HCMV inhibition of cytotrophoblast differentiation through dysregulation of Wnt/?

Summary

Principal Investigator: Deborah E Sullivan
Abstract: 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 [unreadable]-catenin is significantly inhibited in HCMV infected CTBs. [unreadable]-catenin is the key factor in the canonical Wnt/[unreadable]-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/[unreadable]-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/[unreadable]-catenin signaling during TBPC differentiation, and the effect of HCMV infection on Wnt/[unreadable]-catenin signaling. Aim 2 will define the molecular crosstalk between peroxisome proliferator-activated receptor gamma (PPAR?) and [unreadable]-catenin pathways during CTB differentiation. PPAR? has been shown to control trophoblast invasion and differentiation, as well as negatively regulate [unreadable]-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/[unreadable]-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.
Funding Period: 2013-09-15 - 2015-08-31
more information: NIH RePORT

Detail Information

Research Grants30

  1. Pluripotent human stem cells as models for normal and diseased trophoblast
    ROBERT MICHAEL ROBERTS; Fiscal Year: 2013
    ..Also by generating such pluripotent cells from umbilical cords of babies born to mothers that developed pre-eclampsia, we hope to recreate the cell type that caused the disease in the first place. ..
  2. Role of the Renin-Angiotensin system in placental insufficiency
    Eugenia Mata-Greenwood; Fiscal Year: 2013
    ..In addition, the outcomes of this proposal will shed light into the role of RAS genetics in pregnancy outcomes and will provide the scientific community with a novel animal model to study the genetics of placental insufficiency and PE. ..
  3. Small RNAs at the placental maternal communication interface
    Yoel Sadovsky; Fiscal Year: 2013
    ....
  4. Fetal HCMV Infection: Role of the Human Placenta
    LENORE PALMA PEREIRA; Fiscal Year: 2013
    ..These could have clinical application in conjunction with biotherapeutic antibodies that suppress HCMV replication, prevent placental dysfunction and improve chances for a healthy baby. ..
  5. HIF-1 Alpha Regulation of Trophoblast Differentiation in Vivo
    Thomas L Brown; Fiscal Year: 2013
    ..Understanding how oxygen sensing regulators control normal placental development will help us understand how pregnancy-associated disorders arise, can be detected, and treated. ..
  6. Stanford University Center for Reproductive and Stem Cell biology
    Margaret T Fuller; Fiscal Year: 2013
    ..abstract_text> ..
  7. Novel Ubiquitin Dependent Pathways Regulating Neural Tube Closure &Placentation
    Irene E Zohn; Fiscal Year: 2013
    ..The understanding gained from the experiments proposed here may lead to strategies to minimize these complications of pregnancy. ..
  8. Center for the Study of Reproductive Biology and Women's Health
    Jeffrey W Pollard; Fiscal Year: 2013
    ..He holds several senior administrative appointments in the College of Medicine and is well able to administer the proposed SCCPIR internally and to enable effective interactions with other SCCPIRs. ..
  9. Semi-volatile PCBs: Sources, Exposures, Toxicities
    Larry W Robertson; Fiscal Year: 2013
    ..These data and dietary studies in the last Aim will provide a scientific basis for risk assessment and advice for stakeholders with the ultimate goal to protect highly-exposed individuals and populations. ..
  10. Adrenomedullin Signaling at the Maternal-Fetal Interface
    Kathleen M Caron; Fiscal Year: 2013
    ....
  11. Function of Toll-Like Receptors Throughout Gestation
    GIL G MOR; Fiscal Year: 2013
    ....
  12. GATA Factor Function in Trophoblast
    Soumen Paul; Fiscal Year: 2013
    ..We will also determine whether GATA3 have differentiation stage specific target genes. ..
  13. Molecular and Cellular Controls of Placental Metabolism
    Yoel Sadovsky; Fiscal Year: 2013
    ..Our findings may pave the way to clinical research into disease biomarkers, therapeutics and prevention. ..