VEGFD regulation and function in the brain: Focus on neuroprotective activity against stroke-induced dendrite pathology.

血管内皮生长因子D （VEGFD）是一种新发现的成年小鼠大脑神经元形态和认知能力的调节剂（Mauceri等，2011）。它是突触NMDA受体-核钙信号通路的靶点，并介导神经元活动对维持记忆形成所需的树突树突形成的影响。神经元树突的作用是接收和处理突触输入。树突乔木的几何形状的变化，如长度的减少或分支模式的简化，可能会影响生物体的认知表现。事实上，在包括唐氏综合症和阿尔茨海默病在内的几种伴有精神残疾的神经系统疾病中，已经观察到树突的结构改变；它们也与中风后的兴奋性毒性和癫痫发作时过度的突触活动有关。我们最近未发表的研究结果表明，刺激突触外NMDA受体（兴奋性毒性和其他神经退行性疾病中细胞死亡途径的关键启动物）会导致vegf表达显著降低。这表明中风引起的树突改变和vegf功能的急性丧失之间可能存在因果关系。在这里，我们建议研究缺氧缺血条件下突触外NMDA受体激活导致vegf表达关闭的机制。我们将使用体外海马细胞培养模型进行氧-葡萄糖剥夺以及小鼠中风模型来分析vegf表达的变化，表征所涉及的信号通路，并同时监测树突的形态学改变。最后，我们将研究vegf和短vegf肽模拟物在预防中风诱导的神经元损伤和促进功能恢复方面的治疗潜力。

Vascular Endothelial Growth Factor D (VEGFD) is a newly identified regulator of neuronal morphology and cognitive abilities in the adult mouse brain (Mauceri et al., 2011). It is a target of the synaptic NMDA receptor-nuclear calcium signaling pathway and mediates the effects of neuronal activity on the maintenance of dendrite arborization that is required for memory formation. The role of neuronal dendrites is to receive and process synaptic inputs. Changes in the geometry of the dendritic arbor, such as a reduction in length or simplification of the branching patterns, may impact on the cognitive performances of the organism. Indeed, structural alterations of the dendrites have been observed in several neurological disorders with mental inabilities, including Down syndrome and Alzheimers disease; they are also associated with excitotoxicity following a stroke and excessive synaptic activity during seizures. Our recent unpublished results indicate that the stimulation of extrasynaptic NMDA receptors, which are key initiators of cell death pathway in excitotoxicity and also in other neurodegenerative conditions (Hardingham and Bading, 2010), causes a dramatic reduction in VEGFD expression. This suggests a possible causal link between stroke-induced dendrite alterations and the acute loss of VEGFD function. Here we propose to investigate the mechanism through which extrasynaptic NMDA receptor activation by hypoxic-ischemic conditions cause a shut-off of VEGFD expression. We will use an in vitro hippocampal cell culture model for oxygen-glucose deprivation as well as an in vivo mouse stroke model to analyze changes in VEGFD expression, characterize the signaling pathways involved, and monitor, in parallel, morphological alterations of the dendrites. Finally, we will investigate the therapeutic potential of VEGFD and short VEGFD peptide mimetics in protecting against stroke-induced neuronal damage and in facilitating functional recoveries.