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

大脑中的 VEGFD 调节和功能：重点关注针对中风引起的树突病理的神经保护活性。

• 批准号: 233992346
• 负责人: Professor Dr. Hilmar Bading
• 金额: --
• 依托单位: Interdisziplinäres Zentrum für Neurowissenschaften (IZN)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/233992346?language=en
• 关键词: VEGFD; regulation; function; brain; Focus

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 Our recent unpublished results indicate that the stimulation of extrasynaptic NMDA receptors, which are key initiators of cell death pathway in excitotoxicity and also in other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.

血管内皮生长因子D（VEGFD）是新鉴定的成年小鼠脑中神经元形态和认知能力的调节剂（Mauceri等人，2011年）。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枝化的影响。神经元树突的作用是接收和处理突触输入。树枝状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性能。事实上，树突的结构改变已经在几种神经系统疾病中观察到，包括唐氏综合征和阿尔茨海默病;它们也与中风后的兴奋性毒性和癫痫发作期间过度的突触活动有关。我们最近未发表的结果表明，突触外NMDA受体的刺激导致VEGFD表达显著降低，所述突触外NMDA受体是兴奋性毒性以及其他神经退行性疾病中细胞死亡途径的关键起始物（Hardingham和Bading，2010）。这表明中风引起的树突改变和VEGFD功能的急性丧失之间可能存在因果关系。在这里，我们建议调查的机制，通过突触外NMDA受体激活缺氧缺血条件下导致关闭VEGFD的表达。我们将使用体外海马细胞培养模型的氧-葡萄糖剥夺以及体内小鼠中风模型来分析VEGFD表达的变化，表征所涉及的信号通路，并监测，在平行，树突的形态学改变。最后，我们将研究VEGFD和短VEGFD肽模拟物在预防卒中诱导的神经元损伤和促进功能恢复方面的治疗潜力。