HCMV inhibition of cytotrophoblast differentiation through dysregulation of Wnt/?

HCMV 通过 Wnt/? 失调抑制细胞滋养层分化

• 批准号: 8492957
• 负责人: Deborah E Sullivan
• 金额: $ 22.58万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8492957
• 关键词: Affect; Bioreactors; Cell Cycle Regulation; Cell Differentiation process; Cell Nucleus; Cell physiology; Congenital Abnormality; Critical Pathways; Cyclin D1; Cytomegalovirus; Cytomegalovirus Infections; Data; E2F Transcription Factor 1; E2F1 gene; Embryo; Embryonic Development; Fetal Growth Retardation; Fetus; First Pregnancy Trimester; Gene Targeting; Genetic Transcription; Goals; Herpesviridae; Human; Immunocompetent; Individual; Infant; Infection; Injury; MMP2 gene; MMP9 gene; Microarray Analysis; Modeling; Molecular; Neurologic; Newborn Infant; PPAR gamma; Pathology; Pathway interactions; Pharmaceutical Preparations; Phosphotransferases; Placenta; Placentation; Population; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Premature Birth; Protein Kinase; Proteins; Publishing; Regulation; Reporting; Risk; Signal Pathway; Signal Transduction; Spiral Artery of the Endometrium; Spontaneous abortion; Staging; Stem cells; TCF Transcription Factor; Technology; Testing; Therapeutic; United States; Viral; Virion; Virus Diseases; Woman; Work; congenital infection; cytotrophoblast; disability; in utero; in vitro Model; inhibitor/antagonist; innovation; interest; migration; prevent; prognostic; public health relevance; trophoblast

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.

描述（由申请人提供）：人巨细胞病毒（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。虽然在免疫功能正常的个体中通常无症状，但妊娠期间的HCMV感染可导致自发性流产、早产或宫内感染婴儿的永久性神经功能障碍。在许多情况下，是胎盘，而不是胚胎或胎儿显示感染的证据。最近的研究表明，HCMV感染抑制细胞滋养层细胞（CTB）的入侵，导致浅胎盘。提出的研究的总体目标是确定HCMV在胎盘形成期间损害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。我们的初步数据显示，连环蛋白的转录活性显著地 在HCMV感染的CTB中抑制。<$-连环蛋白是经典Wnt/<$-连环蛋白信号传导途径中的关键因子，该途径最近被证明对于胎盘形成期间CTB的侵袭性分化至关重要;然而，HCMV对该途径的影响尚不清楚。待检验的假设是HCMV通过典型Wnt/β-连环蛋白信号传导的失调抑制CTB分化和功能。目的1将采用新发现的人原代滋养层祖细胞（TBPC）和旋转壁血管（RWV）生物反应器技术建立一种创新的胎盘滋养层分化体外模型，以确定HCMV感染对滋养层分化早期和晚期的影响，并证明经典Wnt/Wnt信号通路的重要性。TBPC分化过程中的β-catenin信号传导，以及HCMV感染对Wnt/β-catenin信号传导的影响。目的2将定义过氧化物酶体增殖物激活受体γ（PPAR？）和β-连环蛋白途径。PPAR？已经显示出控制滋养层细胞的侵袭和分化，以及负调节β-连环蛋白。被HCMV UL 97激活的转录因子E2 F1被认为是这些途径的会聚调节的关键。了解HCMV感染CTB后Wnt/<$-catenin信号转导失调的潜在机制可能提供新的预后和治疗方法，以降低先天性感染的风险并预防妊娠期并发症。