| Project/Area Number |
17K15988
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Cardiovascular medicine
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| Research Institution | The University of Tokyo |
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Principal Investigator |
WATANABE Aya 東京大学, 医学部附属病院, 特任助教 (10647887)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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| Keywords | Arid5b / 腫瘍関連マクロファージ / マクロファージ特異的Arid5bノックアウト / 血管新生 / 網羅的遺伝子発現検索 / 次世代シーケンサー / クロマチン免疫沈降 / ルシフェラーゼレポーターアッセイ / LL/2腫瘍細胞皮下移植 / 新生血管の成熟化 / フローサイトメーター / 分子血管学 |
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| Outline of Final Research Achievements |
LL/2 tumors implanted into macrophage-specific Arid5 knockout mice (mutant mice) showed larger than that of wild type. In addition, immunohistochemical staining revealed that neovascularization in tumors transplanted to mutant mice had smaller vessel diameter, less tortuous and more mature than wild type. The population of immune cells in tumors was investigated by flow cytometry, and there was no significant difference between mutant mice and wild type. On the other hand, as a result of RNA sequencing, the expression of genes responsible for angiogenesis was reduced in tumor associated macrophages of mutant mice. To identify the target gene of Arid5b, ChIP sequencing was performed. Consequently, significant enrichment was found in the promoter region of cFos, and we confirmed the direct binding of Arid5b to the AP-1 sequence by the luciferase reporter assay. Finally, We have identified cFos, which is also involved in Vegfa expression, as one of the target gene of Arid5b.
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| Academic Significance and Societal Importance of the Research Achievements |
本邦における死因の第一位は悪性新生物(平成30年、27.4%)、第二位は心疾患(同15.3%)であり、第四位の脳血管疾患(同7.9%)と合わせると血管疾患と悪性腫瘍とで半数以上を占める。虚血性疾患や悪性腫瘍の病態において血管新生・血管網の発達、腫瘍免疫は重要な因子であり、これらを治療のターゲットとした抗Vegf薬、抗PD-L1・PD-1抗体などが広く知られている。本研究によりマクロファージにおけるArid5bが血管新生を制御する遺伝子の調整に関与していることが明らかになり、Arid5bが新しい治療ストラテジーのターゲットとなり得ることが示された。
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