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2019 Fiscal Year Final Research Report

Chemical cardiac reprogramming and mechanisms

Research Project

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Project/Area Number 17K19678
Research Category

Grant-in-Aid for Challenging Research (Exploratory)

Allocation TypeMulti-year Fund
Research Field Organ-based internal medicine and related fields
Research InstitutionUniversity of Tsukuba (2019)
Keio University (2017-2018)

Principal Investigator

Ieda Masaki  筑波大学, 医学医療系, 教授 (70296557)

Project Period (FY) 2017-06-30 – 2020-03-31
Keywordsリプログラミング / 心臓再生
Outline of Final Research Achievements

Direct cardiac reprogramming from fibroblasts can be a promising approach for disease modeling, drug screening, and cardiac regeneration in pediatric and adult patients. In this study, we screened 8400 chemical compounds and found that diclofenac sodium (diclofenac), a non-steroidal anti-inflammatory drug, greatly enhanced cardiac reprogramming in combination with Gata4, Mef2c, and Tbx5 (GMT) or GMT plus Hand2. Intriguingly, diclofenac promoted cardiac reprogramming in mouse postnatal and adult tail-tip fibroblasts (TTFs), but not in mouse embryonic fibroblasts (MEFs). Mechanistically, diclofenac enhanced cardiac reprogramming by inhibiting cyclooxygenase-2, prostaglandin E2/ prostaglandin E receptor 4, cyclic AMP/protein kinase A, and interleukin 1β signaling and by silencing inflammatory and fibroblast programs, which were activated in postnatal and adult TTFs.

Free Research Field

循環器内科

Academic Significance and Societal Importance of the Research Achievements

本研究で行うケミカルバイロジーは、同定した機能性化合物を基に、心筋リプログラミング誘導薬剤を開発できるのみならず、化合物の標的分子を同定することによって心筋リプログラミングの実行メカニズムを明らかにすることができる。高い心筋誘導効率を示す化合物を発見できれば、心筋リプログラミングに必要な遺伝子を減らして、将来的には薬剤のみで心筋誘導ができるようになる可能性がある。このように本研究は心筋リプログラミングとケミカルバイロジーという共に新しい研究の融合領域を切り拓き、従来の心臓治療に大きな変革や転換を与えうる、独創的かつ革新的な研究である。

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Published: 2021-02-19  

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