Regulation of atheroscllerosis by lymphatic endothelial calpain sysmtems
| Project/Area Number |
19K08590
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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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| Review Section |
Basic Section 53020:Cardiology-related
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| Research Institution | Showa University |
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Principal Investigator |
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| Project Period (FY) |
2019-04-01 – 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: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2020: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | カルパイン / リンパ管内皮細胞 / タンパク質分解 / 制御性T細胞 / 動脈硬化症 / 脂質異常症 / リンパ球／制御性T細胞 / TGF-beta / リンパ / 制御性T細胞 / リンパ |
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| Outline of Research at the Start |
申請者はこれまで血管機能を制御する極めてユニークな機構として、ストレス応答性細胞内プロテアーゼ「カルパイン」ファミリーを検証し、同機構が動脈硬化症、網膜症および腫瘍血管などの病態下で血管内皮細胞機能異常の主因となることを解明した。本研究提案では、リンパ管内皮細胞のタンパク質分解異常がいかにして動脈硬化症の形成に寄与するか、制御性T細胞との相互作用を中心に分子メカニズムの解明を目指す。
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| Outline of Final Research Achievements |
This study investigated whether the calpain systems in lymphatic endothelial cells (LECs) associate with the LEC-lymphocyte interaction under hypercholesterolemia. Lipidomic analysis in hypercholesterolemic mice showed that several lysophospholipids, including lysophosphatidic acid (LPA), accumulated in the lymphatic environment. LPA enables the potentiation of calpain systems in cultured LECs, which limits their ability to stabilize regulatory T cells (Treg) without altering other T cell subsets. Targeting calpain systems in LECs expanded Tregs in the blood circulation under hypercholesterolemia, concomitant with the redistribution of Tregs in lymphoid organs. Moreover, LPA-induced calpain overactivation potentiated the IL-18/NF-kB/VCAM1 axis in LECs, thereby inhibiting lymphocyte mobility on the cells. Thus, calpain systems in LECs have a key role in controlling Treg stability and trafficking under hypercholesterolemia.
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| Academic Significance and Societal Importance of the Research Achievements |
一連の結果から、リンパ管内皮細胞のカルパインシステムは、脂質異常症存在下のリンパ管の形態維持だけでなく、制御性T細胞の安定性や動態にも影響することが判明した。既報から、脂質異常症においてリンパ管がリポタンパク質や免疫細胞の輸送経路として重要であることは明らかとなっていたが、直接的な免疫細胞の制御に関わっていることは本研究において初めて解明された。本研究は、動脈硬化症の発症原因の包括的な理解に資するものと期待される。
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Report
(4 results)
Research Products
(35 results)
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[Journal Article] Effects of lipid metabolism on mouse incisor dentinogenesis.2020
Author(s)
Kurotaki, Y., Sakai, N., Miyazaki, T., Hosonuma, M., Sato, Y., Karakawa, A., Chatani, M., Myers, M., Suzawa, T., Negishi-Koga, T., Kamijo, R., Miyazaki, A., Maruoka, Y., Takami, M.
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Journal Title
Scientific Reports
Volume: 10
Issue: 1
Pages: 5102-5102
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Light-at-night exposure affects brain development through pineal allopregnanolone-dependent mechanisms2019
Author(s)
Haraguchi S, Kamata M, Tokita T, Tashiro KI, Sato M, Nozaki M, Okamoto-Katsuyama M, Shimizu I, Han G, Chowdhury VS, Lei XF, Miyazaki T, Kim-Kaneyama JR, Nakamachi T, Matsuda K, Ohtaki H, Tokumoto T, Tachibana T, Miyazaki A, Tsutsui K.
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Journal Title
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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