兴奋性神经元通过Argonaute2调控脑血管网络形成的机制研究

大脑血管网络的构筑是一个高度复杂精细的过程，其发育的异常和障碍将影响整个中枢神经系统的功能，与神经性疾病发生紧密相关。目前，大脑血管网络形成原因的仍是一个未解之谜。Argonaute2作为RNA诱导沉默复合体的核心元件，参与到机体神经系统的发育过程当中。前期研究中，特异性敲除Vglut2兴奋性神经元的Ago2基因，能够抑制脑皮层神经的发育分化，而且还会影响神经血管的形态特征。进一步实验证实，Cadm1作为Ago2-miR128的直接作用底物，共存于神经元和血管内皮细胞中。因此，我们认为Ago2-miR128-Cadm1信号通路通过双向功能调节神经元与血管的互作关系，在时间和空间上协调中枢神经系统发育和神经血管网络的形成。本项目将利用基因工程小鼠，结合多种现代生物学前沿技术，研究脑血管网络发育的宏观规律与微观机制，阐明兴奋性神经元调控血管网络形成的分子机理，为进一步的临床治疗打下基础。

The formation of brain vasculature is a highly complicated and critical process. The irregular development of vacularization can cause dysfunction of the CNS and is associated with many neurological diseases. Until now, it is still unclear how the vascularization is formed during the CNS development. As a core element of RNA-induced silencing complex, Argonaute2 (Ago2) contributes to many physiological and pathological processes, and is especially important for neuronal development. In previous studies, we already generated Vglut2 excitatory neuron-specific Ago2-deficient mice. Loss of Ago2 in Vglut2 neuron can not only inhibit cerebral development, but also effect morphological distribution and patterns of brain vasculature. Further experiments indicated that Cadm1 is a direct target of Ago2-miR128 and expressed in both neurons and endothelial cells. Therefore, we hypothesize that Ago2-miR128-Cadm1 signaling pathway might be in the perfect position to perform a bivalent function to timely and spatially orchestrate both CNS development and vascularization. In the present project, several genetically engineered mice and different advanced bio-techniques will be used. We will investigate the molecular development of brain vasculature and explore the functional role of Ago2 in excitatory neurons on cerebral vascularization during development. This project will further provide basic research data for the potential clinic treatment in the future.