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Development of a treatment for septic AKI using microRNAs and adipose stem cell-derived exosomes.

Research Project

Project/Area Number 19K08676
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 53040:Nephrology-related
Research InstitutionNagoya University

Principal Investigator

Noritoshi Kato  名古屋大学, 医学部附属病院, 講師 (90716052)

Co-Investigator(Kenkyū-buntansha) 前田 佳哉輔  名古屋大学, 医学部附属病院, 助教 (00836306)
丸山 彰一  名古屋大学, 医学系研究科, 教授 (10362253)
古橋 和拡  名古屋大学, 医学部附属病院, 病院講師 (50835121)
勝野 敬之  愛知医科大学, 医学部, 准教授 (60642337)
Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
KeywordsmiRNA / リポソーム / 敗血症 / 腎線維化 / マイクロRNA / 核酸医薬 / エクソソーム / 脂肪由来幹細胞 / Exosomes
Outline of Research at the Start

敗血症は、全世界的にみても死亡率が高い重篤な疾患である。また新たな治療法の開発は遅れ、生存率の改善は停滞している。我々はToll like receptorシグナルをmiRNAによって制御するといった、新しいアプローチによる治療を報告してきた。一方で幹細胞由来のエクソソームには、炎症性疾患における治療効果が報告されており、今回は低血清培地型脂肪由来幹細胞のエクソソームを用いて、我々が見つけ出したmiRNAを敗血症モデルマウスに投与して、治療効果の上乗せが可能かどうか、検証を行う。

Outline of Final Research Achievements

In our previous studies, we have succeeded in suppressing hypercytokinemia and improving survival in sepsis model mice by systemic administration of a plasmid expressing miR-146a, which was mainly taken up by the spleen.
In this study, we focused on the spleen as a target for the treatment of sepsis and investigated the therapeutic effect of local injection into the spleen. We found that most of the nucleic acids after administration were taken up by the spleen, especially by splenic macrophages. While the therapeutic effect was protective against organ damage such as kidney and liver damage, this did not improve the survival rate. Therefore, the target disease and therapeutic miRNAs were changed, and the inhibitory effect on renal fibrosis caused by folic acid nephropathy was examined, and a certain inhibitory effect on fibrosis was confirmed.

Academic Significance and Societal Importance of the Research Achievements

核酸医薬は、細胞治療や抗体医薬と異なり安価に合成できること、また一度治療に関わるプロトコールが完成すれば、疾患ごとに治療ターゲットを変えて、核酸を載せ替えることで、プラットフォームの汎用性が高いことが特徴である。昨今のSARS-CoV-2感染の病態に、SIRSといった全身性の高サイトカイン血症の関与がうたわれているが、我々の既報から、SepsisによるSIRSの治療ターゲット臓器として脾臓をあげている点は新しく、今後議論が広まることを期待している。またリポソームと成熟miRNAによる治療実験の報告は散見されるが、知見を蓄積していく必要があり、本研究もそれに役立てて行きたい。

Report

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

    (3 results)

All 2020 2019

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

  • [Journal Article] miR-146a targeted to splenic macrophages prevents sepsis-induced multiple organ injury.2019

    • Author(s)
      Funahashi Y, Kato N, Masuda T, Nishio F, Kitai H, Ishimoto T, Kosugi T, Tsuboi N, Matsuda N, Maruyama S, Kadomatsu K.
    • Journal Title

      Lab. Invest.

      Volume: - Issue: 8 Pages: 1130-1142

    • DOI

      10.1038/s41374-019-0190-4

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] Exosomes from CKD Patients Have Atherosclerogenic Properties2020

    • Author(s)
      Noritoshi Kato, Fumitoshi Nishio, Takuji Ishimoto, Tomoki Kosugi, Shoichi Maruyama
    • Organizer
      18th ASIANPACIFIC CONGRESS OF NEPHROLOGY
    • Related Report
      2020 Research-status Report
  • [Presentation] NOVEL PATHOPHYSIOLOGIC ROLE OF MIR-146A FOR SPLENIC MACROPHAGE INTERFERENCE IN SEPSIS-RELATED KIDNEY INJURY2019

    • Author(s)
      Yoshio Funahashi ; Noritoshi Kato; Takuji Ishimoto; Tomoki Kosugi; Shoichi Maruyama
    • Organizer
      56th ERA-EDTA CONGRESS
    • Related Report
      2019 Research-status Report

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

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