      6
    • Publisher
      慶應義塾大学保健管理センター編
    • Related Report
      2016 Annual Research Report

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Published: 2016-04-21   Modified: 2021-02-19  

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