The role of CCR4-NOT in the development of atherosclerosis
| Project/Area Number |
20K16153
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 49010:Pathological biochemistry-related
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| Research Institution | Akita University |
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Principal Investigator |
An Jianbo 秋田大学, 医学系研究科, 助教 (40723771)
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| Project Period (FY) |
2020-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2020: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
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| Keywords | 動脈硬化症 / CCR4-NOT / マクロファージ / Interferon / 動脈硬化 / 炎症応答 / 炎症 |
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| Outline of Research at the Start |
RNA制御において不可欠な役割を果たすCCR4-NOT複合体は、炎症性疾患との関連が報告されつつあるが、病態におけるCCR4-NOTの標的や制御といった分子的基盤は全く未解明である。本研究では、作製した組織特異的にCCR4-NOT複合体を欠失した遺伝子組換えマウスと、次世代シーケンサーを用いた解析から、動脈硬化病態形成及び進行におけるCCR4-NOTの役割および制御機構を明確にし、RNA制御による動脈硬化症の新たな予防法・治療法の開発に繋ぐことを目的とする。
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| 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.
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| 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。
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Report
(3 results)
Research Products
(3 results)
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[Journal Article] ACE2-like carboxypeptidase B38-CAP protects from SARS-CoV-2-induced lung injury2021
Author(s)
Yamaguchi T, Hoshizaki M, Minato T, Nirasawa S, Asaka MN, Niiyama M, Imai M, Uda A, Chan JF, Takahashi S, An J, Saku A, Nukiwa R, Utsumi D, Kiso M, Yasuhara A, Poon VK, Chan CC, Fujino Y, Motoyama S, Nagata S, Penninger JM, Kamada H, Yuen KY, Kamitani W, Maeda K, Kawaoka Y, Yasutomi Y, Imai Y, Kuba Keiji
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Journal Title
Nature Communications
Volume: 12
Issue: 1
Pages: 6791-6791
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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