Notch与HIF-1信号转导通路cross-talk在脑海绵状血管瘤血管新生中作用

Cerebral cavernous malformation (CCM) is a most common cerebral vascular malformation, which can cause recurrent hemorrhage and lead to handicap or even death, increasing burdens to patients, families and the community. Our recently published data show that Notch signalling plays an important role in angiogenesis regulation of cerebral cavernous malformations. Moreover, interaction and cross-talk between Notch signalling and hypoxia induced HIF-1 expression has been reported recently, which involved in regulating multiple cellular biological functions of endothelia cells. However, the relationship of HIF-1 and Notch signalling in cerebral cavernous malformation has not yet been clarified. ..The present project is to address the mechanisms of cross-talk between Notch and HIF-1 and its role in regulation of cerebral cavernous malformation endothelial cells (CCMEC) at the molecular and functional level, in Vivo and in Vitro. To examine molecular cross-talk between HIF-1 and Notch signalling, some key molecules of HIF-1 and Notch signalling pathways will be evaluated when one or the other pathway is inhibited or activated. To determine the role of aforementioned cross-talk in cerebral cavernous malformation, endothelial angiogenesis assays under various interventions of HIF-1 and/or Notch signalling will be investigated. In addition, endothelial cells spheroid-based transplant assay will be used to prove the cross-talk between HIF-1 and Notch in vivo. Furthermore, transcriptome microassay will be applied to examine the change of gene expression profiles, and pathway network will be analyzed to define the relevant molecular mechanisms. The data generated from this novel study are highly expected to provide new molecular targets and new strategy for prophylaxis and non-surgical treatment of cerebral cavernous malformation..

脑海绵状血管瘤是最常见的脑血管畸形之一,病变反复出血可导致部分患者残疾甚至死亡，给患者、家庭乃至社会带来了很大的负担。申请者最近的研究及最新文献显示Notch信号通路在脑海绵状血管瘤血管新生中发挥重要调控作用。缺氧诱导产生的HIF-1可能与Notch信号通路产生cross-talk机制, 对内皮细胞多种生物学行为产生影响。基于此研究背景，本项目以脑海绵状血管瘤组织、内皮细胞、小鼠皮下移植内皮细胞球血管芽生模型为实验对象，研究干预HIF-1/Notch信号通路对各关键节点分子表达及生物学行为影响，采用基因微阵列检测基因表达谱变化，分析差异表达基因的功能和信号通路网络。揭示HIF-1和Notch信号通路cross-talk对脑海绵状血管瘤内皮细胞血管新生调控及机制，为以其关键信号通路节点为靶点的潜在非手术治疗和预防策略提供理论基础和实验依据。

脑海绵状血管瘤是最常见的脑血管畸形之一，病变反复出血可导致患者残疾甚至死亡，给患者、家庭乃至社会带来了很大的负担。前期研究显示Notch信号通路在脑海绵状血管瘤血管新生中发挥重要调控作用。缺氧诱导产生的HIF-1可能与Notch信号通路产生cross-talk机制, 对内皮细胞多种生物学行为产生影响。.基于此研究背景，本项目以脑海绵状血管瘤组织、内皮细胞、小鼠皮下移植内皮细胞球血管芽生模型为实验对象，研究干预HIF-1/Notch信号通路对各关键节点分子表达及内皮细胞生物学行为影响。.本研究证实了在内皮细胞中，Notch信号通路和HIF-1信号转导通路具有共表达，缺氧和HIF-1α对Notch信号通路关节节点分子表达正向调控，并激活Notch信号靶基因及下游通路，刺激VEGF以及其受体VEGF-R2表达增加，促进内皮细胞增殖、迁移和血管新生。相反的，通过RNA干扰抑制DLL4表达也能显著改变HIF-1α表达，但对HIF-1β表达无明显影响，提示DLL4表达直接与HIF-1α表达相关。揭示了HIF-1和Notch信号通路cross-talk，对内皮细胞增殖、迁移以及血管新生等细胞生物学行为调控机制，为以其关键信号通路节点为靶点的潜在非手术治疗和预防策略提供理论基础和实验依据。