HCMV inhibition of cytotrophoblast differentiation through dysregulation of Wnt/?

描述（由申请人提供）：人类巨细胞病毒（HCMV）是一种普遍存在的疱疹病毒，目前感染了世界上很大一部分人口。尽管在免疫正常的个体中通常无症状，但妊娠期感染HCMV可能导致自然流产、早产或在子宫内感染的婴儿永久性神经功能障碍。在许多情况下，显示感染迹象的是胎盘，而不是胚胎或胎儿。最近的研究表明，HCMV感染抑制细胞滋养细胞（CTB）的侵袭，导致浅胎盘。拟议研究的总体目标是确定HCMV在胎盘期间损害CTB侵袭的分子机制。在感染过程中，病毒对多种宿主信号通路施加控制。我们的初步数据表明，¿-catenin的转录活性显著

DESCRIPTION (provided by applicant): Human Cytomegalovirus (HCMV) is a ubiquitous herpesvirus that currently infects a large percentage of the world population. Although usually asymptomatic in immunocompetent individuals, HCMV infection during pregnancy may cause spontaneous abortions, premature delivery, or permanent neurological disabilities in infants infected in utero. In many cases, it is the placenta, not the embryo or fetus that shows evidence of infection. Recent studies have demonstrated that HCMV infection inhibits cytotrophoblast (CTB) invasion resulting in shallow placentation. The overall goal of the proposed studies proposed is to determine the molecular mechanism(s) by which HCMV impairs CTB invasion during placentation. During infection, the virus exerts control over a multitude of host signaling pathways. Our preliminary data show that the transcriptional activity of ¿-catenin is significantly inhibited in HCMV infected CTBs. ¿-catenin is the key factor in the canonical Wnt/¿-catenin signaling pathway that has recently been shown to be critical for invasive differentiation of CTBs during placentation; however, the effect of HCMV on this pathway is unknown. The hypothesis to be tested is that HCMV inhibits CTB differentiation and function through dysregulation of canonical Wnt/¿-catenin signaling. Aim 1 will employ an innovative in vitro model of placental trophoblast differentiation employing newly discovered human primary trophoblast progenitor cells (TBPCs) and rotating wall vessel (RWV) bioreactor technology in order to determine the effect of HCMV infection on early and late stages of trophoblast differentiation and demonstrate the importance of canonical Wnt/¿-catenin signaling during TBPC differentiation, and the effect of HCMV infection on Wnt/¿-catenin signaling. Aim 2 will define the molecular crosstalk between peroxisome proliferator-activated receptor gamma (PPAR?) and ¿-catenin pathways during CTB differentiation. PPAR? has been shown to control trophoblast invasion and differentiation, as well as negatively regulate ¿-catenin. The transcription factor E2F1 that is activated by HCMV UL97 is postulated to be key to the convergent regulation of these pathways. An understanding of the mechanisms underlying dysregulation of Wnt/¿-catenin signaling following infection of CTBs by HCMV may provide new prognostic and therapeutic approaches to reduce the risks of congenital infection and prevent complications during pregnancy.