The role of CCR4-NOT in the development of atherosclerosis

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K16153
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49010:Pathological biochemistry-related
• Research Institution: Akita University
• Principal Investigator: An Jianbo 秋田大学, 医学系研究科, 助教 (40723771)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Keywords: 動脈硬化症 / CCR4-NOT / マクロファージ / Interferon

Outline of Final Research Achievements

CCR4-NOT complex was involved in immune/inflammatory diseases. However, the physiological role of CCR4-NOT in the development of atherosclerosis has not been elucidated.
In this study, by using established ApoE null Cnot3 heterodeficient mice (ApoEKO;Cnot3Hetz), it was demonstrated that dysfunction of Cnot3(CCR4-NOT) exacerbates the progression of atherosclerosis. Interestingly, aberrant inflammation was observed in ApoEKO;Cnot3Hetz. It was found that Cnot3 was highly expressed in atherosclerotic lesions, including macrophages. Macrophages play major roles in mediating inflammatory responses during atherosclerosis. The inflammatory response was significantly enhanced in Cnot3 deficient macrophages under Interferon-gamma stimulation, suggesting CCR4-NOT complex was a negative regulator of IFN signaling.

Free Research Field

分子免疫学

Academic Significance and Societal Importance of the Research Achievements

近年、免疫・炎症性疾患におけるCCR4-NOT複合体の役割が注目される中、最近では脳血管の難治疾患であるもやもや病(Moyamoya disease)患者においてCNOT3遺伝子のde novo変異が報告され、CCR4-NOTの血管系疾患における重要性が強く示唆された。本研究課題では動脈硬化症を標的に、RNA制御に重要なCCR4-NOT複合体が如何なる機序を介して動脈硬化病態形成に影響するかを解明することにより、新しい血管系疾患の治療の概念創出に繋がることが期待される。