EV71和CA16是手足口病最重要的病原体，二者能够引起中枢神经系统损伤，对婴幼儿的健康构成巨大的威胁，但二者进入中枢神经系统的机理仍不清楚。我们前期研究发现MMP9在EV71和CA16感染的恒河猴体内及人血管内皮细胞上都显著性上升，且microRNA测序分析结果提示miR-1303可能在EV71和CA16感染中靶向调控MMP9。本课题拟在前期研究的基础上，利用体外细胞和体内SCARB2人源化小鼠模型，探讨病毒调控miR-1303的方式，以及miR-1303是否能靶向调控MMP9介导的血管内皮细胞之间的连接分子的降解过程，最终阐明EV71和CA16打破血脑屏障进入中枢神经系统的机制，在此基础上结合临床样本分析，寻找miR-1303、MMP9与EV71和CA16感染患者临床症状严重程度的相关性，以期为EV71和CA16感染的临床治疗提供候选靶标以及为重症手足口病患者的诊断提供早期预警分子。

Enterovirus 71 (EV71) and coxsackievirus A16 (CA16), as major etiological pathogens of hand, foot and mouth disease (HFMD), caused severe neurological complications which have been emerged as a serious threat to the public health among infants and young children. However, the underlying mechanisms which make the two viruses entry into central nervous system (CNS) remain elusive. Our previous studies have demonstrated that matrix metalloproteinase 9 (MMP9) presented significantly increased in rhesus monkey and human umbilical vein endothelial cells (HUVECs) infected with EV71 and CA16. Moreover, we also found that MMP9 might be the direct target gene of miR-1303 by analysis of high-throughput sequencing. Herein, based on the above research, we aim to adopt an in vitro model using HUVECs and an in vivo model using scavenger receptor class B member 2 (SCARB2) humanized mouse to investigate the regulation mechanisms between viruses and miR-1303, and further explore whether miR-1303 direct targets MMP9 which might degrade tight junctions or adherens junctions molecules and ultimately facilitate EV71 and CA16 to destruct blood-brain barrier and invade CNS. Additionally, clinical samples were used to further verify the correlations between the expression levels of miR-1303 and MMP9 and the severe degree of EV71- and CA16-infected patients. These findings might not only offer novel targets for clinical therapy, but also provide an early warning molecular for the diagnosis of severe HFMD cases.