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Genotype-phenotype analysis in recessive dystrophic epidermolysis bullosa using single cell analysis and mouse models

Research Project

Project/Area Number 21K08324
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 53050:Dermatology-related
Research InstitutionOsaka University

Principal Investigator

Shimbo Takashi  大阪大学, 大学院医学系研究科, 特任准教授(常勤) (70780609)

Project Period (FY) 2021-04-01 – 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 2023: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywordsシングルセル解析 / 劣性栄養障害型表皮水疱症 / 遺伝子型-表現型相関 / 表皮水疱症 / 劣勢栄養障害型表皮水疱症 / 遺伝子型-表現系相関
Outline of Research at the Start

劣性栄養障害型表皮水疱症は、反復性の水疱形成を伴う皮膚遺伝性難病であり、現在根治的治療法はない。本疾患はCOL7A1遺伝子の変異により発症し、患者は生涯にわたって全身熱傷様症状に苦しむ。本研究では、患者ごとに病態が大きく異なる劣性栄養障害型表皮水疱症における遺伝子型-表現型相関を解明し、遺伝子診断情報に基づいた正確な病態予測を可能にするための基盤情報の集積を目的とする。具体的には、迅速マウスゲノム編集技術iGONAD法を活用したマウス遺伝学とシングルセル解析を駆使し、劣性栄養障害型表皮水疱症の発症に関わる各遺伝子変異が皮膚の恒常性、病態に対してどの様な影響を与えるか詳細に解析する。

Outline of Final Research Achievements

Recessive dystrophic epidermolysis bullosa (RDEB) is one of the most severe forms of epidermolysis bullosa caused by mutations in the COL7A1 gene. Currently, there is no cure. This study aimed to clarify the correlation between the type of mutations found in the patients and the clinical manifestations. Through the establishments of mouse models with the patient derived mutations, and by performing single-cell RNA/chromatin analyses, we were able to understand skin homeostasis is disrupted in RDEB, at the molecular level in this disease.

Academic Significance and Societal Importance of the Research Achievements

本研究では、マウスモデルを用いた遺伝子型-表現型相関に基づく病態予測の可能性を探究した。特に、遺伝病や希少遺伝性難病において、遺伝子変異の種類と病態・予後の正確な関連付けのための基盤研究を展開した。この研究成果は、劣性栄養障害型表皮水疱症患者に対する適切な治療方針の決定の助けとなる。さらに、本手法は他の遺伝病にも応用可能であり、難病治療戦略の向上に寄与する可能性があり社会的意義も非常に大きい。

Report

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

    (4 results)

All 2023 2022

All Journal Article (1 results) (of which Peer Reviewed: 1 results,  Open Access: 1 results) Presentation (3 results) (of which Int'l Joint Research: 2 results)

  • [Journal Article] Generation of a recessive dystrophic epidermolysis bullosa mouse model with patient-derived compound heterozygous mutations.2022

    • Author(s)
      Takaki S, Shimbo T, Ikegami K, Kitayama T, Yamamoto Y, Yamazaki S, Mori S, Tamai K
    • Journal Title

      Lab Invest

      Volume: Online ahead of print Issue: 6 Pages: 574-580

    • DOI

      10.1038/s41374-022-00735-5

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Development of a method identifying revertant mosaicism in recessive dystrophic epidermolysis bullosa using long-read sequencing2023

    • Author(s)
      Takashi Shimbo, Atsushi Matsuba, Satoshi Takaki, Katsuto Tamai
    • Organizer
      International Societies for Investigative Dermatology 2023
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Characterization of ectomesenchyme as an original of epidermal stem cells2023

    • Author(s)
      Asaka Miura, Yuki Kobayashi, Yoshikazu Hirose, Ayako Yamanishi, Yuya Ouchi, Ryoma Yamamoto, Tomomi Kitayama, Eiichi Takaki, Takashi Shimbo, Katsuto Tamai
    • Organizer
      International Societies for Investigative Dermatology 2023
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Rapid establishment of model mice for recessive dystrophic epidermolysis bullosa with patient-derived mutations2022

    • Author(s)
      新保敬史
    • Organizer
      日本研究皮膚科学会第47回年次学術大会・総会
    • Related Report
      2022 Research-status Report

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Published: 2021-04-28   Modified: 2025-01-30  

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