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Development of therapy for hemolytic uremic syndrome with a focus on microRNA/high mobility group box-1 signaling

Research Project

Project/Area Number 19K17748
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 53040:Nephrology-related
Research InstitutionFukushima Medical University

Principal Investigator

Ryo Maeda  福島県立医科大学, 医学部, 助教 (60792025)

Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2020: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords溶血性尿毒症症候群 / HMGB1 / miRNA / microRNA / マウス
Outline of Research at the Start

大腸菌感染症に起因する典型的溶血性尿毒症症候群(HUS)は微生物や自己由来の成分を認識し炎症応答を誘導する自然免疫との関連があり、我々はHUSモデルマウスにおいて自然免疫の主要な分子であるHMGB1とそのシグナリングが病態に関与することを明らかにした。さらにHUSモデルマウスにおいてHMGB1シグナリングを制御する標的マイクロRNA(miRNA)を同定した。miRNAのHUSにおける役割の解明し、治療標的もしくはバイオマーカーとなるかを検証する。本研究によりHUSの新たな病態が解明され、治療薬開発などの臨床応用への展開が期待される。

Outline of Final Research Achievements

Typical (Shiga toxin-producing Escherichia coli-associated) hemolytic uremic syndrome (HUS) is the leading cause of acute kidney injury in children, and no specific treatment methods have been established. In HUS-model mice treated with Shiga toxin 2 (Stx2) and lipopolysaccharide (LPS), we conducted array analyses to identify changes in the expression of target microRNAs involved in high mobility group box-1 signaling. We focused on dual Specificity Phosphatase 8 (DUSP8), a miR-21-related mRNA with a large magnitude fold-change. DUSP8 expression was higher in the kidneys of HUS-model mice than in the kidneys of healthy mice. Proximal convoluted tubule (TKPTS) and collecting duct cells (M-1) treated with Stx2 and LPS in vitro showed no appreciable changes. A possible reason is the use of immortalized cells. Thus, we will use primary mouse renal tubular cells in reexaminations.

Academic Significance and Societal Importance of the Research Achievements

HUSモデルマウスとmiRNAとの関与を検討した報告は少ない。本研究ではmiRNAのmiR-21に関連するmRNAのDUSP8がHUSの病態に関与している可能性が示唆された。さらなる検証を進めることでHUSとmiR-21やDUSP8との関連を明らかにでき、病態が解明されることで未だ特異的治療法のないHUSの治療法が確立しうるため、本研究の学術的意義は高い。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (3 results)

All 2019

All Presentation (3 results) (of which Int'l Joint Research: 2 results)

  • [Presentation] HUSモデルマウス腎におけるマイクロRNAプロファイル2019

    • Author(s)
      前田 亮
    • Organizer
      第54回日本小児腎臓病学会
    • Related Report
      2019 Research-status Report
  • [Presentation] Involvement of high-mobility group box 1 in the pathogenesis of severe hemolytic uremic syndrome in a murine model2019

    • Author(s)
      前田 亮
    • Organizer
      pediatric academic societies
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] Involvement of high-mobility group box 1 in the pathogenesis of severe hemolytic uremic syndrome in a murine model2019

    • Author(s)
      前田 亮
    • Organizer
      International DAMPs and Alarmins Symposium
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research

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Published: 2019-04-18   Modified: 2023-01-30  

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