多溴联苯醚致神经血管单元损伤的分子机制研究

PBDEs是环境中广泛存在的持久性有机污染物，神经系统损伤（如神经发育障碍）是PBDEs的主要毒性效应之一。已有的研究主要关注神经细胞损伤，缺乏对神经组织非神经细胞毒性的探讨。本项目将从神经血管单元角度，以环境和生物样品（尤其是人体）中主要的PBDE单体--BDE-47为研究对象，采用高通量单细胞RNA测序技术，分析出生早期BDE-47暴露引起的神经血管单元各组分（神经元、胶质细胞、血管内皮细胞和周细胞）的单细胞基因表达变化特征。基于异类细胞间和同类细胞间比较，探讨神经血管单元各组分毒性反应的异同点和细胞间的异质性。通过体外细胞和整体动物实验，深入研究PBDEs引起的神经元损伤、神经血管发育异常和血脑屏障功能障碍机制，重点关注对神经-血管相互作用的影响，识别神经系统损伤的关键分子事件、毒性通路及其细胞定位，为阐明PBDEs神经毒性机制、筛选生物标志物及生物监测提供重要依据。

PBDEs, a class of persistent organic pollutants, are ubiquitous in the environment. Neurotoxicity (such as developmental neurotoxicity) is one of their major adverse effects. Given that previous studies were mainly focused on neural cells and the effects on non-neural cells are largely unknown, this project is to investigate the neurotoxic effects of BDE-47, a predominant PBDE in the environmental and biological samples (particularly in human tissues), on the neurovascular unit (NVU) which consists of neuronal cells, glial cells, vascular endothelial cells, and pericytes. High-throughput single-cell RNA sequencing and bioinformatics will be applied to characterize the single-cell gene expression profiles of NYU from mice postnatally treated with BDE-47. With the comparisons among different types of cells or identical type of cells, we sought to clarify the shared and disparate responses of cells and cellular heterogeneity of NVU exposed to BDE-47. In addition, we will perform a number of in vitro and in vivo experiments to demonstrate the mechanisms of neuronal injury, neurovascular developmental defect and the impairment of blood-brain barrier with an emphasis on neurovascular interaction. This study will help to identify the key molecules, signaling pathways and their cellular localizations correlated with PBDEs exposure, which will provide valuable insights into the elucidation of neurotoxic effects, screening of biomarkers and biological monitoring of PBDEs.