Exploring the role of JAK/STAT and NFKB signalling pathways in the onset of immune-related preeclampsia
Rationale and Objectives
Preeclampsia (PE) is a pregnancy-associated disorder characterised by the onset of hypertension that occurs after 20 weeks of gestation . It is a leading cause of maternal and perinatal mortality worldwide (15-20% in developed countries). An immune maladaptation of the mother to the foetus, involving the activity of the NFK-B and JAK/STAT signalling pathways, might be underlying the incomplete trophoblast invasion and causing the early onset of PE. The importance of going deeper in understanding PE relies mainly on its unpredictable progression and the absence of effective treatment. This makes essential to develop preventive strategies allowing PE prediction/detection before the onset of its clinical manifestations.
1) Identify genetic variants in the JAK/STAT and NFKB signalling pathways that might predispose to the PE onset by exploring the unique cohort of primary immunodeficient patients available at the clinical laboratories. Novel genetic variants associated with PE will be identified by performing a custom WGS analysis against JAK/STAT- and NFKB-related genes.
2) Assess the potential of JAK/STAT and NFKB genetic variants to alter trophoblast formation in cellular models. Human induced pluripotent stem cells (hereafter hiPSCs), established from PB-MNCs of primary deficient women harbouring genetic variants that correlate with PE (identified in aim1), will be differentiated into trophoblast cells and the impact of the genetic variants evaluated by sc-RNAseq and sc-ATAC-seq.
3) Exploit chromatin accessibility at cell-free foetal DNA (cffDNA) as an early molecular biomarker for PE. Specific accessibility signatures in cfDNA allows for determining the PE-associated apoptosis in the trophoblast. Transcription factors (TFs) potentially binding to the PE-differential chromatin accessible regions will be identified. Finally, the predicted TFs will be compared to the genetic variants correlated with PE onset identified in the patient cohort to validate the PE prediction based on cell-free foetal DNA.
This project aims at identifying novel molecular biomarkers in DNA and cell free DNA that can help better predict PE. DNA analysis through next generation sequencing will likely uncover mutations in the JAK/STAT, NFKB and related signalling pathways whose clinical significance will be tested using cellular models. Moreover, cell free DNA analyses will likely uncover chromatin accessibility patterns that can be related to early onset PE. These results will be incorporated into a model for the early detection of PE.
RFHMO (Stepensky/Schejter) (m10-m11 -1month-) and UKLFR (m11-m12 -1month-) to optimise sample preparation and recruitment; GRL (Vento-Tormo) to profile by sc-omics the impact of specific mutations on trophoblast cells, m25-27 (2 months); and EMBL (Zaugg) to infer the footprints of specific transcription factors in the cfATAC-seq datasets generated, m28-m30 (2 months).
PhD in Biomedicine, University Pompeu Fabra (UPF), Barcelona, Spain