| Project/Area Number |
16K08575
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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 | Akita University |
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Principal Investigator |
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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: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | LPA / GPCR / 血管新生 / YAP/TAZ / DLL4 / Notch / Retinal angiogenesis / YAP / TAZ / LPA4 / LPA6 / リゾホスファチジン酸 / Sprouting / Gタンパク質共役型受容体 |
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| Outline of Final Research Achievements |
Lysophosphatidic acid (LPA)-Gα12/Gα13 signaling plays an important role in embryonic vascular development. However, the responsible LPA receptors and underlying mechanisms are poorly understood. Here, we show a critical role of LPA4 and LPA6 in developmental angiogenesis. In mice, Lpa4;Lpa6 double knockout (DKO) embryos were lethal due to global vascular deficiencies, and endothelial cell (EC)-specific Lpa4;Lpa6 DKO retinas had impaired sprouting angiogenesis. Mechanistically, LPA activated the transcriptional regulators YAP and TAZ through LPA4/LPA6-mediated Gα12/Gα13-Rho-ROCK signaling in ECs. YAP/TAZ knockdown increased β-catenin- and Notch intracellular domain (NICD)-mediated endothelial expression of the Notch ligand delta-like 4 (DLL4). Overall, these results suggest that the Gα12/Gα13-coupled receptors LPA4 and LPA6 synergistically regulate endothelial Dll4 expression through YAP/TAZ activation.
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| Academic Significance and Societal Importance of the Research Achievements |
DLL4は悪性腫瘍などの血管関連病態の発症に密接に関わる原因遺伝子として注目されている。本研究により明らかにされた血管内皮細胞におけるLPA-LPA4/LPA6シグナルが促すYAP/TAZ活性化と、その新規DLL4発現制御の分子機構は、血管形成の基礎的理解の進展にとどまらず、加齢黄斑変性症や悪性腫瘍などの病態解明とLPA受容体を標的とした治療薬開発のための有用な情報提供が期待できると考える。
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