Targeting macrophage pinocytosis in atherosclerosis
| Project/Area Number |
15K09418
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Metabolomics
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| Research Institution | Showa University |
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Principal Investigator |
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| Project Period (FY) |
2015-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2015: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
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| Keywords | 動脈硬化症 / 生活習慣病 / コレステロール / マクロファージ / タンパク質分解 / カルパイン / 動脈硬化 / mRNAスプライシング / エキソン接合部複合体 / 飲作用 / CWC22 / エクソンジャンクション複合体 / pre-mRNAスプライシング / カルパイン－６ |
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| Outline of Final Research Achievements |
We have investigated calpain proteolytic systems as a therapeutic target of the diseases, such as atherosclerosis, tumor angiogenesis and retinopathy. Calpains are intracellular calcium-dependent proteases, which contributes to the proteolytic processing of the target proteins thereby regulating cellular processes, such as inflammatory processes and cellular dynamics. Herein, we investigated the proatherogenic roles of calpain-6, an atypical non-proteolytic calpain member. It appears that calpain-6 disturbs mRNA splicing process of Rac1 by interfering with CWC22/exon junction complexes, resulting in the impaired pinocytotic incorporation of native LDL in macrophages. Accordingly, over expression of calpain-6 in macrophages aggravates atherosclerosis. In addition, our data showed that the contribution of calpain-6 in adipose stromal macrophages to obesity.
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| Academic Significance and Societal Importance of the Research Achievements |
現行の動脈硬化症の病態生理学は、マクロファージがスカベンジャー受容体依存的に酸化LDLを取込むことで泡沫化し、動脈硬化病変が形成される、いわゆる「酸化LDL仮説」に基づく。しかし、生体内に存在する LDL の多くはスカベンジャー受容体が認識するほど高度に酸化されておらず、同仮説だけでは実際に血管壁で起こるマクロファージ泡沫化を合理的に説明することはできなかった。本研究を通して、受容体非依存的なピノサイトーシス経路の一端が明らかとなり、マクロファージコレステロール代謝異常解明の一助となることが期待される。
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Report
(5 results)
Research Products
(48 results)
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[Journal Article] The impact of stromal Hic-5 on the tumorigenesis of colorectal cancer through lysyl oxidase induction and stromal remodeling.2018
Author(s)
Omoto T, Kim-Kaneyama JR, Lei XF, Orimo A, Ohnishi K, Yoshihara K, Miyauchi A, Li S, Gao L, Umemoto T, Tanaka J, Nakahara K, Takeya M, Ishida F, Kudo SE, Haraguchi S, Miyazaki T, Miyazaki A.
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Journal Title
Oncogene.
Volume: 37
Issue: 9
Pages: 1205-1219
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Calpain-6 confers atherogenicity to macrophages by dysregulating pre-mRNA splicing.2016
Author(s)
Miyazaki T, Tonami K, Hata S, Aiuchi T, Ohnishi K, Lei XF, Kim-Kaneyama JR, Takeya M, Itabe H, Sorimachi H, Kurihara H, Miyazaki A
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Journal Title
J Clin Invest
Volume: 126
Issue: 9
Pages: 3417-3432
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
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[Journal Article] Calpastatin counteracts pathological angiogenesis by inhibiting suppressor of cytokine signaling 3 degradation in vascular endothelial cells.2015
Author(s)
Miyazaki, T., Taketomi, Y., Saito, Y., Hosono, T., Lei, X.F., Kim-Kaneyama, J.R., Arata, S., Takahashi, H., Murakami, M., and Miyazaki, A.
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Journal Title
Circ. Res.
Volume: 116
Issue: 7
Pages: 1170-1181
DOI
Related Report
Peer Reviewed / Open Access
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