| Project/Area Number |
18H02970
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Basic Section 57020:Oral pathobiological science-related
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| Research Institution | National Institute for Physiological Sciences (2019-2020)
Osaka University (2018) |
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Principal Investigator |
Maruyama Kenta 生理学研究所, 生体機能調節研究領域, 特別協力研究員 (60724119)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000)
Fiscal Year 2020: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2019: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2018: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
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| Keywords | 敗血症 / 血管新生 / 血管透過性 / VEGF / St18 / マクロファージ / 骨粗鬆症 / 骨破壊 / 浮腫 / 痛覚 / 疼痛 / 骨代謝 |
|---|
| Outline of Final Research Achievements |
St18 was initially reported as candidate tumor suppressor gene. Despite the pleiotropic functions of St18, little is known about its roles in macrophages. Here, we report that myeloid St18 is a potent inhibitor of VEGF-A. Mice lacking St18 in myeloid lineages exhibit increased retinal vasculature with enhanced serum VEGF-A concentrations. Despite the normal activation of NF-κB target genes, these mice are highly susceptible to LPS-induced shock, polymicrobial sepsis, and experimental colitis, accompanied by enhanced vascular and intestinal leakage. Pharmacological inhibition of VEGF signaling rescued the high mortality rate of myeloid-specific St18-deficient mice in response to inflammation. Mechanistically, St18 directly binds to Sp1 and attenuates its activity, leading to the suppression of Sp1 target gene VEGF-A. Using mouse genetic and pharmacological models, we reveal myeloid St18 as a critical septic death protector.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究によって、St18がVEGFの抑制因子であることが判明した。St18の発現を誘導することのできる化合物を発見できた場合には、VEGFのかかわる様々な疾患（敗血症、癌、糖尿病網膜症) の治療が可能となる。
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