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2018 Fiscal Year Final Research Report

Investigation of safer methods of therapeutic miRNA and exosomes

Research Project

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Project/Area Number 16K09610
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Kidney internal medicine
Research InstitutionNagoya University

Principal Investigator

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

Co-Investigator(Kenkyū-buntansha) 丸山 彰一  名古屋大学, 医学系研究科, 教授 (10362253)
小杉 智規  名古屋大学, 医学系研究科, 講師 (90584681)
Research Collaborator Nishio Fumitoshi  
Funahashi Yoshio  
Project Period (FY) 2016-04-01 – 2019-03-31
KeywordsmiRNA / Toll like receptor
Outline of Final Research Achievements

We investigated the pathophysiological role of exogenously applied microRNA (miRNA) in sepsis-induced multiple organ injury. In vitro, we tested possible miRNAs which suppressed the production of pro-inflammatory cytokines. Of these, miR-146a displayed the highest suppressive effect. Sepsis was induced in mice via cecal ligation and puncture (CLP) and an intravenous injection of a complex of miR-146a-expressing plasmid and polyethyleneimine. Treatment with this complex significantly decreased the level of serum inflammatory cytokines, attenuated organ injury, and led to increased survival from sepsis. miR-146a-expressing plasmid was abundantly distributed in splenic macrophages. CLP mice treated with miR-146a displayed significantly decreased NF-κB activation in the spleen. The collective results support the conclusion that the induction of miR-146a expression in splenic macrophages prevents excessive inflammation and sepsis-induced multiple organ injury.

Free Research Field

miRNA

Academic Significance and Societal Importance of the Research Achievements

敗血症は全死亡率が高い重篤な疾患であるが、抗菌治療や、補液などに治療的なエビデンスがあるものの、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、全く新しいアプローチで治療を行った。
結果から全身投与したmiRNA発現ベクターは、主に脾臓マクロファージに取り込まれ、過剰なサイトカイン産生を抑制し、生存率の改善に寄与していた。これは今後の核酸医薬の開発にとって、投与核酸の体内動態、作用を探る上でも意義深い。また、miRNAは低分子医薬や抗体医薬と比べ安価に作成できるため、将来の治療応用にも期待が持てる。

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Published: 2020-03-30  

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