RNA metabolism-based regulation of heart function and its application for treatment of heart failure

2019 Fiscal Year Final Research Report

• Project/Area Number: 17H04028
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General pharmacology
• Research Institution: Akita University
• Principal Investigator: Kuba Keiji 秋田大学, 医学系研究科, 教授 (10451915)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: RNA / heart failure / deadenylation / ubiquitination / ace2 / translation / ATP / fibroblasts

Outline of Final Research Achievements

We conducted this research project to dissect the mechanisms how RNA regulation contributes to cardiac homeostasis in physiological maintenance of heart functions and pathological conditions in heart failure. In physiological conditions, executor of RNA poly(A) degradation CCR4-NOT deadenylase complex was revealed to regulate stability of Atg7 mRNA and thereby maintain healthy cardiomyocytes. In the pathology of heart failure, a deadenylase factor was elucidated to induce cardiac remodeling and fibrosis through RNA regulation in cardiac fibroblasts, suggesting that RNA regulation is a potential target for treating heart failure. Furthermore, defined molecular mechanisms for RNA regulation in cardiac homeostasis were investigated with PAR-CLIP and other comprehensive RNA analyses with deep sequencing, and potential new targets for therapeutics were identified in this study.

Free Research Field

循環薬理学

Academic Significance and Societal Importance of the Research Achievements

本研究により心不全病態におけるCCR4-NOTを介したRNA制御の分子機構や分子実体が明らかになったことから、CCR4-NOT標的因子が心臓の機能改善、再生を含めた新しい治療法の開発につながると考えられる。また、poly(A)制御によるエネルギー代謝が解糖やミトコンドリア呼吸鎖を制御することが分かったので、これらの研究成果は心臓の恒常性や心不全病態のみならず肥満や脂肪肝など代謝性疾患の予防や治療の開発に資することが考えられる。