肿瘤新生血管存在迂曲、内皮连接疏松、平滑肌覆盖不全等结构异常，加重肿瘤缺氧微环境和侵袭转移等恶性表型，促使肿瘤对化/放疗抵抗，但其分子机制不完全清楚。我们发现，阻断内皮Notch信号可引起肿瘤血管结构异常；而激活Notch可使肿瘤血管结构部分"正常化"，提示内皮Notch信号是影响肿瘤血管结构的关键通路之一。本项目拟采用内皮特异性RBP-J基因敲除/NICD转基因小鼠模型，探索Notch信号对小鼠移植瘤血管结构的影响，及其对肿瘤生长、转移和化疗应答的作用；在已完成Notch下游分子芯片筛选的基础上，鉴定Notch信号调控肿瘤血管结构的关键分子，阐明其作用机制；设计干预Notch信号促进肿瘤血管结构"正常化"的新分子，评价其对肿瘤血管结构的影响。本项目可揭示Notch信号对肿瘤血管结构的调控作用、其下游分子及与其他信号通路的相互作用，为干预肿瘤血管结构提供潜在新靶点，具有重要的理论和实际意义

The vessels of maliganant tumors are characterized by multiple structural abnormalities including tortuous shape, loosed endothelial interconnections, and incomplete smooth muscle cell coverage, among others, leading to aggravated tumor hypoxia, invasion and metastasis, and resistance to chemo- and radio-therapies. The molecular mechanisms underlying abnormal vessel structure in tumors are unclear. Recent literatures and our data have shown that blocking Notch signaling leads to structural abnormalities in tumor vessels, while activating Notch signaling ameliorates tumor vessel abnormalities, suggesting that Notch signaling might play an important role in the formation of normal structure in tumor neo-vasculature. In the current research, by employing endothelium-specific RBP-J conditional knockout and NICD transgenic mouse models, we will investigate the effects of endothelium-specific Notch blocking/activating on the structure of vessels in xenogenic tumors. We will also observe the effects of endothelium-specific Notch blocking/activating on tumor growth, metastasis, and chemotherapy, and the relationship with tumor vessel structure. Moreover, based on a preliminary comparison of gene expression profiles using gene chips, we will identify the downstream molecules of Notch signaling in the regulation of structural formation of tumor vessels, and try to elucidate the mechanisms of Notch signaling in the regulation of tumor vessel structure. Finally, we planned to establish methods to intervene with tumor vessel abnormality based on the roles of Notch signaling. These studies will reveal new molecular mechanisms underlying tumor vessel abnormalities, and will provide further evidence and targets for the intervening of tumor vessels.