Molecular mechanism of cooperation between endothelial cell stiffness and functions.
| Project/Area Number |
19K08583
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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 | Shimane University |
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Principal Investigator |
Okamoto Takayuki 島根大学, 学術研究院医学・看護学系, 准教授 (30378286)
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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: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | 血管内皮細胞 / 細胞硬化 / 炎症 / 細胞骨格 / ギャップ結合 / 細胞接着 / メカノバイオロジー / 血管障害性疾患 / YAP |
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| Outline of Research at the Start |
我々は炎症時に血管内皮細胞が硬くなることを明らかにしてきた。本研究では、この細胞の硬化が、細胞の機能制御にどのように関わるかを解析する。ここでは細胞の硬さと機能を制御する可能性がある転写共役分子YAPに着目し、YAPの阻害または活性化が細胞の硬さ、細胞骨格の編成、細胞間相互作用に及ぼす影響を解析し、同時に血管内皮細胞機能の障害（炎症、血液凝固の病的活性化）がどのようにして連動して誘導されるのかを解明する。さらに動脈硬化症および血栓症モデルマウスを用いてYAPの活性化と病変部の形成および硬さ変化を解析する。一連の研究によって、血管硬化を基盤にした血管病変の形成機構を明らかにする。
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| Outline of Final Research Achievements |
In the current study, we analyzed the mechanisms by which endothelial cells increased cell stiffness upon inflammatory stimuli to regulate cellular functions. We found that cytoskeletal reorganization and activation of the transcriptional coactivator YAP, are implicated in cell stiffening upon inflammatory stimuli, lead to suppress Notch1 signaling. Our data also revealed that the expression of pro-inflammatory and angiogenesis related genes in endothelial cells is regulated under Notch1 signaling pathway. Furthermore, we showed that recombinant thrombomodulin protein, an anticoagulant and anti-inflammatory factor, attenuates leukocyte adhesion by inducing cell softening. In summary, our results indicate intracellular signaling and cellular functional changes associated with endothelial cell stiffening and suggest that this molecular pathway may be useful for the control of vascular inflammation.
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| Academic Significance and Societal Importance of the Research Achievements |
動脈血管の弾性増加（硬化）は、心血管イベント発症のリスクであり、また敗血症の予後不良に繋がる可能性が指摘されている。これは血管硬化が血栓形成や炎症の活性化を助長することを示唆し、我々は血管内皮細胞の硬化が炎症の増悪化を招く可能性を示してきた。本研究では細胞硬化を基軸として炎症拡大を引き起こす新しい分子機構を明らかにした点で学術的価値に優れる。また、本分子機構が動脈硬化や敗血症の基盤に存在する血管炎症を制御するための標的となる可能性を示し、これら疾患の新しい治療法への応用に繋がると考える。
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Report
(4 results)
Research Products
(39 results)
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[Journal Article] Endotoxins and Non-Alcoholic Fatty Liver Disease2021
Author(s)
Kessoku T, Kobayashi T, Imajo K, Tanaka K, Yamamoto A, Takahashi K, Kasai Y, Ozaki A, Iwaki M, Nogami A, Honda Y, Ogawa Y, Kato S, Higurashi T, Hosono K, Yoneda M, Okamoto T, Usuda H, Wada K, Kobayashi N, Saito S, Nakajima A
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Journal Title
Frontiers in Endocrinology
Volume: 12
Pages: 770986-770986
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] The Lectin-Like Domain of Thrombomodulin Inhibits β1 Integrin-Dependent Binding of Human Breast Cancer-Derived Cell Lines to Fibronectin.2021
Author(s)
Kawamoto E, Nago N, Okamoto T, Gaowa A, Masui-Ito A, Akama Y, Darkwah S, Appiah MG, Myint PK, Obeng G, Ito A, Caidengbate S, Esumi R, Yamaguchi T, Park EJ, Imai H, Shimaoka M.
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Journal Title
Biomedicines
Volume: 9
Issue: 2
Pages: 162-162
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Anti-adhesive effects of human soluble thrombomodulin and its domains2019
Author(s)
Kawamoto Eiji、Nago Nodoka、Okamoto Takayuki、Gaowa Arong、Masui-Ito Asami、Sakakura Yosuke、Akama Yuichi、Soe Zay Yar、Prajuabjinda Onmanee、Darkwah Samuel、Appiah Michael G.、Myint Phyoe Kyawe、Obeng Gideon、Park Eun Jeong、Imai Hiroshi、Shimaoka Motomu
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Journal Title
Biochemical and Biophysical Research Communications
Volume: 511
Issue: 2
Pages: 312-317
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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