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Exploring skeletal muscle pathology in spinal and bulbar muscular atrophy using in silico analysis.

Research Project

Project/Area Number 22K15705
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 52020:Neurology-related
Research InstitutionNagoya University

Principal Investigator

Iida Madoka  名古屋大学, 医学系研究科, 助教 (40815437)

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: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
Fiscal Year 2022: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords球脊髄性筋萎縮症 / 骨格筋病態 / In silico解析 / 治療薬開発 / in silico解析 / 細胞モデル / マウスモデル
Outline of Research at the Start

球脊髄性筋萎縮症(SBMA)は成人男性のみに発症する進行性の遺伝性神経筋疾患である。本研究課題では、in silico解析を活用してSBMAの骨格筋病態の解明を目指す。SBMA細胞モデルおよびマウスモデルを用いた既存の遺伝子発現解析の結果を利用して、骨格筋病態の改善が期待される候補薬をin silico解析により抽出し、SBMA細胞モデルやマウスモデルに投与して病態抑止効果を評価した上で、変化している分子シグナルに注目して骨格筋の分子病態を解明する。またパスウェイ解析ならびに薬剤データベースを用いて、候補薬の作用機序および他の組織への潜在的な効能について解析する。

Outline of Final Research Achievements

Spinal and bulbar muscular atrophy (SBMA) is a progressive hereditary neuromuscular disease. We aimed to elucidate the skeletal muscle pathophysiology of SBMA using gene expression analysis information available in the Gene Expression Omnibus (GEO) and the Library of Integrated Network-based Cellular Signatures (LINCS) databases. We identified drugs and their mechanisms of action that induce genetic alterations negatively correlated with the pathophysiology of SBMA. Among them, we selected eight drugs that are expected to ameliorate SBMA pathology. We administered them to a muscle cell model of SBMA and identified drugs that improved SBMA model cell viability and suppressed cell toxicity.
Some of the compounds are existing drugs and have potential for drug repositioning. The mechanism of action of one of the drugs targets the known pathophysiology of SBMA and we plan to confirm its effect in SBMA mouse models in the future.

Academic Significance and Societal Importance of the Research Achievements

球脊髄性筋萎縮症(SBMA)は成人男性のみに発症する進行性の遺伝性神経筋疾患である。約3割の患者は発症後20年で移動に車椅子が必要となり、呼吸筋の筋力低下により呼吸器感染症で死亡することが多い。現在リュープリン酢酸塩がSBMAの唯一の治療薬として日本で承認を受けているが、性ホルモン抑制や骨格筋の同化作用による副作用をみとめ、新規治療薬の開発が望まれている。本研究によりSBMAの病態理解が進み、新たな治療薬開発につながると考えられる。また治療薬開発のプロセスは他の疾患にも応用でき、SBMAのみならず多くの疾患の治療薬開発に結びつくことが期待される。

Report

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

    (9 results)

All 2024 2023 2022

All Journal Article (7 results) (of which Peer Reviewed: 7 results,  Open Access: 7 results) Presentation (1 results) Book (1 results)

  • [Journal Article] Exercise attenuates polyglutamine-mediated neuromuscular degeneration in a mouse model of spinal and bulbar muscular atrophy.2024

    • Author(s)
      Hirunagi T, Nakatsuji H, Sahashi K, Yamamoto M, Iida M, Tohnai G, Kondo N, Yamada S, Murakami A, Noda S, Adachi H, Sobue G, Katsuno M.
    • Journal Title

      J Cachexia Sarcopenia Muscle

      Volume: 15 Issue: 1 Pages: 159-172

    • DOI

      10.1002/jcsm.13344

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Autoantibodies Against Dihydrolipoamide S-Acetyltransferase in Immune-Mediated Neuropathies.2024

    • Author(s)
      Fukami Y, Iijima M, Koike H, Yagi S, Furukawa S, Mouri N, Ouchida J, Murakami A, Iida M, Yokoi S, Hashizume A, Iguchi Y, Imagama S, Katsuno M.
    • Journal Title

      Neurol Neuroimmunol Neuroinflamm.

      Volume: 11(2) Issue: 2

    • DOI

      10.1212/nxi.0000000000200199

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Dysregulation of Aldh1a2 underlies motor neuron degeneration in spinal muscular atrophy2023

    • Author(s)
      Kataoka Mayumi、Sahashi Kentaro、Tsujikawa Koyo、Takeda Jun-ichi、Hirunagi Tomoki、Iida Madoka、Katsunoa Masahisa
    • Journal Title

      Neuroscience Research

      Volume: - Pages: 58-65

    • DOI

      10.1016/j.neures.2023.04.007

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Clinical implication of denervation in sporadic inclusion body myositis2022

    • Author(s)
      Noda Seiya、Murakami Ayuka、Kazuta Tomoyuki、Hirano Satoko、Kimura Seigo、Nakanishi Hirotaka、Matsuo Koji、Tsujikawa Koyo、Yamada Shinichiro、Iida Madoka、Koike Haruki、Kuru Satoshi、Katsuno Masahisa
    • Journal Title

      Journal of the Neurological Sciences

      Volume: 439 Pages: 120317-120317

    • DOI

      10.1016/j.jns.2022.120317

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Label-free morphological sub-population cytometry for sensitive phenotypic screening of heterogenous neural disease model cells2022

    • Author(s)
      Imai Yuta、Iida Madoka、Kanie Kei、Katsuno Masahisa、Kato Ryuji
    • Journal Title

      Scientific Reports

      Volume: 12 Issue: 1 Pages: 9296-9296

    • DOI

      10.1038/s41598-022-12250-0

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Mid1 is associated with androgen-dependent axonal vulnerability of motor neurons in spinal and bulbar muscular atrophy2022

    • Author(s)
      Ogura Yosuke、Sahashi Kentaro、Hirunagi Tomoki、Iida Madoka、Miyata Takaki、Katsuno Masahisa
    • Journal Title

      Cell Death & Disease

      Volume: 13 Issue: 7 Pages: 601-601

    • DOI

      10.1038/s41419-022-05001-6

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Metabolome and transcriptome analysis on muscle of sporadic inclusion body myositis.2022

    • Author(s)
      Murakami, A., Noda, S., Kazuta, T., Hirano, S., Kimura, S., Nakanishi, H., Matsuo, K., Tsujikawa, K., Iida, M., Koike, H., Sakamoto, K., Hara, Y., Kuru, S., Kadomatsu, K., Shimamura, T., Ogi, T., Katsuno, M.
    • Journal Title

      Ann Clin Transl Neurol.

      Volume: 9 Issue: 10 Pages: 1602-1615

    • DOI

      10.1002/acn3.51657

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Single cell analysis reveals oligodendrocyte heterogeneity in spinal and bulbar muscular atrophy2023

    • Author(s)
      飯田 円
    • Organizer
      第64回日本神経学会学術大会
    • Related Report
      2023 Annual Research Report
  • [Book] CLINICAL NEUROSCIENCE2022

    • Author(s)
      飯田 円
    • Total Pages
      3
    • Publisher
      中外医学社
    • Related Report
      2022 Research-status Report

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

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