| Project/Area Number |
17K10763
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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 |
Cardiovascular surgery
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| Research Institution | Jichi Medical University |
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Principal Investigator |
Koji Kawahito 自治医科大学, 医学部, 教授 (90281740)
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| Co-Investigator(Kenkyū-buntansha) |
木村 直行 自治医科大学, 医学部, 教授 (20382898)
中村 匡徳 名古屋工業大学, 工学(系)研究科(研究院), 教授 (20448046)
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| Project Period (FY) |
2017-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥260,000 (Direct Cost: ¥200,000、Indirect Cost: ¥60,000)
Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2017: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
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| Keywords | 大動脈二尖弁 / 剪断応力 / 共培養モデル / 遺伝子発現解析 / 壁せん断応力 / 血管内皮細胞 / 血管平滑筋細胞 / 細胞間接着分子 / MMP / 数値流体力学計算 / 胸部大動脈拡大 / 先天性大動脈二尖弁 / 大動脈瘤 / 数値流体力学 / 遺伝子 |
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| Outline of Final Research Achievements |
We conducted a gene expression profiling using tissues and endothelial cells (EC)-smooth muscle cells (SMC) culture model. In patients with bicuspid valve, the ascending aorta tissues were harvested in the greater (high WSS) and lesser (low WSS) curvature, respectively (n=2-4). Three in vitro models, including EC monoculture, SMC monoculture, and EC-SMC coculture, were exposed to high (20 Pa) or low (2 Pa) WSS for 24 hours (n=2). RNAs were isolated in tissues and in vitro models for microarray.
Of 58341 probes, 1039 were differentially expressed (1.2> fold change and p<0.1) both in tissues and at least 1 in vitro model. The differentially expressed genes fell into 4 clusters: Cluster 1 (up in tissue and EC monoculture, n=147), Cluster 2 (up in tissue and all 3 models, n=289), Cluster 3 (down in tissue and all 3 models, n=205), and Cluster 4 (down in tissue and 1 model, n=398). Gene ontology analysis showed SMC migration, EC proliferation, and apoptosis pathways were affected by WSS.
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| Academic Significance and Societal Importance of the Research Achievements |
大動脈弁二尖弁は約半数の症例で上行大動脈が拡大する。胸部大動脈拡大は解離や破裂の原因となるため、病態解明は治療成績向上のため重要だが、大動脈二尖弁症例に合併する胸部大動脈拡大の発生機序は十分に解明されていない。
本研究により、大動脈二尖弁に特有な血行力学ストレスに感受性を有する遺伝子群と疾患経路が同定され、従来提唱されてきたMMP・TIMP代謝異常以外の疾患経路が存在する可能性が示唆された。大動脈二尖弁症例は、解離や破裂などの重篤な大動脈疾患の発生頻度が高いことが報告されているが、本研究成果は、治療成績向上につながる創薬および新規バイオマーカー開発につながる可能性を有する。
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