半胱天冬酶Caspase-4/11通过抑制Dll4-Notch1信号通路促进血管新生的机制研究

血管新生对生长发育及缺血性疾病的发生起着至关重要的作用。Dll4-Notch1信号在血管新生中起着重要作用，但相关调控机制仍未完全阐明。本课题组发现在后肢缺血模型中，Caspase-11(人同源的为Caspase-4基因)全身敲除小鼠血管新生能力明显受损。离体试验发现敲减Caspase-4显著降低内皮细胞成管能力。我们发现抑制内皮细胞Caspase-4的表达后，γ-Secretase的活性明显增强，其Dll4-Notch1信号通路活化增加。因此，我们提出假设:Caspase-4/11通过抑制γ-Secretase的活性下调Dll4-Notch1信号，继而促进血管新生。本项目将用全身和内皮特异性小鼠从离体、在体及分子水平证实该假设，为治疗血管新生类疾病提供新的治疗靶标。

Angiogenesis plays an important role in development and ischemic diseases. Dll4-Notch1 signaling pathway is critical for angiogenesis. However, the related mechanisms are poorly understood. In vivo, we showed that Caspase-11 (human homologue Caspase-4) global KO mice had significant impaired angiogenesis in hindlimb ischemia model. In vitro, depletion of Caspase-4 in human umbilical vein endothelial cells (HUVECs) by siRNA remarkably decreased the tube formation. Indeed, we demonstrated the massively increased γ-Secretase activity in Caspase-4 knockdown HUVECs. Furthermore, inhibition of Caspase-4 enhanced Dll4-Notch1 signaling pathway. Based on the evidence, we hypothesized that Caspase-4/11 promoted angiogenesis by suppressing γ-Secretase activity and downregulating Dll4-Notch1 signaling. To prove this hypothesis, we will study the role of Caspase-4/11 in angiogenesis by Caspase-11 global and endothelial specific knock out mice, and the related molecular mechanisms. Successfully accomplishment of this proposal will provide a novel therapeutic strategy on angiogenesis related diseases.