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Elucidation of the mechanism of Cdc42-dependent salivary gland acinar cell formation

Research Project

Project/Area Number 19K20764
Project/Area Number (Other) 17H07212 (2017-2018)
Research Category

Grant-in-Aid for Research Activity Start-up

Allocation TypeMulti-year Fund (2019)
Single-year Grants (2017-2018)
Research Field Functional basic dentistry
Research InstitutionAsahi University

Principal Investigator

Shitara Akiko  朝日大学, 歯学部, 講師 (30508718)

Project Period (FY) 2017-08-25 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywords唾液腺 / 細胞内輸送 / Cdc42 / 細胞極性 / in vivoイメージング / アクチン細胞骨格 / 小胞輸送 / エンドサイトーシス / 分泌顆粒 / 形態形成 / 発生 / 上皮 / 極性 / 管腔 / 再生医学 / 細胞・組織 / 歯学 / 発生・分化 / 動物
Outline of Research at the Start

唾液腺は唾液をつくる腺房と、それを口腔内まで輸送する導管からなる。腺房細胞は導管細胞より外来ストレスに弱く、口腔がん治療時の放射線照射などによりダメージを受け、唾液分泌量低下による口腔乾燥症を引き起こし、QOLの低下を招く。以前の研究で研究代表者は腺房細胞を形成する際、Cdc42という分子が重要な役割を果たすことを明らかにした。そこでこの研究では、Cdc42がどのような仕組みで腺房細胞の形成をコントロールしているのかを遺伝子を改変したマウスを解析することにより明らかにする。この研究から放射線照射などによりダメージを受けた唾液腺を再生する技術を開発するための重要な基本情報が得られると考えらえる。

Outline of Final Research Achievements

To define the role of Cdc42 during development of salivary acinar cell, we analyzed the morphological change of acinar cell in Cdc42-depleted mouse. Depletion of Cdc42 at late embryonic stages resulted in a complete inhibition of apical membrane their post-natal formation. In addition, intravital subcellular microscopy revealed that reduced levels of Cdc42 affected membrane trafficking from and towards the plasma membrane, highlighting a novel role for Cdc42 in membrane remodeling through the negative regulation of selected endocytic pathways.
We further showed that Cdc42 depletion alters the ultrastructure of large secretory granules analyzed by transmission electron microscopy. We found that lack of Cdc42 increases the number of granules per cell and alters their structure. Specifically, granules are smaller, less circular and exhibit heterogenous electron densities in their lumen. Our findings suggest a novel role for Cdc42 in controlling granule biogenesis and/or maturation.

Academic Significance and Societal Importance of the Research Achievements

本研究では唾液腺発生の後期に始まる腺房細胞発生機構に着目し、低分子量Gタンパク質であるCdc42が細胞内輸送の制御を介して腺房細胞の腺腔側膜の形成に重要な役割を果たすことを示した。これまで障害を受けた唾液腺を再生する技術を開発するために、唾液腺の発生機構の解析が行われてきた。本研究成果は発生前期の分枝形態形成期の唾液腺を用いた従来の多くの研究と、成熟した唾液腺組織の間のギャップを埋めるものであり、この研究から唾液腺の再生療法の確立に大きく前進する「Cdc42依存性の腺房細胞の発生機構」という新規の重要なトピックが提供された。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Annual Research Report
  • 2017 Annual Research Report
  • Research Products

    (13 results)

All 2020 2019 2018 2017 Other

All Int'l Joint Research (3 results) Journal Article (3 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 3 results,  Open Access: 3 results) Presentation (6 results) (of which Int'l Joint Research: 3 results) Remarks (1 results)

  • [Int'l Joint Research] 米国国立衛生研究所(米国)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] National Institutes of Health(米国)

    • Related Report
      2018 Annual Research Report
  • [Int'l Joint Research] 米国国立癌研究所(米国)

    • Related Report
      2017 Annual Research Report
  • [Journal Article] Cdc42 controls secretory granules morphology in rodent salivary glands in vivo2020

    • Author(s)
      Shitara Akiko、Bleck Christopher K. E.、Weigert Roberto
    • Journal Title

      Communicative & Integrative Biology

      Volume: 13 Issue: 1 Pages: 22-26

    • DOI

      10.1080/19420889.2020.1724605

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Cdc42 negatively regulates endocytosis during apical membrane maintenance in live animals2019

    • Author(s)
      Shitara A., Malec L., Ebrahim S., Chen D., Bleck C., Hoffman M. P., Weigert R.
    • Journal Title

      Molecular Biology of the Cell

      Volume: 30 Issue: 3 Pages: 324-332

    • DOI

      10.1091/mbc.e18-10-0615

    • Related Report
      2019 Annual Research Report 2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Cdc42 negatively regulates endocytosis during apical plasma membrane maintenance and development in mouse tubular organs in vivo2018

    • Author(s)
      Shitara Akiko、Malec Lenka、Ebrahim Seham、Chen Desu、Bleck Christopher、Hoffman Matthew P、Weigert Roberto
    • Journal Title

      bioRxiv

      Volume: -

    • DOI

      10.1101/402677

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Cdc42 Negatively Regulates Endocytosis During Apical Membrane Maintenance in Live Animals2019

    • Author(s)
      Shitara Akiko, Lenka Malec, Seham Ebrahim, Desu Chen, Christopher Bleck, Matthew P. Hoffman, and Roberto Weigert
    • Organizer
      Salivary Glands and Exocrine Biology, Gordon Research Conference 2019
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Cdc42はin vivoでマウス唾液腺の分泌顆粒の形態を制御する2019

    • Author(s)
      設楽彰子、柏俣正典
    • Organizer
      第61回歯科基礎医学会学術大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Cdc42はエンドサイトーシス を負に制御することにより管腔を維持する2019

    • Author(s)
      設楽彰子、柏俣正典
    • Organizer
      第64回公益社団法人日本口腔外科学会総会・学術大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Cdc42 negatively regulates endocytosis during lumen maintenance in live mice.2019

    • Author(s)
      A. Shitara, CKE Bleck, R. Weigert
    • Organizer
      2019 ASCB|EMBO Meeting
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Cdc42 Negatively Regulates Endocytosis During Apical Membrane Maintenance in Live Animals2019

    • Author(s)
      Akiko Shitara、Christopher Bleck、Matthew Hoffman、Roberto Weigert
    • Organizer
      Gordon Research Conference, Salivary Glands and Exocrine Biology 2019
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 管状臓器の管腔維持、形成におけるCdc42の役割2017

    • Author(s)
      設楽彰子
    • Organizer
      2017年度生命科学系学会合同年次大会(ConBio2017)
    • Place of Presentation
      神戸ポートアイランド
    • Year and Date
      2017-12-06
    • Related Report
      2017 Annual Research Report
  • [Remarks] ConBio2017における発表報告

    • URL

      http://scw.asahi-u.ac.jp/~pharmaco/report/index.html#20171209

    • Related Report
      2017 Annual Research Report

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Published: 2017-08-25   Modified: 2024-03-26  

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