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Epigenetic placental alterations in preeclampsia

English title Epigenetic placental alterations in preeclampsia
Applicant Hahn Sinuhe
Number 129654
Funding scheme Project funding
Research institution Labor für Pränatale Medizin und Gynäkologische Onkologie Frauenklinik / Universität Basel
Institution of higher education University of Basel - BS
Main discipline Gynaecology
Start/End 01.04.2010 - 31.05.2013
Approved amount 375'000.00
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All Disciplines (3)

Discipline
Gynaecology
Molecular Biology
Genetics

Keywords (10)

microRNA; preeclampsia; epigenetics; methylation; trophoblast; cell-free nucleic acids; placenta; miRNA; gene regulation; differentiation

Lay Summary (English)

Lead
Lay summary
Preeclampsia is a severe disorder of pregnancy for which there is no known cure, other than delivery, frequently involving very premature babies. The underlying cause of preeclampsia appears to involve the placenta, as most cases with preeclampsia resolve upon removal of the placenta. Furthermore, many cases of early onset severe preeclampsia are characterized by abnormal placental development. These pathologic changes involve the failure of invasive cytotrophoblast cells to adequately modify the maternal spiral arteries, thereby leading to an inadequate blood flow, resulting in placental hypoxia.The changes, however, may be more subtle, as is evident from the slightly altered villous structure in cases with preeclampsia. The villous tree is a unique tissue, in that it is covered by a single multinucleate cell layer, the syncytiotrophoblast. The syncytiotrophoblast has a surface area of many square meters, and is the source of a considerable amount of micro-debris, that is released into the maternal circulation. This material has been shown to have inflammatory characteristics, and can trigger a reaction by maternal immune cells. Recent studies have suggested that the maternal immune response to such placental particulate matter may be overtly strong. In neutrophils, this debris triggers a process termed netosis, whereby these cells release their DNA into the extracellular environment. Examinations of placental sections in cases with preeclampsia have shown that the inter-villous space is filled by neutrophils that have undergone netosis.The question therefore arises why more inflammatory placental micro-debris is released during preeclampsia, than in normal healthy pregnancies? One possible explanation is that the reduced blood flow in preeclampsia leads to abnormal syncytiotrophoblast development. This deregulation would then lead to the increased release of inflammatory micro-debris by this tissue, thereby triggering an overt maternal immune reaction.In order to study this facet in more detail, we plan to examine the molecular genetic pathways regulating the process of syncytialization, and then determine whether these are affected by conditions associated with preeclampsia, such as hypoxia. In this study we will focus on the potential role of miRNA molecules. This is because these unique small regulatory molecules, have been shown to play a key role in development and differentiation. Due to the complexity of placental tissue, we will first study in-vitro model systems, and then determine whether any key regulatory events we have detected, are pathologically altered in preeclamptic placentae.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
miR455 is linked to hypoxia signaling and is deregulated in preeclampsia
Lalevee Sebastien, Lapaire Olav, Bühler marc (2014), miR455 is linked to hypoxia signaling and is deregulated in preeclampsia, in Cell Death Dis, 4(5), e1408.

Collaboration

Group / person Country
Types of collaboration
Department of Pathology, Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Medical University Graz Austria (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure

Scientific events



Self-organised

Title Date Place
Autumn Symposium on Feto-Maternal Health 22.11.2012 Basel, Switzerland
Basel-Aarau Research Retreat 22.09.2012 Engelberg, Switzerland
Autumn Symposium on Maternal Health: Bench to Bedside 24.11.2011 University Hospital Basel, Switzerland

Knowledge transfer events



Self-organised

Title Date Place
Autumn Symposium on Feto-Maternal Health 22.11.2012 Basel, Switzerland
Basel-Arrau Research Retreat 20.09.2012 Engelberg, Switzerland
Autumn Symposium on Maternal health: Bench to Bedside 24.11.2011 University Hospital Basel, Switzerland

Associated projects

Number Title Start Funding scheme
107625 Examination of the inflammatory nature of different placental syncytiotrophoblast micro-particles (STBM) preparation on maternal endothelial and immune cells 01.04.2005 Project funding

Abstract

Background: Epigenetic mechanisms have been shown to be important in the regulation of gene expression, especially during tissue differentiation. These include methylation of regulatory gene sequences, as well as gene modulation by microRNAs (miRNAs). Preeclampsia (PE) is a severe pregnancy-related disorder. The underlying etiology has been proposed to involve aberrant differentiation of placental trophoblast tissues. miRNA molecules and epigenetically modified DNA sequences can be detected in plasma in the form of cell-free nucleic acids.Working Hypothesis: PE involves alterations in epigenetic regulation leading to aberrant trophoblast differentiation.Aim: To examine for possible epigenetic mechanisms (miRNA and methylation) controlling trophoblast syncytialization, tissue modification/invasion or response to hypoxia/hyperoxia, in order to determine whether these play a role in the underlying etiology of PE.Experiment Design: In addition to affected placentae, use will be made of villous explant cultures and established trophoblast-like cell lines (BeWo and Jeg-3), in order to establish experimental techniques. miRNA mechanisms regulating trophoblast differentiation, syncytialization and response to O2 stress will be examined for by “deep sequencing” technology. Epigenetically silenced genes regulating these events will be screened for using a MeDIP (Methyl-DNA immunoprecipitation) approach, as well as pharmacological unmasking by treatment with 5-aza-2’-deoxycytodine (5-AZT). Alterations in protein expression levels will be confirmed by quantitative iTraq mass spectrometry. The pathological significance of miRNA or unmasked target genes will be reaffirmed by the blinded analysis of villous tissue from preeclamptic and healthy placentae, and their biomarker potential will be examined for using a dedicated maternal plasma bio-bank.Expected value of the proposed project: This interdisciplinary and inter-institutional research project could shed new light on potentially crucial regulatory mechanisms controlling placental development and their possible dysregulation in pregnancy-related pathologies (PE). Key regulatory molecules detected during this process could serve as the basis for a new generation of screening markers to reliably detect at-risk pregnancies.
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