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Development of a new treatment for pulmonary hypertension by controlling calmodulin

Research Project

Project/Area Number 22K15686
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 52010:General internal medicine-related
Research InstitutionYamaguchi University

Principal Investigator

Nakamura Yoshihide  山口大学, 医学部, 助教(特命) (80933481)

Project Period (FY) 2022-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2023: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2022: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
Keywords肺高血圧 / リアノジン受容体 / カルモジュリン / ダントロレン / ryanodine receptor / calmodulin / pulmonary hypertension / dantrolene / 肺高血圧症 / 肺動脈性肺高血圧症
Outline of Research at the Start

本研究の目的は、肺動脈性肺高血圧症(PAH)対してカルモジュリン(CaM)のリアノジン受容体(RyR2)への結合を薬理学的に強固にすることにより、RyR2の4量体構造を安定化させCa2+漏出を阻止し、右心不全への進展を抑制し予後を改善させるという新しい発想に基づいた治療法を確立することである。
i)モノクロタリン単回皮下注PAHモデルおよび肺動脈縮窄(PAB)モデルを作成し、ダントロレン慢性投与により右室の肥大・拡大は抑制されるか検討する。
さらにRyR2に対するCaM結合親和性を増強したknock-in(KI)ラットを用いて、右室肥大・拡大の抑制、生命予後の改善につながるかを検証する。

Outline of Final Research Achievements

The aim of this study was to develop a treatment that would inhibit the progression of right ventricular hypertrophy to right heart failure even under pressure overload, thereby improving prognosis, by strengthening the binding of CaM to RyR2.
In an MCT-induced rat model, dantrolene inhibited right ventricular myocardial hypertrophy while maintaining right heart function by inhibiting the dissociation of CaM from RyR2, significantly improving prognosis.
In a pulmonary artery coarctation (PAB) rat model, administration of dantrolene inhibited right ventricular myocardial hypertrophy and maintained right heart function. However, no effect was observed in the RyR2 V3580K SD-rat that we developed, in which the affinity of CaM only for RyR2 was increased. It was thought that there was a problem with these rats themselves.

Academic Significance and Societal Importance of the Research Achievements

本研究は、RyR2に対するCaMの結合親和性増強→CaM解離、Ca2+漏出抑制→右心肥大抑制→右心不全の阻止、という明確な機序に基づき、従来の肺血管抵抗でなく、右室機能保持をターゲットとした点が意義がある。PAHは今なお難病に分類され生命予後も不良な難治性疾患であり、新規治療法の開発は喫緊の課題である。この点、ダントロレンは安全性が高く、従来の血管拡張療法との併用も可能である点でも、本研究は臨床的意義がある。

Report

(3 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • Research Products

    (11 results)

All 2024 2023 2022

All Journal Article (6 results) (of which Peer Reviewed: 6 results,  Open Access: 4 results) Presentation (5 results)

  • [Journal Article] RyR2-targeting therapy prevents left ventricular remodeling and ventricular tachycardia in post-infarction heart failure2023

    • Author(s)
      Fujii Shohei、Kobayashi Shigeki、Chang Yaowei、Nawata Junya、Yoshitomi Ryosuke、Tanaka Shinji、Kohno Michiaki、Nakamura Yoshihide、Ishiguchi Hironori、Suetomi Takeshi、Uchinoumi Hitoshi、Oda Tetsuro、Okuda Shinichi、Okamura Takayuki、Yamamoto Takeshi、Yano Masafumi
    • Journal Title

      Journal of Molecular and Cellular Cardiology

      Volume: 178 Pages: 36-50

    • DOI

      10.1016/j.yjmcc.2023.03.007

    • Related Report
      2023 Annual Research Report 2022 Research-status Report
    • Peer Reviewed
  • [Journal Article] Dantrolene improves left ventricular diastolic property in mineralcorticoid-salt-induced hypertensive rats2023

    • Author(s)
      Nawata Junya、Yamamoto Takeshi、Tanaka Shinji、Yano Yasutake、Uchida Tomoyuki、Fujii Shohei、Nakamura Yoshihide、Suetomi Takeshi、Uchinoumi Hitoshi、Oda Tetsuro、Kobayashi Shigeki、Yano Masafumi
    • Journal Title

      Biochemistry and Biophysics Reports

      Volume: 34 Pages: 101449-101449

    • DOI

      10.1016/j.bbrep.2023.101449

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Herpud1 modulates hypertrophic signals independently of calmodulin nuclear translocation in rat myocardium-derived H9C2 cells2023

    • Author(s)
      Fujioka Riko、Yamamoto Takeshi、Maruta Akihiro、Nakamura Yoshihide、Tominaga Naoomi、Inamitsu Masako、Oda Tetsuro、Kobayashi Shigeki、Yano Masafumi
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 652 Pages: 61-67

    • DOI

      10.1016/j.bbrc.2023.02.038

    • Related Report
      2022 Research-status Report
    • Peer Reviewed
  • [Journal Article] Stabilizing cardiac ryanodine receptor with dantrolene treatment prevents left ventricular remodeling in pressure-overloaded heart failure mice2023

    • Author(s)
      Yano Yasutake、Kobayashi Shigeki、Uchida Tomoyuki、Chang Yaowei、Nawata Junya、Fujii Shohei、Nakamura Yoshihide、Suetomi Takeshi、Uchinoumi Hitoshi、Oda Tetsuro、Yamamoto Takeshi、Yano Masafumi
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 642 Pages: 175-184

    • DOI

      10.1016/j.bbrc.2022.12.063

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Endoplasmic reticulum stress promotes nuclear translocation of calmodulin, which activates phenotypic switching of vascular smooth muscle cells2022

    • Author(s)
      Uchida Tomoyuki、Oda Tetsuro、Yamamoto Takeshi、Inamitsu Masako、Sakai Chihiro、Uchinoumi Hitoshi、Suetomi Takeshi、Nakamura Yoshihide、Okamoto Yoko、Tateda Satomi、Fujii Shohei、Tanaka Shinji、Nawata Junya、Okamura Takayuki、Kobayashi Shigeki、Yano Masafumi
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 628 Pages: 155-162

    • DOI

      10.1016/j.bbrc.2022.08.069

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Dantrolene reduces platelet-derived growth factor (PDGF)-induced vascular smooth muscle cell proliferation and neointimal formation following vascular injury in mice2022

    • Author(s)
      Sakai Chihiro、Mikawa Mei、Yamamoto Takeshi、Uchida Tomoyuki、Nakamura Yoshihide、Akase Hideaki、Suetomi Takeshi、Tominaga Naoomi、Inamitsu Masako、Oda Tetsuro、Okamura Takayuki、Kobayashi Shigeki、Yano Masafumi
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 623 Pages: 51-58

    • DOI

      10.1016/j.bbrc.2022.07.038

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Two Cases of ATTR Type Cardiac Amyloidosis Diagnosed with Endomyocardial Biopsies2024

    • Author(s)
      藤田美穂、小林茂樹、石川真帆、中嶋佑輔、中村吉秀、福田昌和、末冨 建、宮崎要介、藤村達大、内海仁志、望月 守、小田哲郎、岡村誉之
    • Organizer
      The 88th Annual Scientific Meeting of the Japanese Circulation Society
    • Related Report
      2023 Annual Research Report
  • [Presentation] リアノジン受容体安定化治療が心筋梗塞後の左室リモデリングや心室頻拍を抑制する2023

    • Author(s)
      藤井翔平、小林茂樹、矢野泰健、内田智之、常 耀偉、縄田純也、中村吉秀、 末冨 建、内海仁志、小田哲郎、岡村誉之、山本 健、矢野雅文
    • Organizer
      第9回日本心筋症研究会
    • Related Report
      2023 Annual Research Report
  • [Presentation] 心筋型リアノジン受容体 4 量体構造の安定化は心筋梗塞後の予後を改善する2023

    • Author(s)
      藤井翔平、小林茂樹、矢野泰健、内田智之、常 耀偉、中村吉秀、末冨 建、 内海仁志、小田哲郎、岡村誉之、山本 健、矢野雅文
    • Organizer
      第122回日本循環器学会中国四国合同地方会
    • Related Report
      2023 Annual Research Report
  • [Presentation] 当院における ATTR 型心アミロイドーシスにおける予後予測因子の検討2023

    • Author(s)
      藤田美穂、小林茂樹、石川真帆、中嶋佑輔、中村吉秀、小室あゆみ、 石口博智、福田昌和、末冨 建、宮崎要介、内海仁志、望月 守、小田哲郎、岡村誉之、矢野雅文
    • Organizer
      第122回日本循環器学会中国四国合同地方会
    • Related Report
      2023 Annual Research Report
  • [Presentation] たこつぼ心筋症患者における内因性カテコラミンと心筋内酸化ストレスの関係に関する検討2023

    • Author(s)
      石川真帆、小林茂樹、中嶋佑輔、松山哲也、中村吉秀、南野巧真、尾崎功治、 石口博智、小田聖子、福田昌和、末冨 建、宮崎要介、藤村達大、内海仁志、 望月 守、小田哲郎、岡村誉之、矢野雅文
    • Organizer
      第122回日本循環器学会中国四国合同地方会
    • Related Report
      2023 Annual Research Report

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Published: 2022-04-19   Modified: 2025-01-30  

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