Mechanistic insights into spatio-temporal regulation of RNA in cardio-metabolic disease

2022 Fiscal Year Final Research Report

• Project/Area Number: 20H03426
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 48030:Pharmacology-related
• Research Institution: Akita University
• Principal Investigator: Kuba Keiji 秋田大学, 医学系研究科, 非常勤講師 (10451915)
• Co-Investigator(Kenkyū-buntansha): 今井 由美子 国立研究開発法人医薬基盤・健康・栄養研究所, 医薬基盤研究所 ワクチン・アジュバント研究センター, プロジェクトリーダー (50231163)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: RNA分解 / 翻訳 / ユビキチン修飾 / CCR-NOT / 心不全 / 肥満 / 脂肪細胞

Outline of Final Research Achievements

Spatiotemporal regulation of RNA in obesity, fatty liver and heart failure was studied focusing on the molecular mechanisms of regulation of translation and mRNA degradation in intracellular organelles. The regulatory mechanism by CNOT4 in adipose and liver was found to be important for nuclear RNA/epigenome regulation, and CNOT4 was found to be involved in the pathogenesis of obesity and fatty liver by inducing adipocyte differentiation and enhancing inflammatory responses through binding to RNA binding proteins. In heart failure, mRNA degradation of fibrosis-inducing factors by RNA poly(A)-degrading factor CNOT6L was found to be important in suppressing cardiac remodeling. We also found that mitochondria are key organelles for the new role of the CCR4-NOT complex in energy metabolism. Furthermore, we identified new candidate therapeutic target factors by time-series analysis of the translation dynamics of heart failure.

Free Research Field

薬理学

Academic Significance and Societal Importance of the Research Achievements

本研究により心不全や肥満・脂肪肝における時空間的なRNA分解や翻訳制御の分子メカニズムが明らかになり合わせて新たな治療標的の候補因子を見出したことから、新しい治療法の開発に資することが考えられる。また、CCR4-NOT複合体やその関連因子を介したミトコンドリア機能や核内恒常性維持の制御機構が新たに見出され、RNAとオルガネラ制御という観点で学術的意義が高いと思われる。