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Elucidation of the pathophysiology and etiology of congenital long QT syndrome type 6 by myocardial cell screening and iPS technology

Research Project

Project/Area Number 17K08539
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field General physiology
Research InstitutionTottori University

Principal Investigator

SHIRAYOSHI Yasuaki  鳥取大学, 医学部, 准教授 (90249946)

Co-Investigator(Kenkyū-buntansha) 李 佩俐  鳥取大学, 医学(系)研究科(研究院), 助教 (40464292)
池田 信人  鳥取大学, 医学(系)研究科(研究院), 助教 (50620316)
Project Period (FY) 2017-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywords疾患iPS細胞 / QT延長症候群 / 蛍光タンパク質 / ペースメーカ細胞 / 心室筋 / 先天性QT延長症候群 / MIRP1 / HCN4 / MLC2v / 洞結節ペースメーカ / イオンチャネル / 可視化 / ヒトiPS 細胞 / 心筋 / ゲノム編集 / 心室筋細胞 / MiRP1 / 再生医学 / 生理学 / バイオテクノロジー / iPS細胞
Outline of Final Research Achievements

In this study, we aimed to elucidate the etiology and pathophysiology of congenital long QT syndrome type 6 (LQTS6). Using patient-derived disease iPS cells, we succeeded in establishing a cell line in which sinus node pacemaker cells and ventricular cells having the same MiRP1 gene mutation as the patient can be individually visualized by fluorescent proteins. The fractionated cardiomyocytes showed the specific maker expression and electrophysiological characteristics of sinus node pacemakers or ventricular muscle cells. Although we have not reached a detailed analysis of the etiology and pathophysiology, we would like to proceed with the elucidation of the pathophysiology because cardiomyocyte with the same property of patient can be prepared by using the established LQTS6 iPS cell. At the same time, we have succeeded in improving the method for inducing myocardial differentiation and developing a new visualization-selective collection method for sinus node pacemaker cells.

Academic Significance and Societal Importance of the Research Achievements

先天性QT延長症候群タイプ6(LQTS6)の病因・病態解明のために必要な洞結節ペースメーカ細胞と心室筋細胞を、選択的に可視化-選別採取できるLQTS6疾患iPS細胞株の作製に成功している。この細胞株を使い電気生理学的解析等を詳細に進めることができれば、LQTS6に特有な徐脈とQT延長という2つの異なった症状を生み出す分子メカニズムの詳細に迫ることができると考えている。また、原因遺伝子MiRP1について、患者と同等の変異を持つこれらの細胞は、LQTS6患者の診断、薬剤スクリーニングを通じて、病気の治療のみならず、心臓の拍動制御システムの解明にも貢献すると期待している。

Report

(6 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (28 results)

All 2021 2020 2019 2018 2017 Other

All Int'l Joint Research (5 results) Journal Article (6 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 6 results,  Open Access: 6 results) Presentation (15 results) (of which Int'l Joint Research: 2 results) Remarks (1 results) Patent(Industrial Property Rights) (1 results)

  • [Int'l Joint Research] コロンビア大学(米国)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] コロンビア大学(米国)

    • Related Report
      2020 Research-status Report
  • [Int'l Joint Research] コロンビア大学(米国)

    • Related Report
      2019 Research-status Report
  • [Int'l Joint Research] コロンビア大学(米国)

    • Related Report
      2018 Research-status Report
  • [Int'l Joint Research] コロンビア大学(米国)

    • Related Report
      2017 Research-status Report
  • [Journal Article] Novel dual-reporter transgenic rodents enable cell tracking in animal models of stem cell transplantation2019

    • Author(s)
      Morikawa K, Nakamura K, Suyama Y, Yamamoto K, Fukuoka K, Yagi S, Shirayoshi Y, Ohbayashi T, Hisatome I.
    • Journal Title

      Biochem Biophys Rep.

      Volume: 18 Pages: 100645-100645

    • DOI

      10.1016/j.bbrep.2019.100645

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Inhibitory effects of class I antiarrhythmic agents on Na+ and Ca2+ currents of human iPS cell-derived cardiomyocytes.2019

    • Author(s)
      Yonemizu S, Masuda K, Kurata Y, Notsu T, Higashi Y, Fukumura K, Li P, Ninomiya H, Miake J, Tsuneto M, Shirayoshi Y, Hisatome I.
    • Journal Title

      Regen Ther.

      Volume: 10 Pages: 104-111

    • DOI

      10.1016/j.reth.2018.12.002

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Isolation and characterization of ventricular-like cells derived from NKX2-5 eGFP/w and MLC2v mCherry/w double knock-in human pluripotent stem cells2018

    • Author(s)
      Yamauchi Kaori、Li Junjun、Morikawa Kumi、Liu Li、Shirayoshi Yasuaki、Nakatsuji Norio、Elliott David A.、Hisatome Ichiro、Suemori Hirofumi
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 495 Issue: 1 Pages: 1278-1284

    • DOI

      10.1016/j.bbrc.2017.11.133

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Restoration of mutant hERG stability by inhibition of HDAC62018

    • Author(s)
      Li Peili、Kurata Yasutaka、Endang Mahati、Ninomiya Haruaki、Higaki Katsumi、Taufiq Fikri、Morikawa Kumi、Shirayoshi Yasuaki、Horie Minoru、Hisatome Ichiro
    • Journal Title

      J mol Cell cardiol

      Volume: 115 Pages: 158-169

    • DOI

      10.1016/j.yjmcc.2018.01.009

    • NAID

      120007170666

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Molecular mechanisms underlying the pilsicainide-induced stabilization of hERG proteins in transfected mammalian cells2017

    • Author(s)
      Onohara, Takeshi; Hisatome, Ichiro; Kurata, Yasutaka; Li, Peili; Notsu, Tomomi; Morikawa, Kumi; Otani, Naoyuki; Yoshida, Akio; Iitsuka, Kazuhiko; Kato, Masaru; Miake, Junichiro; Ninomiya, Haruaki; Higaki, Katsumi; Shirayoshi, Yasuaki; Nishihara, Takashi; Itoh, Toshiyuki; Nakamura, Yoshinobu; Nishimura, Motonobu
    • Journal Title

      J. Arrhythmia,

      Volume: 32 Issue: 3 Pages: 226-233

    • DOI

      10.1016/j.joa.2016.09.003

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] <b>Tbx18-positive cells differentiated from murine ES cells serve as proepicardial progenitors to give rise to vascular smooth muscle cells and fibr</b><b>oblasts </b>2017

    • Author(s)
      IKEDA Nobuhito、NAKAZAWA Natsumi、KURATA Yasutaka、YAURA Hisako、TAUFIQ Fikri、MINATO Hiroyuki、YOSHIDA Akio、NINOMIYA Haruaki、NAKAYAMA Yuji、KUWABARA Masanari、SHIRAYOSHI Yasuaki、HISATOME Ichiro
    • Journal Title

      Biomedical Research

      Volume: 38 Issue: 4 Pages: 229-238

    • DOI

      10.2220/biomedres.38.229

    • NAID

      130005966981

    • ISSN
      0388-6107, 1880-313X
    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] HCN4/Shox2遺伝子標識によるヒトiPS細胞からの心臓洞結節ペースメーカ細胞の分取システムの構築2021

    • Author(s)
      脇水孝之、經遠智一、白吉安昭、久留一郎
    • Organizer
      心電学関連春期大会2021
    • Related Report
      2021 Annual Research Report
  • [Presentation] 予定心臓領域特異的マーカー遺伝子の発現を可視化したIPS細胞株の樹立2021

    • Author(s)
      重永雅人、今川明梨、經遠智一、久留一郎、白吉安昭
    • Organizer
      第44回 日本分子生物学会年会
    • Related Report
      2021 Annual Research Report
  • [Presentation] ヒトiPS細胞に由来するHCN4陽性心筋細胞のはっせい・分化能とその特性解析2021

    • Author(s)
      谷本久実、足立隆、經遠智一、久留一郎、白吉安昭
    • Organizer
      第44回 日本分子生物学会年会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 心房細動関連遺伝子PRRX1のヒト心房筋様細胞における機能解析2021

    • Author(s)
      幸哲夫、經遠智一、三明淳一郎、久留一郎、白吉安昭
    • Organizer
      第44回 日本分子生物学会年会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 心臓洞結節ペースメーカ細胞の分取、解析のためのヒトiPS 細胞株の作製2021

    • Author(s)
      脇水孝之、足立隆、林裕也、経遠智一、白吉安昭、久留一郎
    • Organizer
      第20回 日本再生医療学会総会
    • Related Report
      2020 Research-status Report
  • [Presentation] HCN4/Sox2遺伝子標識によるヒトiPS細胞からの心臓洞結節ペースメーカ細胞の分取システムの構築2021

    • Author(s)
      脇水孝之、経遠智一、白吉安昭、久留一郎
    • Organizer
      心電学関連春期大会2021
    • Related Report
      2020 Research-status Report
  • [Presentation] ヒトiPS 細胞から心臓ペースメーカ細胞への全分化過程の検討2020

    • Author(s)
      脇水孝之、足立隆、林裕也、経遠智一、久留一郎、白吉安昭
    • Organizer
      第43回 日本分子生物学会年会
    • Related Report
      2020 Research-status Report
  • [Presentation] サブタイプ心筋の分取、解析のためのヒト多能性幹細胞の作製2019

    • Author(s)
      足立隆、林裕也、脇水孝之、経遠智一、久留一郎、白吉安昭
    • Organizer
      第42回 日本分子生物学会年会
    • Related Report
      2019 Research-status Report
  • [Presentation] 心臓発生メカニズムの解明を目的とする新規hiPS細胞株の樹立と解析2019

    • Author(s)
      増田啓一郎、米水彩香、東祐平、野津智美、経遠智一、久留一郎、白吉安昭
    • Organizer
      第18回 日本再生医療学会総会
    • Related Report
      2018 Research-status Report
  • [Presentation] Selective isolation of cardiac progenitor cells derived from human iPS cells2018

    • Author(s)
      Yasuaki Shirayoshi, kenta Fukumura, Yuhei Higashi, Kumi Morikawa, Motokazu Tsuneto, Ichiro Hisatome
    • Organizer
      Weinstein Cardiovascular Development and Regeneration Conference 2018
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] ヒトiPS細胞由来HCN4陽性心筋の電気生理学的特性解析と薬剤応答性2018

    • Author(s)
      白吉安昭、増田啓一郎、米水彩香、野津智美、久留一郎
    • Organizer
      第45回 日本毒性学会学術年会 大阪国際会議場
    • Related Report
      2018 Research-status Report
  • [Presentation] Establishment of novel human iPS cell lines aiming for sustained purification of iPS cell-derived cardyomyocytes2018

    • Author(s)
      Konomi Miyagi, Yuhei Higashi, Keiichiro Masuda, Sayaka Yonemizu, Ichiro Hisatome, Yasuaki Shirayosh
    • Organizer
      第41回日本分子生物学会年会 パシフィコ横浜
    • Related Report
      2018 Research-status Report
  • [Presentation] Selective isolation and analysis of cardiac progenitor cells derived from human iPS cells2018

    • Author(s)
      Yuhei Higashi, Kenta Fukumura, Keiichiro Masuda, Sayaka Yonemizu, Ichiro Hisatome, Yasuaki Shirayoshi
    • Organizer
      第41回日本分子生物学会年会 パシフィコ横浜
    • Related Report
      2018 Research-status Report
  • [Presentation] Fluorescent human reporter lines offer useful platforms to study cardiac subtype specification and cell-based therapies of cardiac disease2017

    • Author(s)
      Shirayoshi Yasuaki、Fukumura Kenta、Morikawa Kumi、Hisatome Ichiro
    • Organizer
      ISSCR 2017 Annual Meeting
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Selective isolation and analysis of cardiac progenitor cells derived from human iPS cells2017

    • Author(s)
      Higashi Yuhei、Fukumura Kenta、Masuda Keiichiro、Yonemizu Sayaka、Hisatome Ichiro、Shirayoshi Yasuaki
    • Organizer
      第40回 日本分子生物学会年会
    • Related Report
      2017 Research-status Report
  • [Remarks] 遺伝子再生医療学講座 再生医療学部部門

    • URL

      https://www.med.tottori-u.ac.jp/regmed/518/1195.html

    • Related Report
      2021 Annual Research Report
  • [Patent(Industrial Property Rights)] 新規刺激伝導系様細胞2018

    • Inventor(s)
      白吉安昭、森川久未、久留一郎
    • Industrial Property Rights Holder
      白吉安昭、森川久未、久留一郎
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2018-062705
    • Filing Date
      2018
    • Related Report
      2017 Research-status Report

URL: 

Published: 2017-04-28   Modified: 2023-01-30  

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