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Supervisors: Professor Chris O'Callaghan, Mr William Dawes
Investigating the Pathogenetic Mechanisms of Hydrocephalus and Neurodevelopmental Delay following Neonatal Intraventricular Haemorrhage and Developing New Targeted Therapeutics
Background:
Neonatal intraventricular haemorrhage (NIVH) in babies born prematurely is common, devastating and without treatment. It is the leading cause of hydrocephalus and neurodevelopmental delay in children. With the rate of premature birth continuing to increase and survival from extreme prematurity becoming the norm rather than the exception, finding new treatments to mitigate the secondary brain injury, caused by the toxic impact of blood in the CSF, is of paramount importance.
Aims:
The primary aim of this project is to develop novel cell and tissue-based platforms to facilitate testing novel therapeutic interventions to reduce the rate of hydrocephalus and improve neurodevelopmental outcome following NIVH of prematurity.
Objectives
To build on world class collaborations established with the Crick Institute London and the MRC Toxicology Unit in Cambridge to:
(1) Analyse the impact that NIVH has on the cerebrospinal fluid
(2) Characterise the human multiciliated ependymal cells, which line the walls of the ventricular system
(3) To define the injury phenotype resulting from exposure to blood-stained CSF.
(4) To develop and test novel therapies aimed at mitigating the damage to the ependymal cell layer and the periventricular tissues.
Methods:
(1) We have privileged access to samples of human CSF taken from neonates with NIVH (and non IVH controls). This is collected as part of the ENLIVEN, DOLPHIN and BASICS clinical trials. An omic approach with bioinformatic analysis will be used to analyse the impact of NIVH on the CSF.
(2) We have privileged access to samples of tissue taken from the wall of the human lateral ventricle as part of the SOLVe trial. Serial block face focused ion beam electron microscopy will be used for ultrastructural analysis of the human multiciliated ependymal cell.
(3) The impact of blood-stained CSF on neuronal, astrocytic and microglial cultures will be analysed using RNA sequencing with orthogonal validation from human tissue samples.
(4) Multiciliated ependymal cell cultures will be developed from the wall of the human lateral ventricle from tissue accessed as part of the SOLVe trial.
References:
1. Dawes W Secondary brain injury following neonatal intraventricular haemorrhage: The role of the ciliated ependyma. Frontiers in Paediatrics 2022 (in press)
2. Dolphin Uk Collaborators: A Standardised Protocol for Neuroendoscopic Lavage for Post-haemorrhagic Ventricular Dilatation: A Delphi Consensus Approach. Medrxiv 2022
3. Dawes W, Obernier K, Tisdall M: Modelling neonatal intraventricular haemorrhage using organotypic samples from the wall of the lateral ventricle. Journal of Neurology, Neurosurgery & Psychiatry March 2019, 90(3)e26-e25
4. Dawes WJ, Zhang X, Fancy SPJ, Rowitch D, Marino S: Moderate-Grade Germinal Matrix Haemorrhage Activates Cell Division in the Neonatal Mouse Subventricular Zone. Developmental Neuroscience 2016;38(6):430-444
5. www.PremBrain.com