Notch通过Slit/miR-218/Robo1信号调控血管形成的作用和机制研究

血管形成中，Notch信号通过决定顶端细胞和茎细胞分化等环节调控血管芽的生长，但Notch作用的下游分子和机制仍不完全清楚。最近，申请人用小RNA测序对比了来自条件激活性Notch胞内段转基因小鼠的内皮细胞和野生型内皮细胞的miRNA表达谱，发现在Notch激活的内皮细胞（相当于茎细胞）中，miR-218表达明显升高。miR-218抑制Robo1，而Robo1促进血管形成。因此Notch信号很可能通过miR-218抑制Robo1来调控血管形成中血管芽的生长。本课题拟①明确内皮细胞中Notch信号通过miR-218调控Robo1的机制；②阐明Notch-Slit/miR-218/Robo1信号对内皮细胞表型的调控作用；③揭示Notch-Slit/miR-218/Robo1信号对生理和病理性血管形成的作用和机制。这些研究不仅可进一步阐明血管形成的分子调控网络，还可为其干预提供潜在新策略。

During angiogenesis, Notch signaling regulates the formation and growth of sprouts by several mechanisms including the segregation of tip and stalk cells. However it has not yet been completely understood how Notch signaling regulates sprouting and results in differential phenotypes of endothelial cells. Recently, we compared miRNA expression profiles between endothelial cells (ECs) with forced Notch activation (conditional overexpression of Notch intracellular domain or NICD) and wild type ECs by using small RNA sequencing, and found that miR-218 was highly expressed in ECs with Notch activation (equivalent to stalk cells). It has been reported that in ECs, miR-218 represses Robo1, which promotes angiogenesis. We therefore speculate that Notch signaling likely regulates sprouting and the differentiation of tip and stalk cells through Slit/miR-218/Robo1 pathway. In the current project, we will ① elucidate the mechanisms of Notch signal-mediated modulation of Slit/Robo1 through miR-218 in ECs; ② reveal the role of Notch signaling in regulating ECs phenotypes through Slit/miR-218/Robo1; and ③ clarify the significance of Notch- Slit/miR-218/Robo1 pathway in physiological and pathological angiogenesis such as tumor neovascularization. These studies will further reveal the molecular network underlying angiogenesis, and provide potentially novel strategies for intervening with pathological neovascularization.