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

Exploring therapeutic candidate compounds for LMNA-mutant dilated cardiomyopathy

Research Project

Project/Area Number 21K16082
Research Category

Grant-in-Aid for Early-Career Scientists

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

Principal Investigator

Ito Maamichi  東京大学, 医学部附属病院, 特任助教 (70794642)

Project Period (FY) 2021-04-01 – 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: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2022: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords拡張型心筋症 / 化合物スクリーニング / LMNA変異 / iPS創薬 / iPS細胞由来心筋細胞 / iPS細胞 / DNA損傷 / 創薬 / ラミン変異
Outline of Research at the Start

ラミン変異患者由来iPS心筋細胞にはDNA損傷が高度に蓄積していることが判明しているため、この細胞を用いて心筋細胞のDNA損傷蓄積を軽減する化合物のスクリーニングを実施する。
化合物ライブラリーをiPS由来心筋細胞に投与し、投薬後細胞を固定してγH2AXの陽性箇所を計測することでDNA損傷の程度を定量化する。溶媒コントロールに対してDNA損傷を有意に軽減させる化合物を抽出する。ヒット化合物が得られた場合、心不全モデルマウスに薬剤を投与することで、機能的な改善効果が確認されるか検証する。

Outline of Final Research Achievements

Dilated cardiomyopathy (DCM) with LMNA mutation is known to be associated with a progressive course and poor prognosis, but no specifc treatments are available. We aimed to identify novel candidate compounds for the treatment of LMNA-mutant DCM by using iPS cell-derived cardiomyocytes established from patients with LMNA p.Q353R mutantation, searching for compounds that reduce DNA damage accumulation in cardiomyocytes.
As a result of screening, vitamin D2 (VD) was found to be effective in reducing DNA damage in the LMNA mutant cardiomyocytes. Gene expression analysis revealed that VD upregulated the expression of several DNA repair enzymes in cardiomyocytes. In addition, LMNA Q353R mutant protein was found to repress the transcriptional activity of VD by binding to its receptor, VDR. Our findings provide a new seed for treatment of LMNA-mutatant cardiomyopathy.

Academic Significance and Societal Importance of the Research Achievements

本研究によって難病である特発性拡張型心筋症の新たな治療薬候補を提示することができた。同定されたvitamin Dは安全性が確立されている既存薬であり、drug repositionを目指した臨床試験のシーズとなる可能性がある。
また本研究の手法は心筋症のヒト変異iPS細胞由来心筋細胞を用いたスクリーニングの成功例として他変異の心筋症や疾患に応用できる可能性があり、個別化医療およびiPS創薬の1成功例として資するものである。

Report

(3 results)
  • 2023 Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • Research Products

    (9 results)

All 2023 2022 2021 Other

All Journal Article (5 results) (of which Peer Reviewed: 4 results,  Open Access: 4 results) Presentation (2 results) (of which Int'l Joint Research: 2 results,  Invited: 1 results) Remarks (2 results)

  • [Journal Article] TEAD1 trapping by the Q353R?Lamin A/C causes dilated cardiomyopathy2023

    • Author(s)
      Yamada S、et al.,
    • Journal Title

      Science Advances

      Volume: 9 Issue: 15 Pages: 1-1

    • DOI

      10.1126/sciadv.ade7047

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Functional Evaluation of Human Bioengineered Cardiac Tissue Using iPS Cells Derived from a Patient with Lamin Variant Dilated Cardiomyopathy2022

    • Author(s)
      Miura K, Matsuura K, Yamasaki Itoyama Y, Sasaki D, Takada T, Furutani Y, Hayama E, Ito M, Nomura S, Morita H, Toyoda M, Umezawa A, Onoue K, Saito Y, Aburatani H, Nakanishi T, Hagiwara N, Komuro I, Shimizu T.
    • Journal Title

      International Heart Journal

      Volume: 63 Issue: 2 Pages: 338-346

    • DOI

      10.1536/ihj.21-790

    • ISSN
      1349-2365, 1349-3299
    • Year and Date
      2022-03-30
    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] 循環器病領域における疾患iPS細胞の臨床応用のこれまでとこれから2022

    • Author(s)
      伊藤正道
    • Journal Title

      医学のあゆみ

      Volume: 283-14 Pages: 1432-1437

    • Related Report
      2022 Research-status Report
  • [Journal Article] Fibroblast-Cardiomyocyte Interaction in Pediatric Restrictive Cardiomyopathy2021

    • Author(s)
      Sato T, Ito M
    • Journal Title

      Circulation Journal

      Volume: 85 Issue: 5 Pages: 687-689

    • DOI

      10.1253/circj.CJ-21-0100

    • NAID

      130008028989

    • ISSN
      1346-9843, 1347-4820
    • Year and Date
      2021-04-23
    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Titin Truncation Variant in Dilated Cardiomyopathy2021

    • Author(s)
      Ito M, Morita H
    • Journal Title

      International Heart Journal

      Volume: 62 Issue: 2 Pages: 221-223

    • DOI

      10.1536/ihj.21-053

    • NAID

      130008007423

    • ISSN
      1349-2365, 1349-3299
    • Year and Date
      2021-03-30
    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Impaired Vitamin D Signaling Causes LMNA Mutation-related Cardiomyopathy2022

    • Author(s)
      Masamichi Ito
    • Organizer
      日本循環器学会
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research
  • [Presentation] Disease modeling and drug discovery for LMNA-mutant dilated cardiomyopathy2022

    • Author(s)
      Masamichi Ito
    • Organizer
      日本循環器学会
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research / Invited
  • [Remarks] 東大病院プレスリリース 重症拡張型心筋症の病態を解明し新たな治療標的を同定

    • URL

      https://www.h.u-tokyo.ac.jp/press/__icsFiles/afieldfile/2023/04/17/release_20230417.pdf

    • Related Report
      2022 Research-status Report
  • [Remarks] 東京大学医学部附属病院循環器内科 研究部門 疾患iPS研究グループの研究内容

    • URL

      https://cardiovasc.m.u-tokyo.ac.jp/study/ips/about

    • Related Report
      2021 Research-status Report

URL: 

Published: 2021-04-28   Modified: 2025-01-30  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi