| Project/Area Number |
16K08601
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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 |
General medical chemistry
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| Research Institution | Institute of Physical and Chemical Research |
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Principal Investigator |
Kitazume Shinobu 国立研究開発法人理化学研究所, 脳神経科学研究センター, 客員研究員 (80301753)
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| Project Period (FY) |
2016-04-01 – 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 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | 腫瘍血管新生 / シアル酸 / PECAM / インテグリン / VEGFR2 / アポトーシス / α2,6-シアル酸 / ST6Gal I / 血管内皮細胞 / 糖鎖 / ＶＥＧＦＲ２ / 化合物アレイ / 血管内内皮細胞 / 血管新生 / アンタゴニスト |
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| Outline of Final Research Achievements |
We found that ST6Gal I KO mice, which lack a2,6-sialic acid, exhibit retarded tumor growth due to impaired tumor angiogenesis. Actualy ST6Gal I KO endothelial cells exhibited a reduction in the cell surface residency of platelet endothelial cell adhesion molecule (PECAM). In this study, we found that in ST6Gal I KO cells, cell surface PECAM-VEGFR2 complexes were lost, and both VEGFR2 internalization and the VEGFR-dependent signaling pathway were enhanced. Second, enhanced anoikis was observed, suggesting that theabsence of α2,6-sialic acid leads to dysregulated integrin signaling. Taken together, acid, leading to abnormal signal transduction, resulting in enhanced endothelial apoptosis. Endothelial α2,6-sialylation could be a novel target for antiangiogenesis
therapy.
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| Academic Significance and Societal Importance of the Research Achievements |
血管内皮細胞におけるα2,6-シアル酸は、新規の抗血管新生阻害剤標的となり得ることが本研究から明らかになりました。α2,6-シアル酸欠損マウスは免疫系の軽微な異常が見られるため、阻害剤は免疫系の副作用をもたらす可能性があります。現在、α2,6-シアル酸を模倣した低分子化合物のスクリーニング中であり、将来的にPECAMの相互的結合を阻害するような選択的化合物を得られれば、新たな抗血管新生阻害剤の候補になると期待できます。
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