Elucidation of transcriptional and epigenomic circuit ro reveal molecular mechanisms underlying heart failure and identify novel therapeutic targets

2022 Fiscal Year Final Research Report

• Project/Area Number: 20H03673
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Shinshu University
• Principal Investigator: Kuwahara Koichiro 信州大学, 学術研究院医学系, 教授 (30402887)
• Co-Investigator(Kenkyū-buntansha): 木下 秀之 京都大学, 医学研究科, 特定准教授 (30467477) ; 元木 博彦 信州大学, 学術研究院医学系, 准教授 (50532058) ; 中川 靖章 京都大学, 医学研究科, 助教 (70452357)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 心不全 / 転写 / シグナル経路 / エピゲノム / 心筋 / カルシウムシグナル

Outline of Final Research Achievements

In this study, we studied the significance of two pathological calcium signaling circuits related to transcriptional and epigenomic regulation in the progress of heart failure and pathological myocardial remodeling as therapeutic targets based on results of our previous research, and also investigated the significance of histone-modifying enzymes HDAC1/2, LSD1, and G9a in maintaining myocardial homeostasis, which were discovered as epigenomic regulatory factors involved in pathways described above, by mainly using myocardium-specific knockout mice. As a result, we clarified the significance of the NRSF-CaMKII-GNAO1 pathway in heart failure progression and its detailed mechanism, and found its significance as a new therapeutic target for heart failure. Other molecules and pathways are also being clarified for their significance in the progression of heart failure.

Free Research Field

循環器内科学

Academic Significance and Societal Importance of the Research Achievements

予後不良の疾患症候群である心不全の増加に伴い、その病態解明に基づく新規予防・治療法開発が求められている。本研究では、我々が今までが明らかにしてきた心臓の恒常性維持とその破綻としての心不全発症・進展に関わる、転写・エピゲノム制御ネットワークの研究から得られた知見をさらに展開し、心不全発症・進展および心収縮能低下にかかわる新規分子機序の解明と、それに基づく新規治療標的同定に関する複数の成果を得た。本研究の成果は、将来的な新規慢性心不全予防・治療薬開発を可能とし、心不全有病率の減少、予後改善に寄与しうることが期待される。