人巨细胞病毒感染介导的蛋白质磷酸化修饰对外周神经细胞异常分化影响的分子机制研究

人巨细胞病毒（HCMV）先天感染主要引起小头畸形等中枢神经异常和先天性巨结肠、听力丧失等外周神经缺如或损伤性疾病。文献报道HCMV通过泛素化降解Hes1等方式扰乱胎脑神经前体细胞分化，但关于HCMV感染对外周神经系统影响的机制尚不清楚。前期，我们使用从胚胎外胚层神经嵴衍生的乳牙牙髓干细胞（SHED）证实了HCMV感染阻碍了SHED向神经细胞分化；细胞中参与蛋白质磷酸化修饰基因的转录水平显著增加，细胞分化相关信号通路发生紊乱，调控向神经细胞分化的分子转录异常。推测，HCMV感染通过调控蛋白质磷酸化修饰影响细胞分化相关信号通路和参与分化形成神经细胞过程调控分子的表达，导致SHED向神经细胞分化异常。本项目使用SHED进行研究，将揭示HCMV先天感染对同样起源于外胚层神经嵴的外周神经系统影响的分子机制，为先天性巨结肠、听力丧失等HCMV先天感染引起的外周神经缺如或损伤疾病的有效防治提供科学依据。

The main diseases caused by congenital human cytomegalovirus (HCMV) infection are those with dysfunction of central neural system as microcephaly and with defects of peripheral neurons as congenital megacolon and hearing loss. It has been reported that by degradation of Hes1 through ubiquitination and other ways, HCMV disrupts differentiation of neural precursor cells from neonatal brain. However, the interfering mechanism of HCMV on differentiations of peripheral neurons is still unclear. Using stem cell from human exfoliated deciduous teeth (SHED) that derived from neural crest of ectoblast, our preliminary experiments demonstrated that HCMV infection disrupted the differentiation of SHED to neurons, significantly increased the transcriptional levels of genes related to phosphorylation modification in the cells, and dysregulated the signaling pathways that play important roles in cell differentiation as well as the transcriptions of key functional molecules for regulation of neural cell differentiation. We hypothesized that HCMV infection affect expressions of the key functional molecules in the signaling pathways and regulation molecules relate to neural cell differentiation, by regulating phosphorylation modification, and result in dysrugulation of differentiation from SHED to neurons. Using SHED from peripheral tissues, the study will has the opportunity to discover the mechanisms of congenital megacolon and hearing loss that caused by HCMV congenital infection and showed deletion or abnormality of their peripheral neurons. The accomplishment of this project will provide scientific data for developing the evaluative prevention tools to HCMV congenital infections.