Dissecting the haematological and immune components of preeclampsia and their functional significance - the role of placental extracellular vesicles
lead supervisor: dr manu vatish, Nuffield Department of Women’s and Reproductive Health
Commercial partner: Sysmex UK, Milton Keynes
Preeclampsia (PE), a placentally-driven disease, is a leading cause of maternal and fetal morbidity/mortality worldwide, causing >75,000 maternal and 500,000 perinatal deaths annually. Whilst well recognized in the UK, the incidence of hypertensive disorders in Africa (10%) and Asia (8%) exceeds UK case numbers and highlights the global importance of the project. Worldwide, clinicians remain unable to determine who will get PE or how severe it will be.
The syncytiotrophoblast (STB), the placental layer in direct contact with the mother’s circulation releases extracellular vesicles (EVs) in normal pregnancy but in significantly greater amounts in PE. Circulating STBEV contribute significantly to PE pathogenesis (clotting, immune and endothelial function) Specific STBEV interrogation of circulating EVs could be a vital diagnostic breakthrough. Through ‘omics studies, we have identified several promising biomarkers (significantly different in STBEV from normal and PE). We have successfully tested and validated the Sysmex/JVC Exocounter (a new EV analysing device) for quantitation and detection of STBEVs with disease characteristics in plasma.
Equally importantly, the evolution of haematological and immunological dysfunction in PE is incompletely defined despite sophisticated diagnostic devices (e.g. SYSMEX XN analysers) being widely available. Their wide range of technical capabilities has not been fully exploited to dissect PE-specific changes. Indeed, most obstetricians are unaware of their abilities and accessibility (SYSMEX devices process 50% of ALL EDTA tubes globally). Improving knowledge in this area could benefit the global health community since findings could be translated without need for additional equipment.
1) Quantify circulating STBEVs (carrying a unique marker – placental-alkaline-phosphatase) using a new Sysmex/JVC device (Exocounter), which uses antibody-based capture/interrogation with laser-counting to precisely measure specific STBEVs in plasma. We will interrogate/quantify circulating STBEV in both biobanked and clinical samples.
2) Investigate longitudinal pregnancy (normal and PE) changes in haematological/immune function (in an Oxford patient cohort), using Sysmex clinical analysers, providing large amounts of reproducible data and are available in all tiers of health-care worldwide.
3) Explore the effects of STBEV (normal/PE) on haematological, immune and endothelial cell-lines using proteomic, transcriptomic and advanced imaging data.
4) Integrate data from 1), 2) & 3) to identify potential pathways implicated in disease in order to create biological/clinical evidence for the medically relevant phenotypic changes identified in 2).
5) Utilize the combined international networks of NDWRH and Sysmex to establish a worldwide patient validation cohort, (including African and Asian patients) to ensure the findings of 2) are translatable and can impact patient care globally.
6) Empower the student to develop/commercialize relevant discoveries in local, regional or global markets