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Dr O Cordero Llana,
Prof James Uney
Applications accepted all year round
Self-Funded PhD Students Only
About the Project
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 perinatal brain injury in preterm infants is bleeding extending from the germinal matrix into the lateral ventricles of the brain, 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 the brain (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 that can improve developmental outcomes in preterm infants with IVH
Methodology
The student will use the following techniques: culturing of human neural progenitor cells and human induced pluripotent stem cells; 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 (Germany). The applicant will be based predominantly at Bristol but will also be offered the opportunity to undertake part of this work at the University of Oldenburg.
Apply for this project
This project will be based in Bristol Medical School - Translational Health Sciences.
Please contact brms-pgradmin@bristol.ac.uk for further details on how to apply.
References
1. Spaull R, McPherson B, Gialeli A, Clayton A, Uney J, Heep A, Cordero-Llana Ó. Exosomes populate the cerebrospinal fluid of preterm infants with post-haemorrhagic hydrocephalus. 2019. Int J Dev Neurosci. Jan 9;73:59-65.
2. Jiménez, Antonio Jesús, José Manuel García-Verdugo, César Aliro González, Luis Federico Bátiz, Luis Manuel Rodríguez-Pérez, Patricia Páez, Mario Soriano-Navarro, et al. 2009. Disruption of the Neurogenic Niche in the Subventricular Zone of Postnatal Hydrocephalic Hyh Mice. Journal of Neuropathology and Experimental Neurology 68 (9): 1006–20.
3. Lehtinen, Maria K., Mauro W. Zappaterra, Xi Chen, Yawei J. Yang, Anthony D. Hill, Melody Lun, Thomas Maynard, et al. 2011. The Cerebrospinal Fluid Provides a Proliferative Niche for Neural Progenitor Cells. Neuron 69 (5): 893–905.
4. Morales, D.M., Townsend, R.R., Malone, J.P., Ewersmann, C.A., Macy, E.M., Inder, T.E., and Limbrick, D.D., 2012. Alterations in protein regulators of neurodevelopment in the cerebrospinal fluid of infants with posthemorrhagic hydrocephalus of prematurity. Molecular & cellular proteomics: MCP, 11 (6), M111.011973.
5. Pellegrini L, Bonfio C, Chadwick J, Begum F, Skehel M, Lancaster MA. Human CNS barrier-forming organoids with cerebrospinal fluid production. Science. 2020 Jul 10;369(6500):eaaz5626.
2. Jiménez, Antonio Jesús, José Manuel García-Verdugo, César Aliro González, Luis Federico Bátiz, Luis Manuel Rodríguez-Pérez, Patricia Páez, Mario Soriano-Navarro, et al. 2009. Disruption of the Neurogenic Niche in the Subventricular Zone of Postnatal Hydrocephalic Hyh Mice. Journal of Neuropathology and Experimental Neurology 68 (9): 1006–20.
3. Lehtinen, Maria K., Mauro W. Zappaterra, Xi Chen, Yawei J. Yang, Anthony D. Hill, Melody Lun, Thomas Maynard, et al. 2011. The Cerebrospinal Fluid Provides a Proliferative Niche for Neural Progenitor Cells. Neuron 69 (5): 893–905.
4. Morales, D.M., Townsend, R.R., Malone, J.P., Ewersmann, C.A., Macy, E.M., Inder, T.E., and Limbrick, D.D., 2012. Alterations in protein regulators of neurodevelopment in the cerebrospinal fluid of infants with posthemorrhagic hydrocephalus of prematurity. Molecular & cellular proteomics: MCP, 11 (6), M111.011973.
5. Pellegrini L, Bonfio C, Chadwick J, Begum F, Skehel M, Lancaster MA. Human CNS barrier-forming organoids with cerebrospinal fluid production. Science. 2020 Jul 10;369(6500):eaaz5626.
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