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PROJECT TITLE

Studying the role of mitophagy in Pre-eclampsia 

DESCRIPTION OF PROJECT

Pre-eclampsia (PET) is a major cause of poor outcome in pregnancy.  It is a leading cause of maternal deaths worldwide.  Furthermore pre-eclampsia can lead to stillbirth, fetal growth restriction, low birth weight, preterm delivery, respiratory distress syndrome, and admission to neonatal intensive care. Mitochondrial disease is one of many risk factors for PET but the role of mitochondria has not been extensively studied.

PET is a disease of the placenta in two stages. The first stage, occurring in early pregnancy,  concerns the relative failure of early trophoblast invasion and remodelling of the spiral arteries, leading to a poor blood supply to the placenta, exposing it to oxidative stress. The second stage is the maternal syndrome, which is characterised by a generalised systemic inflammatory response, likely signalled by premature placental ageing. MV has recently optimised a new biomarker of PET based on the ratio of two angiongenic factors in the maternal circulation, soluble fms-like tyrosine kinase (sFlt-1) and placental growth factor (PlGF).  sFlt-1 alters angiogenic balance and leads to an anti-angiogenic state. Administration of exogenous sFlt-1 to pregnant rats leads to reduced PlGF and a PET-like syndrome. However, these feature are only present in the second stage of the disease.     

Oxidative stress, the hallmark of the first stage, disrupts pluripotent stem cell function, and this is linked to mitochondrial dysfunction.  Hence impaired mitochondrial quality control could play a key role in PET.  Mitophagy (a type of mitochondrial recycling) is one such cellular process that play a key role in maintaining stem cell health, in which damaged mitochondrial fragments are engulfed by autophagosomes characterised by LC3.  We hypothesise that dysregulated mitophagy plays a key role in PET and that drug modulators of mitophagy might protect against it.  Mitochondrial diseases could lower the threshold for other PET risk factors by overloading the placenta’s capacity for mitophagy and ageing syncytiotrophoblast stem cells.

We will test these hypotheses by looking for evidence of decreased mitophagy in trophoblast/explants from women with PET compared to controls using (i) next generation sequencing to detect damaged mtDNA (ii) high throughput imaging to identify co-localisation of mitochondria and autophagosomes.  We will further characterise these processes in our bank of placenta from women with PET +/- mitochondrial disease.  We will also model the effects of hypoxia and sFlt-1 on mitophagy in vivo and ex vivo models.  In one such model mitophagy can be visualised because mitochondria and autophagosomes are labelled with fluorescent markers.

 

Training opportunities

This project spans two multi-disciplinary, dynamic groups based at the Nuffield Department of Women's & Reproductive Health, with strong links to other centres locally (e.g. Oxford Vesicle Group, Weatherall Institute for Molecular Medicine, Target Discovery Institute, Welcome Trust Centre for Human Genetics  the Big Data Institute and the Specialist Mitochondrial Disorders Service (NHS Highly Specialised Service) within the Oxford Genetics laboratory).

Students will be strongly encouraged to publish their work, present at international conferences, attend biweekly group meetings, journal clubs, as well as departmental seminars and training courses. Above projects will be utilising a broad spectrum of molecular biology methods including high throughput fluorescence microscopy, primary cell cultures, placental perfusion, and flow cytometry. Additional techniques may include high-throughput sequencing (targeted, exome, whole genome, single cell transcriptomics) and Western blotting as well as immunoprecipitation.

The university also provides a wide-range of training opportunities.