• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

Elucidation of the Mechanism of Cardiac Pathology Caused by Mutations in the Splicing Regulator Rbm20

Research Project

Project/Area Number 20K08467
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 53020:Cardiology-related
Research InstitutionTokyo Medical and Dental University

Principal Investigator

Ihara Kensuke  東京医科歯科大学, 大学院医歯学総合研究科, 特任助教 (50770210)

Project Period (FY) 2020-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2020: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
KeywordsRBM20 / 選択的スプライシング / 拡張型心筋症 / 心房細動 / RNA代謝 / RNA顆粒 / Rbm20
Outline of Research at the Start

拡張型心筋症(DCM)は心不全の重要な基礎心疾患の一つであるが病態メカニズムの解明が進んでおらず、医療技術の進歩によってもいまだ根本的治療は心移植しかない難病である。近年、DCM原因遺伝子の解析が進み、原因遺伝子毎に重症度が異なることが報告されてきた。なかでも重症DCMを呈するとされるRBM20遺伝子に関して、患者型変異を導入した遺伝子変異マウスで心機能を解析したところ、ヒトと同様に重篤なDCMを呈することが分かった。本研究では同マウスを使用して、なぜRBM20がより重篤なDCMを呈するのかそのメカニズムを明らかにするため、次世代シークエンスを用いて解析を行う。

Outline of Final Research Achievements

In this study, RNA immunoprecipitation and co-immunoprecipitation experiments were conducted on the mutant RBM20, revealing that the mutant RBM20 binds to RNA in the cytoplasm and interacts with proteins involved in RNA degradation. Additionally, when a mouse model specifically expressing the mutant RBM20 in the atria was created, it was found that the mutant RBM20 exhibited pathogenicity without affecting splicing functionality. This suggests that dilated cardiomyopathy caused by RBM20 mutations may contribute to the disease pathology through mechanisms different from the previously thought splicing regulation abnormalities, particularly implicating abnormalities in RNA metabolism due to the presence of mutant RBM20 in the cytoplasm.

Academic Significance and Societal Importance of the Research Achievements

本研究により変異型RBM20の不整脈原性への寄与が明らかとなり、また、変異型RBM20は細胞質においてP-bodyと相互作用を来しRNA代謝に影響を及ぼしている可能性が示唆された。変異型RBM20はRBM20変異による心病態において、新たな治療標的となりうることが示された。
また、近年RBM20遺伝子は一般人口においても心房細動発症に関与する遺伝子として報告されてきており、本研究結果は拡張型心筋症病態解明にとどまらず、脳梗塞の主要な原因となり社会的損失が大きく、やはり新たな治療法開発が望まれている心房細動に関しても全く新たな病態解明・治療法開発に波及効果をもたらす可能性が期待される。

Report

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

    (27 results)

All 2024 2023 2022 2021 2020

All Journal Article (10 results) (of which Peer Reviewed: 10 results,  Open Access: 7 results) Presentation (17 results)

  • [Journal Article] Sacubitril/valsartan attenuates atrial conduction disturbance and electrophysiological heterogeneity with ameliorating fibrosis in mice2024

    • Author(s)
      Iwamiya Satoshi、Ihara Kensuke、Furukawa Tetsushi、Sasano Tetsuo
    • Journal Title

      Frontiers in Cardiovascular Medicine

      Volume: 11 Pages: 1341601-1341601

    • DOI

      10.3389/fcvm.2024.1341601

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Risk stratification of atrial fibrillation and stroke using single nucleotide polymorphism and circulating biomarkers2023

    • Author(s)
      Sasano Tetsuo、Ihara Kensuke、Tanaka Toshihiro、Furukawa Tetsushi
    • Journal Title

      PLOS ONE

      Volume: 18 Issue: 10 Pages: e0292118-e0292118

    • DOI

      10.1371/journal.pone.0292118

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Genetic risk score of cerebral infarction in atrial fibrillation genome‐wide association study2023

    • Author(s)
      Ebana Yusuke、Liu Lian、Ihara Kensuke、Abe Keiko、Terao Chikashi、Kamatani Yoichiro、Sasano Tetsuo、Furukawa Tetsushi
    • Journal Title

      European Journal of Clinical Investigation

      Volume: 53 Issue: 12

    • DOI

      10.1111/eci.14084

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Extracellular Vesicles for the Treatment of Atrial Fibrillation.2023

    • Author(s)
      Ihara K and Sasano T.
    • Journal Title

      JACC Clin Electrophysiol.

      Volume: 9 Issue: 2 Pages: 159-160

    • DOI

      10.1016/j.jacep.2023.01.007

    • Related Report
      2022 Research-status Report
    • Peer Reviewed
  • [Journal Article] I536T variant of RBM20 affects splicing of cardiac structural proteins that are causative for developing dilated cardiomyopathy.2022

    • Author(s)
      Yamamoto T, Sano R, Miura A, Imasaka M, Naito Y, Nishiguchi M, Ihara K, Otani N, Kominato Y, Ohmuraya M, Karangi H, Nishio H.
    • Journal Title

      J. Mol. Med.

      Volume: 100 Issue: 12 Pages: 1741-1754

    • DOI

      10.1007/s00109-022-02262-8

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Gene therapy to terminate tachyarrhythmias.2022

    • Author(s)
      Kawajiri K, Ihara K, Sasano T.
    • Journal Title

      Expert Rev Cardiovasc Ther.

      Volume: 20 Issue: 6 Pages: 431-442

    • DOI

      10.1080/14779072.2022.2085686

    • Related Report
      2022 Research-status Report
    • Peer Reviewed
  • [Journal Article] Systemic DNA/RNA heteroduplex oligonucleotide administration for regulating the gene expression of dorsal root ganglion and sciatic nerve.2022

    • Author(s)
      Kaburagi H, Nagata T, Enomoto M, Hirai T, Ohyagi M, Ihara K, Yoshida-Tanaka K, Ebihara S, Asada K, Yokoyama H, Okawa A, Yokota T.
    • Journal Title

      Mol. Ther. Nucleic. Acids.

      Volume: 6 Pages: 910-919

    • DOI

      10.1016/j.omtn.2022.05.006

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Effect of the recording condition on the quality of a single-lead electrocardiogram.2022

    • Author(s)
      Hamada S, Sasaki K, Kito H, Tooyama Y, Ihara K, Aoyagi E, Ichimura N, Tohda S, Sasano T.
    • Journal Title

      Heart Vessel.

      Volume: 37 Issue: 6 Pages: 1010-1026

    • DOI

      10.1007/s00380-021-01991-z

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Role of Inflammation in the Pathogenesis of Atrial Fibrillation2022

    • Author(s)
      Ihara Kensuke、Sasano Tetsuo
    • Journal Title

      Frontiers in Physiology

      Volume: 13 Pages: 862164-862164

    • DOI

      10.3389/fphys.2022.862164

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] A missense mutation in the RSRSP stretch of Rbm20 causes dilated cardiomyopathy and atrial fibrillation in mice2020

    • Author(s)
      Ihara K, Sasano T, Hiraoka Y, Togo-Ohno M, Soejima Y, Sawabe M, Tsuchiya M, Ogawa H, Furukawa T, Kuroyanagi H
    • Journal Title

      Scientific Reports

      Volume: 10 Issue: 1 Pages: 17894-17894

    • DOI

      10.1038/s41598-020-74800-8

    • NAID

      120007031666

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Cytoplasmic RBM20 Granules Cause Atrial Arrhythmogenicity in Mice.2024

    • Author(s)
      Ihara K、Iwamiya S、Hiraoka Y、Kuroyanagi H、Furukawa T、Sasano T.
    • Organizer
      The 88th Annual Scientific Meeting of the Japanese Circulation Society.
    • Related Report
      2023 Annual Research Report
  • [Presentation] The Electrophysiological Properties against Atrial Arrhythmogenicity in Murine Heart Failure Treated with Sacubitril/Valsartan.2024

    • Author(s)
      Iwamiya S、Ihara K、Furukawa T、Sasano T.
    • Organizer
      The 88th Annual Scientific Meeting of the Japanese Circulation Society.
    • Related Report
      2023 Annual Research Report
  • [Presentation] RBM20変異と心房性不整脈.2023

    • Author(s)
      井原健介.
    • Organizer
      日本心血管作動物質学会若手研究者交流シンポジウム.
    • Related Report
      2023 Annual Research Report
  • [Presentation] 心房細動時に心房筋が心外膜脂肪組織に与える影響の解明.2022

    • Author(s)
      石川紗佳、鈴木杏奈、岩嵜利奈、井原健介、古川哲史、笹野哲郎.
    • Organizer
      第266回日本循環器学会関東甲信越地方会.
    • Related Report
      2022 Research-status Report
  • [Presentation] 異常RNA顆粒による心筋症・不整脈発症機序の検討.2022

    • Author(s)
      井原健介.
    • Organizer
      第22回関東心・血管フォーラム.
    • Related Report
      2022 Research-status Report
  • [Presentation] Involvement of Potential microRNAs in Signaling Pathway Networks in Murine Angiotensin II-Mediated Atrial Fibrillation Model.2022

    • Author(s)
      Sun Y, Kawajiri K, Iwamiya S, Abe K, Ihara K, Sasano T, Furukawa T.
    • Organizer
      The 68th Annual Meeting of the Japanese Heart Rhythm Society.
    • Related Report
      2022 Research-status Report
  • [Presentation] The Exosomal miRNA Secreted by Paced Cardiomyocytes Regulates Adipocyte Differentiation.2022

    • Author(s)
      Kawajiri K, Nyo ZLM, Ihara K, Furukawa T, Sasano T.
    • Organizer
      The 68th Annual Meeting of the Japanese Heart Rhythm Society.
    • Related Report
      2022 Research-status Report
  • [Presentation] Epicardial Adipose Tissue Remodeling Evoked by Extracellular Vesicles Released from Atrial Myocytes.2022

    • Author(s)
      Ishikawa S, Suzuki A, Iwasaki R, Ihara K, Furukawa T, Sasano T.
    • Organizer
      The 68th Annual Meeting of the Japanese Heart Rhythm Society.
    • Related Report
      2022 Research-status Report
  • [Presentation] ペーシング刺激を受けた心筋細胞から分泌されたexosome含有miRNAの、脂肪細胞分化に対する影響.2022

    • Author(s)
      川尻紘平、ニョ ジン レイ モン、井原健介、古川哲史、笹野哲郎.
    • Organizer
      心電学関連春季大会2022.
    • Related Report
      2022 Research-status Report
  • [Presentation] 心房筋細胞から放出された細胞外小胞による心外膜脂肪の炎症誘導機転.2022

    • Author(s)
      石川紗佳、鈴木杏奈、岩嵜利奈、井原健介、古川哲史、笹野哲郎.
    • Organizer
      心電学関連春季大会2022.
    • Related Report
      2022 Research-status Report
  • [Presentation] Atrial Fibrillation in Cardiomyopathy Mice with Rbm20 Mutation.2022

    • Author(s)
      Ihara K, Kuroyanagi H, Hiraoka Y, Sasano T, Furukawa T.
    • Organizer
      The 86th Annual Scientific Meeting of the Japanese Circulation Society.
    • Related Report
      2021 Research-status Report
  • [Presentation] The effects of Sacubitril/Valsartan on murine atria with pressure overload.2022

    • Author(s)
      Iwamiya S, Ihara K, Furukawa T, Sasano T.
    • Organizer
      The 86th Annual Scientific Meeting of the Japanese Circulation Society.
    • Related Report
      2021 Research-status Report
  • [Presentation] 不整脈原性拡張型心筋症の新規発症機序.2021

    • Author(s)
      井原健介、黒柳秀人、平岡優一、笹野哲郎、古川哲史.
    • Organizer
      第25回日本心不全学会学術集会.
    • Related Report
      2021 Research-status Report
  • [Presentation] 心不全モデルマウスにおけるSacubitril/Valsartanの心房への電気生理学的効果.2021

    • Author(s)
      岩宮賢、井原健介、古川哲史、笹野哲郎.
    • Organizer
      心電学関連春季大会2021.
    • Related Report
      2021 Research-status Report
  • [Presentation] スプライシング制御因子RBM20変異を持つ心房細動モデルマウスの確立.2020

    • Author(s)
      井原健介、黒柳秀人、平岡優一、笹野哲郎、古川哲史.
    • Organizer
      心電学関連研究会2020.
    • Related Report
      2020 Research-status Report
  • [Presentation] A mutation in the RSRSP stretch of Rbm20 causes atrial fibrillation in mice.2020

    • Author(s)
      Ihara K, Kuroyanagi H, Hiraoka Y, Sasano T, Furukawa T.
    • Organizer
      The 4th JCS Council Forum on Basic CardioVascular Research.
    • Related Report
      2020 Research-status Report
  • [Presentation] Cytoplasmic Expansion of RNA-Binding Motif Protein 20 (RBM20) is Critical for Development of Atrial Fibrillation in Mice.2020

    • Author(s)
      Ihara K, Kuroyanagi H, Hiraoka Y, Sasano T, Furukawa T.
    • Organizer
      The 84th Annual Scientific Meeting of the Japanese Circulation Society.
    • Related Report
      2020 Research-status Report

URL: 

Published: 2020-04-28   Modified: 2025-01-30  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi