Preterm infants, born at under 32-weeks gestation, are at risk of long-term neurodevelopmental impairment including cerebral palsy and compromised cortical development. The most common cause of damage is bleeding into the lateral ventricles, called intraventricular haemorrhage (IVH). Severely affected infants progress to hydrocephalus which is a build-up of cerebrospinal fluid (CSF) due in part to reactive astrogliosis leading to impairment of CSF flow through the brain. CSF is generated by the choroid plexus and during development the composition of this CSF is highly dynamic including a variable population of Endosome-derived extracellular vesicles (EVs). Previous research in our laboratory has shown selective enrichment in proteins and microRNAs within CSF-EVs during IVH progression (Spaul 2019). We have also found that exosomal microRNAs from preterm infants cause a premature neurodevelopmental shift towards astrocyte differentiation of human fetal neural stem cells in vitro which could underlie the reactive astrogliosis seen in vivo (Gialeli, in press). We now wish to develop an in vitro model of IVH using human CNS barrier-forming organoids which have been shown to be able to produce CSF (Pellegrini 2020).
Aims and Objectives
Our overarching aim is to improve neurodevelopmental outcomes of preterm infants suffering intraventricular haemorrhage. Our objectives are:
- To establish a developmental profile of CNS barrier-forming organoids / assembloids and how this recapitulates human cerebroventricular development.
- To profile miRNA and EV content of organoid-derived CSF and how this is affected by IVH-like insults.
- To develop pharmacological interventions targeting astrogliosis / pro-inflammatory pathways.
The student will use the following techniques: culturing of hfNPCs and iPSCs, neural organoid and assembloid differentiation, RNA analysis, qPCR, Western blot analysis microRNA seq, proteomics, bioinformatics, immunofluorescence, high-content microscopy, confocal microscopy, AAV/lenti-viral gene knock-down, immuno assays/ELISAs and bioinformatics. This project is a collaboration between the Regenerative Medicine Laboratories at the University of Bristol and the Perinatal Neurobiology Department at the University of Oldenburg. The applicant will be based predominantly at Bristol but will also be expected to undertake work at the University of Oldenburg
iPSC, organoids, neurodevelopment, intraventricular haemorrhage, neurogenesis, gliogenesis, choroid plexus
How to apply for this project
This project will be based in Bristol Medical School - Translational Health Sciences in the Faculty of Health Sciences at the University of Bristol.
Please visit the Faculty of Health Sciences website for details of how to apply