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Elucidating factors underlying the diverse phenotypes observed in SLC26A4 gene mutations

Research Project

Project/Area Number 20K09728
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 56050:Otorhinolaryngology-related
Research InstitutionTokyo Medical and Dental University

Principal Investigator

Ito Taku  東京医科歯科大学, 大学院医歯学総合研究科, 講師 (40401400)

Project Period (FY) 2020-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
KeywordsSLC26A4 / 前庭水管拡大 / ペンドレッド / メラニン / マクロファージ / Mondini / IP-II / マイクロCT
Outline of Research at the Start

SLC26A4変異では先天性高度難聴を呈することが多いが、非先天性で軽度~中等度で発症し進行性を示すこともある。このように多彩な表現型がどのような要因によるのかは不明である。申請者はモデルマウスにおいて内耳血管条の過剰色素沈着が組織マクロファージの増殖・活性化を誘導して聴覚障害を重症化させていることを報告した。本研究ではこれまで注目されてこなかった血管条内色素沈着に着目した病状進行の予防法確立を目的とする。そのためにメラニン色素を欠損したマウスを用いて、聴性脳幹反射、内リンパ電位の測定、血管条内マクロファージの形態観察、および血管条内のRNA発現の解析を行い難聴レベルに関与する要因を特定する。

Outline of Final Research Achievements

Research using knockout mice was conducted to elucidate the pathogenic mechanisms caused by SLC26A4 gene mutations. Morphological analyses showed distinct labeling patterns of macrophage markers between wildtype and mutant mice. Three-dimensional analysis further unveiled a distinct polarity in the morphology of activated macrophages.Reanalysis of microarray data identified upregulated molecules in the stria vascularis of mutants. Comprehensive analysis integrating single-cell data elucidated changes in macrophages. These results suggest SLC26A4 deficiency affects macrophage activation and polarity formation, leading to degeneration of the spiral ligament and stria vascularis.
Experiments administering the mTOR inhibitor sirolimus were planned but suspended due to revised animal facility regulations. While this research uncovered part of the mechanism underlying the diverse phenotypes associated with SLC26A4 mutations, further analysis, including the sirolimus experiments, is necessary.

Academic Significance and Societal Importance of the Research Achievements

本研究は、SLC26A4遺伝子変異による難聴・平衡障害の発症メカニズムの一端を明らかにした点で学術的に意義がある。SLC26A4欠損がマクロファージの機能異常を引き起こし、内耳の変性に関与することを示した。この知見は内リンパ水腫などの内耳奇形の分子病態解明に貢献する。
一方、社会的には難聴患者の病因解明と新規治療法開発への手がかりを与えた。SLC26A4遺伝子変異は先天性難聴の主要な原因であり、マクロファージ制御を標的とした新しいアプローチが有望視される。さらに、m-TOR阻害剤によるマクロファージ活性調節が内耳変性抑制に有効かを検証する重要性が示された。

Report

(5 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (12 results)

All 2024 2023 2022 2021 2020

All Journal Article (12 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 8 results,  Open Access: 6 results)

  • [Journal Article] Eight-and-a-Half Syndrome with Hearing Impairment2024

    • Author(s)
      伊藤 卓(東京医科歯科大学 耳鼻咽喉科), 堤 剛
    • Journal Title

      Equilibrium Research

      Volume: 83 Issue: 1 Pages: 51-54

    • DOI

      10.3757/jser.83.51

    • ISSN
      0385-5716, 1882-577X
    • Year and Date
      2024-02-29
    • Related Report
      2023 Annual Research Report
  • [Journal Article] 側頭骨手術ナビ/Template Guided SurgeryおよびHologram Assisted Surgeryへの展開2024

    • Author(s)
      伊藤 卓(東京医科歯科大学 耳鼻咽喉科), 本田 圭司, 堤 剛
    • Journal Title

      JOURNAL OF JAPAN SOCIETY FOR HEAD AND NECK SURGERY

      Volume: 33 Issue: 3 Pages: 287-291

    • DOI

      10.5106/jjshns.33.287

    • ISSN
      1349-581X, 1884-474X
    • Related Report
      2023 Annual Research Report
  • [Journal Article] 医療DXの可能性が広がる!XR(VR・AR・MR)とメタバースの最前線(第14回) 耳鼻咽喉科・頭頸部外科領域におけるXR,メタバースの活用について2024

    • Author(s)
      伊藤 卓(東京医科歯科大学 耳鼻咽喉科)
    • Journal Title

      INNERVISION(0913-8919)39巻2号 Page78-83(2024.01)

      Volume: 解説 Pages: 78-83

    • Related Report
      2023 Annual Research Report
  • [Journal Article] The role of SLC26A4 in bony labyrinth development and otoconial mineralization in mouse models2024

    • Author(s)
      Ito Taku、Watanabe Hiroki、Honda Keiji、Fujikawa Taro、Kitamura Ken、Tsutsumi Takeshi
    • Journal Title

      Frontiers in Molecular Neuroscience

      Volume: 17

    • DOI

      10.3389/fnmol.2024.1384764

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Detailed Clinical Features of PTPRQ-Associated Hearing Loss Identified in a Large Japanese Hearing Loss Cohort2024

    • Author(s)
      Sakuma Naoko、Nishio Shin-ya、Goto Shin-ichi、Honkura Yohei、Oda Kiyoshi、Takeda Hidehiko、Kobayashi Marina、Kumakawa Kozo、Iwasaki Satoshi、Takahashi Masahiro、Ito Taku、Arai Yasuhiro、Isono Yasuhiro、Obara Natsuko、Matsunobu Takeshi、Okubo Kimihiro、Usami Shin-ichi
    • Journal Title

      Genes

      Volume: 15 Issue: 4 Pages: 489-489

    • DOI

      10.3390/genes15040489

    • Related Report
      2023 Annual Research Report
  • [Journal Article] Combined genetic polymorphisms of the GSTT1 and NRF2 genes increase susceptibility to cisplatin-induced ototoxicity: A preliminary study2024

    • Author(s)
      Fujikawa Taro、Ito Taku、Okada Ryuhei、Sawada Mitsutaka、Mohri Kaori、Tateishi Yumiko、Takahashi Ryosuke、Asakage Takahiro、Tsutsumi Takeshi
    • Journal Title

      Hearing Research

      Volume: 445 Pages: 108995-108995

    • DOI

      10.1016/j.heares.2024.108995

    • URL

      https://pure.teikyo.jp/en/publications/a7250c34-a10a-4ceb-b26c-ce17137da184

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Three-dimensionally visualized ossification and mineralization process of the otic capsule in a postnatal developmental mouse2023

    • Author(s)
      Bai Jing、Ito Taku、Fujikawa Taro、Honda Keiji、Kawashima Yoshiyuki、Watanabe Hiroki、Kurata Natsuko、Tsutsumi Takeshi
    • Journal Title

      Laryngoscope Investigative Otolaryngology

      Volume: 8 Issue: 4 Pages: 1036

    • DOI

      10.1002/lio2.1090

    • URL

      https://pure.teikyo.jp/en/publications/d3194e1c-384d-455c-b439-7a4e20b28d26

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Quantitative analysis and correlative evaluation of video-oculography, micro-computed tomography, and histopathology in Pendrin-null mice2023

    • Author(s)
      Watanabe Hiroki、Ito Taku、Aoki Natsuki、Bai Jing、Honda Keiji、Kawashima Yoshiyuki、Fujikawa Taro、Ikeda Takuo、Tsutsumi Takeshi
    • Journal Title

      Neurobiology of Disease

      Volume: 183 Pages: 106194-106194

    • DOI

      10.1016/j.nbd.2023.106194

    • URL

      https://pure.teikyo.jp/en/publications/7d56c860-d697-4145-ac82-19ed951db2f9

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Tissue-Resident Macrophages in the Stria Vascularis2022

    • Author(s)
      Ito Taku、Kurata Natsuko、Fukunaga Yoko
    • Journal Title

      Frontiers in Neurology

      Volume: 13

    • DOI

      10.3389/fneur.2022.818395

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cochlear Pathomorphogenesis of Incomplete Partition Type II in Slc26a4-Null Mice2021

    • Author(s)
      Ito Taku、Fujikawa Taro、Honda Keiji、Makabe Ayane、Watanabe Hiroki、Bai Jing、Kawashima Yoshiyuki、Miwa Toru、Griffith Andrew J.、Tsutsumi Takeshi
    • Journal Title

      Journal of the Association for Research in Otolaryngology

      Volume: 22 Issue: 6 Pages: 681

    • DOI

      10.1007/s10162-021-00812-4

    • URL

      https://pure.teikyo.jp/en/publications/efb6983c-e726-4c31-8488-ac44ee75d44d

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Genetic Hearing Loss Associated With Autoinflammation2020

    • Author(s)
      Nakanishi Hiroshi、Prakash Pragya、Ito Taku、Kim H. Jeffrey、Brewer Carmen C.、Harrow Danielle、Roux Isabelle、Hosokawa Seiji、Griffith Andrew J.
    • Journal Title

      Frontiers in Neurology

      Volume: 11 Pages: 141-141

    • DOI

      10.3389/fneur.2020.00141

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Systemic Fluorescent Gentamicin Enters Neonatal Mouse Hair Cells Predominantly Through Sensory Mechanoelectrical Transduction Channels2020

    • Author(s)
      Makabe A, Kawashima Y, Sakamaki Y, Maruyama A, Fujikawa T, Ito T, Kurima K, Griffith AJ, Tsutsumi T.
    • Journal Title

      JARO (in press)

      Volume: 21 Issue: 2 Pages: 137

    • DOI

      10.1007/s10162-020-00746-3

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Int'l Joint Research

URL: 

Published: 2020-04-28   Modified: 2025-01-30  

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