The role of Skp2 in macrophage proliferation in atherosclerotic lesion
Project/Area Number |
17K09863
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Research Field |
Metabolomics
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Research Institution | Kumamoto University |
Principal Investigator |
ISHII NORIO 熊本大学, 病院, 特任助教 (10599111)
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Co-Investigator(Kenkyū-buntansha) |
瀬ノ口 隆文 熊本大学, 大学院生命科学研究部(医), 助教 (00530320)
近藤 龍也 熊本大学, 病院, 講師 (70398204)
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Project Period (FY) |
2017-04-01 – 2020-03-31
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Project Status |
Completed (Fiscal Year 2019)
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Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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Keywords | 動脈硬化症 / マクロファージ / 細胞周期 / 動脈硬化 |
Outline of Final Research Achievements |
The presence of proliferating macrophages in the atherosclerotic lesion of atherosclerosis model mice was confirmed, and these macrophages had a high proportion of Skp2 expression.On the other hand, proliferation-suppressed macrophages showed increased ubiquitination of p27kip, whereas p27kip was less endogenously expressed in macrophages and was not altered by proliferation stimulation, but its expression was increased by induction of AMPK activity. Macrophages overexpress Skp2 in response to proliferation stimulation; stimulation by AMPK suppresses ubiquitination-mediated p27kip expression, while simultaneously increasing p27kip expression and ultimately causing G1 arrest of the cell cycle. AMPK and Skp2 may be novel therapeutic target molecules for atherosclerosis in that they suppress atherosclerosis via Mφ proliferation inhibition.
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Academic Significance and Societal Importance of the Research Achievements |
動脈硬化における巣増殖マクロファージではユビキチンリガーゼSkp2発現が増加しており、AMPK刺激による増殖抑制は、Skp2によるp27kipユビキチン化低下に伴うp27kip発現増加を認め、最終的に細胞周期G1 arrestを誘導する可能性が示された。今回の研究を通じて動脈硬化症の発症・進展においてマクロファージのAMPK、Skp2およびp27kipが重要な役割を担っていることを明らかにした。マクロファージ増殖阻害を介して動脈硬化症の発症・進展を抑制するという新たな治療法の確立においてAMPK、Skp2およびp27kipが有力な分子標的となり得ることが証明された。
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Report
(4 results)
Research Products
(18 results)
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[Journal Article] Inhibition of local macrophage growth ameliorates focal inflammation and suppresses atherosclerosis.2018
Author(s)
Yamada S, Senokuchi T, Matsumura T, Morita Y, Ishii N, Fukuda K, Murakami S, Nishida S, Kawasaki S, Motoshima H, Furukawa N, Komohara Y, Fujiwara Y, Koga T, Yamagata K, Takeya M, Araki E
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Journal Title
Arteriosclerosis, Thrombosis, and Vascular Biology
Volume: 印刷中
Issue: 5
Pages: 994-1006
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Presentation] Effects of linagliptin on macrophages and on progression of atherosclerosis in high fat-fed apoE-deficient mice.2019
Author(s)
Nishida S, Matsumura T, Senokuchi T, Ishii N, Murakami-Nishida S, Yamada S, Morita Y, Wada T, Motoshima H, Kondo T, Araki E
Organizer
The 11th Scientific Meeting of the Asian Association for the Study of Diabetes. 2019/5/23,
Related Report
Int'l Joint Research
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[Presentation] Pioglitazone Suppresses Macrophage Proliferation in Apolipoprotein-e Deficient Mice by Activating PPARγ.2019
Author(s)
Murakami-Nishida S, Matsumura T, Nishida S, Senokuchi T, Ishi N, Yamada S, Morita Y, Wada T, Motoshima H, Kondo T, Araki E
Organizer
The 79th ADA Scientific Meetng. 2019/6/8
Related Report
Int'l Joint Research
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[Presentation] Linagliptin induces M2 macrophage polarization and suppresses progression of atherosclerosis in high fat-fed apoE-deficient mice.2019
Author(s)
Nishida S, Matsumura T, Senokuchi T, Ishii N, Murakami-Nishida S, Yamada S, Morita Y, Wada T, Motoshima H, Kondo T, Araki E
Organizer
The 79th ADA Scientific Meeting. 2019/6/10
Related Report
Int'l Joint Research
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[Presentation] Empagliflozin suppresses atherosclerotic lesion formation in apolipoprotein E deficient mice by inhibiting macrophage activation.2018
Author(s)
Matsumura T, Murakami-Nishida S, Senokuchi T, Ishii N, Nishida S, Kondo T, Motoshima H, Araki E.
Organizer
54th EASD Annual Meeting, Berlin, Germany, Oral.
Related Report
Int'l Joint Research
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[Presentation] マクロファージ局在のSGLT2を標的とした新規糖尿病大血管症抑制機序の解明.2018
Author(s)
西田彩子, 松村 剛, 瀬ノ口隆文, 石井規夫, 山田沙梨恵, 守田雄太郎, 西田周平, 佐藤美希, 本島寛之, 近藤龍也, 荒木栄一
Organizer
第61回日本糖尿病学会総会 東京, 口演
Related Report
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[Presentation] Empagliflozin, a sodium-glucose cotransporter 2 inhibitor, suppresses the progression of atherosclerosis in diabetic apoE-deficient mice2017
Author(s)
Murakami S, Matsumura T, Senokuchi T, Ishii N, Fukuda K, Yamada S, Morita Y, Nishida S, Sato M, Motoshima H, Kondo T, Araki E
Organizer
The 8th AASD Scientific Meeting
Related Report
Int'l Joint Research
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[Presentation] エンパクリフロジンによる糖尿病大血管症進展抑制効果の検討.2017
Author(s)
村上彩子, 松村 剛, 瀬ノ口隆文, 石井規夫, 福田一起, 山田沙梨恵, 守田雄太郎, 西田周平, 佐藤美希, 本島寛之, 近藤龍也, 荒木栄一
Organizer
第60回日本糖尿病学会総会
Related Report
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[Presentation] エンパクリフロジンによる糖尿病大血管症進展抑制効果の検討2017
Author(s)
村上彩子, 松村 剛, 瀬ノ口隆文, 石井規夫, 福田一起, 山田沙梨恵, 守田雄太郎, 西田周平, 佐藤美希, 本島寛之, 近藤龍也, 荒木栄一
Organizer
第67回日本体質医学会総会
Related Report
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[Presentation] SGLT-2阻害薬によるマクロファージ活性抑制を介した糖尿病大血管症進展抑制効果の解析2017
Author(s)
松村剛, 村上彩子, 瀬ノ口隆文, 石井規夫, 山田沙理恵, 守田雄太郎, 西田周平, 久木留大介, 本島寛之, 近藤龍也, 沼田朋大, 荒木栄一
Organizer
第32回日本糖尿病合併症学会
Related Report
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