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Pathophysiological Study on Aortopathy towards Prevention

Research Project

Project/Area Number 19K08535
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 53020:Cardiology-related
Research InstitutionThe University of Tokyo

Principal Investigator

MORISAKI TAKAYUKI  東京大学, 大学院新領域創成科学研究科, 特任教授 (30174410)

Co-Investigator(Kenkyū-buntansha) 森崎 裕子  公益財団法人榊原記念財団(臨床研究施設・研究部門), 臨床遺伝科医局, 科長 (40311451)
小原 收  公益財団法人かずさDNA研究所, その他部局等, 副所長 (20370926)
藤木 亮次  公益財団法人かずさDNA研究所, ゲノム事業推進部, 特任研究員 (40534516)
Project Period (FY) 2019-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywords病因遺伝子 / 循環器 / 遺伝性疾患 / 病態解析 / 大動脈
Outline of Research at the Start

本研究は、疾患コホートや未診断で病変を有する症例について遺伝学的解析により病因遺伝子変異バリアント検出法の評価を行い、また、RNA解析を併用して既存のDNA検査では同定困難な病因遺伝子変異バリアントの検出手法を確立して、病状発症予防に資する遺伝学的検査の改善を行い、あわせて、対象とすべき患者選別についての基準も検討する。さらに、高精度な新規病因遺伝子バリアント同定法や疾患コホート研究で得られたゲノム情報を活用して病型分類や病態修飾につながる遺伝型の同定についても検討する。以上により、遺伝性動脈疾患の病因解明をすすめ、致命的イベントの予防につながる診断法開発につながる新知見の獲得を目指す。

Outline of Final Research Achievements

Recent study revealed numbers of pathogenic genes for hereditary aortic diseases. However, many patients with these diseases due to unknown genetic cause had not been diagnosed or properly managed. This study aimed to improve genetic test and precise classification of aortic diseases, improving better medical care for them. We performed exome analysis of young patients including 43 cases with past history of aortic diseases as well as undiagnosed 304 cases with aortic diseases. As a result, we identified PMEPA1 gene as a new pathogenic gene for hereditary aortopathy by an international collaborative study with other researchers. Furthermore, we identified more aortic patients with PMEPA1 gene variants. Genetic and phenotypic study of these patients revealed characteristics of patients with this particular gene mutation. These results will help better medical care and prevention of aortic diseases.

Academic Significance and Societal Importance of the Research Achievements

本研究では、遺伝性動脈疾患の新規病因遺伝子PMEPA1が同定され、国内外の研究者との連携により、PMEPA1変異症例の表現型の検討が進んだ。既知遺伝子変異を有する遺伝性動脈疾患との表現型比較も進めることができ、遺伝性動脈疾患患者について、より高精度な診断にむけての学術基盤と情報基盤を整えることができた。結果として遺伝性動脈疾患の診断、治療につながる知見が明らかとなり、致死的な疾患イベントにつながりやすい大動脈疾患の克服にむけた成果につなげることができ、診療の高度化が可能となり、社会的意義は大きい。

Report

(6 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (15 results)

All 2023 2022 2021 2020 2019

All Journal Article (12 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 12 results,  Open Access: 6 results) Presentation (3 results) (of which Int'l Joint Research: 2 results)

  • [Journal Article] JCS/JSCVS/JATS/JSVS 2020 Guideline on Diagnosis and Treatment of Aortic Aneurysm and Aortic Dissection2023

    • Author(s)
      Ogino Hitoshi、Iida Osamu、Akutsu Koichi、、Ueda Tatsuo、et al. on behalf of the Japanese Circulation Society, the Japanese Society for Cardiovascular Surgery, the Japanese Association for Thoracic Surgery and the Japanese Society for Vascular Surgery Joint Working Group
    • Journal Title

      Circulation Journal

      Volume: 87 Issue: 10 Pages: 1410-1621

    • DOI

      10.1253/circj.CJ-22-0794

    • ISSN
      1346-9843, 1347-4820
    • Year and Date
      2023-09-25
    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Aortic Dissection and a Previously Unreported ACTA2 Missense Variant Mutation in a Young Patient: A Case Report2023

    • Author(s)
      Marutani Satoshi、Nishino Takako、Shimokawa Osamu、Pooh Ritsuko K.、Morisaki Hiroko、Inamura Noburu
    • Journal Title

      Pediatric and Developmental Pathology

      Volume: 26 Issue: 5 Pages: 494-498

    • DOI

      10.1177/10935266231194701

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Computational and Experimental Analyses for Pathogenicity Prediction of ACVRL1 Missense Variants in Hereditary Hemorrhagic Telangiectasia2023

    • Author(s)
      Iwasa Toru、Urasaki Akihiro、Kakihana Yuki、Nagata-Akaho Nami、Harada Yukihiro、Takeda Soichi、Kawamura Teruhisa、Shiraishi Isao、Kurosaki Kenichi、Morisaki Hiroko、Yamada Osamu、Nakagawa Osamu
    • Journal Title

      Journal of Clinical Medicine

      Volume: 12 Issue: 15 Pages: 5002-5002

    • DOI

      10.3390/jcm12155002

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Detection of trait-associated structural variations using short read sequencing.2023

    • Author(s)
      Shunichi Kosugi, Yoichiro Kamatani, Katsutoshi Harada, Kohei Tomizuka, Yukihide Momozawa, Takayuki Morisaki, The Biobank Japan Project, and Chikashi Terao
    • Journal Title

      Cell Genomics

      Volume: 3 Issue: 6 Pages: 100328-100328

    • DOI

      10.1016/j.xgen.2023.100328

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Genetic association analysis of 77,539 genomes reveals rare disease etiologies2023

    • Author(s)
      Greene D; GenomEnglResCons; Pirri D, Frudd K, Sackey E, Al-Owain M, Giese APJ, Ramzan K, Riaz S, Yamanaka I, Boeckx N, Thys C, Gelb BD, Brennan P, Hartill V, Harvengt J, Kosho T, Mansour S, Masuno M, Ohata T, Stewart H, Taibah K, Turner CLS, Imtiaz F, Riazuddin S, Morisaki T, Ostergaard P, Loeys BL, Morisaki H, et al
    • Journal Title

      Nature Medicine

      Volume: 29 Issue: 3 Pages: 679-688

    • DOI

      10.1038/s41591-023-02211-z

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Long-term durability of a reimplantation valve-sparing aortic root replacement can be expected in both Marfan syndrome and Loeys-Dietz syndrome2022

    • Author(s)
      Seike Yoshimasa、Yokawa Koki、Koizumi Shigeki、Masada Kenta、Inoue Yosuke、Morisaki Hiroko、Morisaki Takayuki、Sasaki Hiroaki、Matsuda Hitoshi
    • Journal Title

      European Journal of Cardio-Thoracic Surgery

      Volume: 61 Issue: 6 Pages: 1318-1325

    • DOI

      10.1093/ejcts/ezac050

    • Related Report
      2022 Research-status Report
    • Peer Reviewed
  • [Journal Article] Loeys-Dietz Cardiomyopathy? Long-term Follow-up After Onset of Acute Decompensated Heart Failure2022

    • Author(s)
      Yokota Takashi、Koiwa Hiroaki、Matsushima Shouji、Tsujinaga Shingo、Naya Masanao、Morisaki Hiroko、Morisaki Takayuki
    • Journal Title

      Canadian Journal of Cardiology

      Volume: 38 Issue: 3 Pages: 389-391

    • DOI

      10.1016/j.cjca.2021.11.010

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Mouse Model of Loeys?Dietz Syndrome Shows Elevated Susceptibility to Periodontitis via Alterations in Transforming Growth Factor-Beta Signaling2021

    • Author(s)
      Yamada Satoru、Tsushima Kenichiro、Kinoshita Masaki、Sakashita Hiromi、Kajikawa Tetsuhiro、Fujihara Chiharu、Yuan Hang、Suzuki Shigeki、Morisaki Takayuki、Murakami Shinya
    • Journal Title

      Frontiers in Physiology

      Volume: 12 Pages: 1-13

    • DOI

      10.3389/fphys.2021.715687

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Clinical and molecular features of 66 patients with musculocontractural Ehlers?Danlos syndrome caused by pathogenic variants in <i>CHST14</i> (mcEDS-<i>CHST14</i>)2021

    • Author(s)
      Minatogawa Mari、... 、Miyake Noriko、Kosho Tomoki
    • Journal Title

      Journal of Medical Genetics

      Volume: Epub ahead of print Issue: 9 Pages: 107623-107623

    • DOI

      10.1136/jmedgenet-2020-107623

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Surgical Outcome and Histological Differences between Individuals with <i>TGFBR1</i> and <i>TGFBR2</i> Mutations in Loeys-Dietz Syndrome2021

    • Author(s)
      Seike Yoshimasa、Matsuda Hitoshi、Ishibashi-Ueda Hatsue、Morisaki Hiroko、Morisaki Takayuki、Minatoya Kenji、Ogino Hitoshi
    • Journal Title

      Annals of Thoracic and Cardiovascular Surgery

      Volume: 27 Issue: 1 Pages: 56-63

    • DOI

      10.5761/atcs.oa.20-00223

    • NAID

      130007988475

    • ISSN
      1341-1098, 2186-1005
    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Discovery of novel biomarkers for atherosclerotic aortic aneurysm through proteomics-based assessment of disease progression2020

    • Author(s)
      Yagi Hiroaki、Nishigori Mitsuhiro、Murakami Yusuke、Osaki Tsukasa、Muto Sayaka、Iba Yutaka、Minatoya Kenji、Ikeda Yoshihiko、Ishibashi-Ueda Hatsue、Morisaki Takayuki、Ogino Hitoshi、Tanaka Hiroshi、Sasaki Hiroaki、Matsuda Hitoshi、Minamino Naoto
    • Journal Title

      Scientific Reports

      Volume: 10 Issue: 1 Pages: 6429-6429

    • DOI

      10.1038/s41598-020-63229-8

    • Related Report
      2020 Research-status Report 2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Histologic differences between the ascending and descending aortas in young adults with fibrillin-1 mutations2020

    • Author(s)
      Seike Yoshimasa、Minatoya Kenji、Matsuda Hitoshi、Ishibashi-Ueda Hatsue、Morisaki Hiroko、Morisaki Takayuki、Kobayashi Junjiro
    • Journal Title

      The Journal of Thoracic and Cardiovascular Surgery

      Volume: 159 Issue: 4 Pages: 1214-1220.e1

    • DOI

      10.1016/j.jtcvs.2019.01.126

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Presentation] PMEPA1 mutation found in 3 Japanese families with systemic connective tissue disorders2023

    • Author(s)
      Hiroko Morisaki, Itaru Yamanaka, Takako Ohata, Tomoki Kosho, Keiko Wakui, Mitsuo Masuno, Tetsuro Watabe, Yukihide Watanabe, Takayuki Morisaki
    • Organizer
      European Society of Human Genetics
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] PMEPA1 mutation found in 3 Japanese families with MFS/LDS like features2023

    • Author(s)
      Hiroko Morisaki, Itaru Yamanaka, Takako Ohata, Tomoki Kosho, Keiko Wakui, Mitsuo Masuno, Tetsuro Watabe, Yukihide Watanabe, Takayuki Morisaki
    • Organizer
      Human Genetics Asia 2023
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Pulmonary complications and CT findings of vascular Ehlers-Danlos syndrome.2019

    • Author(s)
      Hiroko Morisaki, Hitoshi Ogino, Kenji Minatoya, Takayuki Morisaki
    • Organizer
      American Society of Human Genetics Annual Meeting (ASHG2020)
    • Related Report
      2019 Research-status Report

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Published: 2019-04-18   Modified: 2025-01-30  

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