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Elucidation of molecular mechanisms of defective neuromuscular signal transmission as a primary cause of sarcopenia

Research Project

Project/Area Number 19K22802
Research Category

Grant-in-Aid for Challenging Research (Exploratory)

Allocation TypeMulti-year Fund
Review Section Medium-sized Section 59:Sports sciences, physical education, health sciences, and related fields
Research InstitutionNagoya University

Principal Investigator

大野 欽司  名古屋大学, 医学系研究科, 教授 (80397455)

Project Period (FY) 2019-06-28 – 2022-03-31
Project Status Granted (Fiscal Year 2020)
Budget Amount *help
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2020: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Fiscal Year 2019: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Keywordsサルコペニア / 廃用性筋萎縮 / 神経筋接合部 / リボタグマウス / 遺伝子発現プロファイル / 神経筋信号伝達障害
Outline of Research at the Start

サルコペニアと廃用性筋萎縮における神経筋接合部(NMJ)信号伝達障害が一次的な原因として注目されている。サルコペニアモデルマウスの脊髄運動神経細胞とNMJ筋終板(endplate)において、RiboTag mouseを用いた網羅的遺伝子発現プロファイリング解析とSPPLAT法によるproximity proteomics解析を行い、サルコペニアの原因に関わるSMN分子・endplate分子を同定し、CRISPR/Cas9によるノックアウトiPS細胞・ノックアウトマウスの解析により、サルコペニアにおけるNMJ病態を明らかにし新規治療法開発につなげる。

Outline of Annual Research Achievements

サルコペニアにおける神経筋接合部(NMJ)信号伝達障害が近年注目されており、廃用性筋萎縮を含めてNMJ信号伝達障害はこれら筋萎縮病態の一次的な原因である可能性が示されている。サルコペニアモデルマウスの脊髄運動神経細胞(SMN)とNMJ筋終板において、細胞特異的なリボゾームタンパクRPL22へのHAタグの付加を可能にするRiboTagマウスを用いた網羅的遺伝子発現プロファイリング解析を行い、サルコペニアにより発現が変動するSMN分子・筋終板分子を同定し、iPS細胞から構築をしたin vitro NMJならびにノックアウトマウスによる機能解析に繋げることを目的とした。
令和2年度に細胞特異的なリボゾームタンパクRPL22へのHAタグの付加を可能にするRiboTagマウスを用いたNMJ筋終板の網羅的な遺伝子発現プロファイリング解析を論文にまとめて報告した(Huang et al. Front Mol Neurosci 2020, 13: 154)。サルコペニアにおけるSMNとNMJ筋終板の網羅的な遺伝子発現解析を目的として、サルコペニアモデルマウスとRiboTagマウスのかけ合わせたマウスの脊髄と骨格筋のRNA-seq解析を現在行なっている。

Current Status of Research Progress
Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

細胞特異的なリボゾームタンパクRPL22へのHAタグの付加を可能にするRiboTagマウスを用いたNMJ筋終板の網羅的な遺伝子発現プロファイリングを明らかにし、サルコペニアモデルマウスへの展開を開始できた。

Strategy for Future Research Activity

サルコペニアにより発現が変動するSNM分子・NMJ筋終板分子を明らかにする。その機能解析を行うために、CRISPR/Cas9によるiPS細胞のノックアウト実験系を確立を行なった。iPS細胞から作成するin vitro神経筋接合部の構築実験を開始しており、この系を使ってサルコペニアのNMJ病態解明を今後さらに進めていく。

Report

(2 results)
  • 2020 Research-status Report
  • 2019 Research-status Report

Research Products

(21 results)

All 2021 2020 2019

All Journal Article (18 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 18 results,  Open Access: 13 results) Presentation (3 results) (of which Int'l Joint Research: 2 results)

  • [Journal Article] Screening of signaling pathways for agrin-induced AChR clustering in C2C12 myotubes2021

    • Author(s)
      Noto K, Ohkawara B, Ishii H, Ito M, Masuda A, Hirata H, Ohno K.
    • Journal Title

      Genes Cells

      Volume: -

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Efficacy of salbutamol monotherapy in slow‐channel congenital myasthenic syndrome caused by a novel mutation in CHRND2021

    • Author(s)
      Tawara Nozomu、Yamashita Satoshi、Takamatsu Koutaro、Yamasaki Yoshimune、Mukaino Akihiro、Nakane Shunya、Farshadyeganeh Paniz、Ohno Kinji、Ando Yukio
    • Journal Title

      Muscle & Nerve

      Volume: 63

    • DOI

      10.1002/mus.27166

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Hierarchical non-negative matrix factorization using clinical information for microbial communities2021

    • Author(s)
      Abe Ko、Hirayama Masaaki、Ohno Kinji、Shimamura Teppei
    • Journal Title

      BMC Genomics

      Volume: 22 Pages: 104-104

    • DOI

      10.1186/s12864-021-07401-y

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Secreted Signaling Molecules at the Neuromuscular Junction in Physiology and Pathology2021

    • Author(s)
      Ohkawara Bisei、Ito Mikako、Ohno Kinji
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 22 Pages: 2455-2455

    • DOI

      10.3390/ijms22052455

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Desloratadine inhibits heterotopic ossification by suppression of BMP2‐Smad1/5/8 signaling2021

    • Author(s)
      Kusano T, Nakatani M, Ishiguro N, Ohno K, Yamamoto N, Morita M, Yamada H, Uezumi A, Tsuchida K
    • Journal Title

      J Orthop Res.

      Volume: - Pages: 11-11

    • DOI

      10.1002/jor.24625

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] tRIP-seq reveals repression of premature polyadenylation by co-transcriptional FUS-U1 snRNP assembly.2020

    • Author(s)
      Masuda A, Kawachi T, Takeda JI, Ohkawara B, Ito M, Ohno K.
    • Journal Title

      EMBO reports

      Volume: -

    • DOI

      10.15252/embr.201949890

    • NAID

      120006884959

    • Related Report
      2020 Research-status Report 2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Congenital myasthenic syndrome?associated agrin variants affect clustering of acetylcholine receptors in a domain-specific manner2020

    • Author(s)
      Ohkawara Bisei、Shen XinMing、Selcen Duygu、Nazim Mohammad、Bril Vera、Tarnopolsky Mark A.、Brady Lauren、Fukami Sae、Amato Anthony A.、Yis Uluc、Ohno Kinji、Engel Andrew G.
    • Journal Title

      JCI Insight

      Volume: 5

    • DOI

      10.1172/jci.insight.132023

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Meta‐Analysis of Gut Dysbiosis in Parkinson's Disease2020

    • Author(s)
      Nishiwaki Hiroshi、Ito Mikako、Ishida Tomohiro、Hamaguchi Tomonari、Maeda Tetsuya、Kashihara Kenichi、Tsuboi Yoshio、Ueyama Jun、Shimamura Teppei、Mori Hiroshi、Kurokawa Ken、Katsuno Masahisa、Hirayama Masaaki、Ohno Kinji
    • Journal Title

      Movement Disorders

      Volume: 35 Pages: 1626-1635

    • DOI

      10.1002/mds.28119

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] InMeRF: prediction of pathogenicity of missense variants by individual modeling for each amino acid substitution2020

    • Author(s)
      Takeda Jun-ichi、Nanatsue Kentaro、Yamagishi Ryosuke、Ito Mikako、Haga Nobuhiko、Hirata Hiromi、Ogi Tomoo、Ohno Kinji
    • Journal Title

      NAR Genomics and Bioinformatics

      Volume: 2 Pages: 1-11

    • DOI

      10.1093/nargab/lqaa038

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] CTGF/CCN2 facilitates LRP4‐mediated formation of the embryonic neuromuscular junction2020

    • Author(s)
      Ohkawara Bisei、Kobayakawa Akinori、Kanbara Shunsuke、Hattori Takako、Kubota Satoshi、Ito Mikako、Masuda Akio、Takigawa Masaharu、Lyons Karen M、Ishiguro Naoki、Ohno Kinji
    • Journal Title

      EMBO reports

      Volume: 21

    • DOI

      10.15252/embr.201948462

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Zonisamide ameliorates progression of cervical spondylotic myelopathy in a rat model2020

    • Author(s)
      Kanbara Shunsuke、Ohkawara Bisei、Nakashima Hiroaki、Ohta Kyotaro、Koshimizu Hiroyuki、Inoue Taro、Tomita Hiroyuki、Ito Mikako、Masuda Akio、Ishiguro Naoki、Imagama Shiro、Ohno Kinji
    • Journal Title

      Scientific Reports

      Volume: 10 Pages: 13138-13138

    • DOI

      10.1038/s41598-020-70068-0

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Gene Expression Profile at the Motor Endplate of the Neuromuscular Junction of Fast-Twitch Muscle2020

    • Author(s)
      Huang Kun、Li Jin、Ito Mikako、Takeda Jun-Ichi、Ohkawara Bisei、Ogi Tomoo、Masuda Akio、Ohno Kinji
    • Journal Title

      Frontiers in Molecular Neuroscience

      Volume: 13 Pages: 154-154

    • DOI

      10.3389/fnmol.2020.00154

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Short-Chain Fatty Acid-Producing Gut Microbiota Is Decreased in Parkinson’s Disease but Not in Rapid-Eye-Movement Sleep Behavior Disorder2020

    • Author(s)
      Nishiwaki Hiroshi、Hamaguchi Tomonari、Ito Mikako、Ishida Tomohiro、Maeda Tetsuya、Kashihara Kenichi、Tsuboi Yoshio、Ueyama Jun、Shimamura Teppei、Mori Hiroshi、Kurokawa Ken、Katsuno Masahisa、Hirayama Masaaki、Ohno Kinji
    • Journal Title

      mSystems

      Volume: 5

    • DOI

      10.1128/msystems.00797-20

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Identification of Qk as a Glial Precursor Cell Marker that Governs the Fate Specification of Neural Stem Cells to a Glial Cell Lineage2020

    • Author(s)
      Takeuchi Akihide、Takahashi Yuji、Iida Kei、Hosokawa Motoyasu、Irie Koichiro、Ito Mikako、Brown J.B.、Ohno Kinji、Nakashima Kinichi、Hagiwara Masatoshi
    • Journal Title

      Stem Cell Reports

      Volume: 15 Pages: 883-897

    • DOI

      10.1016/j.stemcr.2020.08.010

    • NAID

      120006888017

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Zonisamide ameliorates neuropathic pain partly by suppressing microglial activation in the spinal cord in a mouse model2020

    • Author(s)
      Koshimizu Hiroyuki、Ohkawara Bisei、Nakashima Hiroaki、Ota Kyotaro、Kanbara Shunsuke、Inoue Taro、Tomita Hiroyuki、Sayo Akira、Kiryu-Seo Sumiko、Konishi Hiroyuki、Ito Mikako、Masuda Akio、Ishiguro Naoki、Imagama Shiro、Kiyama Hiroshi、Ohno Kinji
    • Journal Title

      Life Sci

      Volume: 263 Pages: 118577-118577

    • DOI

      10.1016/j.lfs.2020.118577

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Inhibition of cyclooxygenase-1 by nonsteroidal anti-inflammatory drugs demethylates MeR2 enhancer and promotes Mbnl1 transcription in myogenic cells.2020

    • Author(s)
      Huang K, Masuda A, Chen G, Bushra S, Kamon M, Araki T, Kinoshita M, Ohkawara B, Ito M, Ohno K
    • Journal Title

      Scientific Reports

      Volume: 10 Pages: 154-154

    • DOI

      10.1038/s41598-020-59517-y

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Ubiquitination of DNA Damage-Stalled RNAPII Promotes Transcription-Coupled Repair2020

    • Author(s)
      Nakazawa Y, Hara Y, Oka Y, Komine O, van den Heuvel D, Guo C, Daigaku Y, Isono M, He Y, Shimada M, Kato K, Jia N, Hashimoto S, Kotani Y, Miyoshi Y, Tanaka M, Sobue A, Mitsutake N, Suganami T, Masuda A, Ohno K, Nakada S, Mashimo T, Yamanaka K, Luijsterburg MS, Ogi T
    • Journal Title

      Cell

      Volume: 19 Pages: 1228-1244

    • DOI

      10.1016/j.cell.2020.02.010

    • NAID

      120006871293

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Agrin Myasthenia: Distinct effects of variants in different domains on clustering of acetylcholine receptors2020

    • Author(s)
      Ohkawara B, Shen X-M, Selcen D, Nazim M, Bril V, Tarnopolsky MA, Brady L, Fukami S, Amato AA, Yis U, Ohno K, Engel AG
    • Journal Title

      JCI Insight

      Volume: -

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] InMeRF: A set of random forest models for each amino acid substitution to predict pathogenicity of missense variants in the human genome2020

    • Author(s)
      Takeda J, Nanatsue K, Yamagishi R, Ito M, Ohno K
    • Organizer
      European Society of Human Genetics Virtual Conference
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] Effect of zonisamide on acetylcholine receptor cluster at the neuromuscular junction2020

    • Author(s)
      Inoue T, Ohkawara B, Nakashima H, Imagama S, Ishiguro N, Ohno K
    • Organizer
      ORS 2020 Annual Meeting (Poster), Phoenix, Arizona, USA
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] Inhibition of cyclooxygenase-1 by nonsteroidal anti-inflammatory drugs demethylates MeR2 enhancer and promotes Mbnl1 transcription in myogenic cells2019

    • Author(s)
      Huang K, Masuda A, Ohkawara B, Ito M, Ohno K
    • Organizer
      5th Annual Meeting of Japan Muscle Society (Poster), Tokyo, Japan
    • Related Report
      2019 Research-status Report

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Published: 2019-07-04   Modified: 2021-12-27  

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