Sophie Quick wins David S Miller Young Scientist Award at 13th CVB Conference 2019
Congratulations to Sophie Quick on winning Young Scientist Award at the 13th International Conference on Cerebral Vascular Biology 2019.
Sophie is a third year Tissue Repair PhD student in the labs of Prof Anna Williams and Prof Charles ffrench Constant at the MRC Centre for Regenerative Medicine, where she studies cerebral small vessel disease (cSVD).
Sophie's research is focused on understanding the blood–brain barrier and white matter changes in cSVD, as this may lead to potential new targets for therapies. Sophie has characterised a new model (the ATP11BKO rat) that will provide a novel platform to study endothelial dysfunction and may offer a new model of cSVD to trial new approaches to tackling this disease.
Sophie presented her work during the conference in Miami both as oral presenttaion and as poster. Her conference abstract is published in Fluids and Barriers of the CNS 2019 16 (Suppl 1): A63 (https://doi.org/10.1186/s12987-019-0135-8)
A63 Exploring Endothelial dysfunction: a potential new in vivo model for Cerebral Small Vessel Disease.
Sophie Quick1, Jon Moss1, Mairi Brittan2, Joanna Wardlaw2, Anna Williams1
1University of Edinburgh, Edinburgh, United Kingdom; 2Centre for Cardiovascular Science, Edinburgh, UK
Fluids and Barriers of the CNS 2019, 16(Suppl 1):A63
Objective: Cerebral small vessel disease (cSVD) is the leading cause of vascular dementia and triples patients’ risk of stroke. Recent work from our lab using the Spontaneously Hypertensive Rat Stroke Prone (SHRSP) model of cSVD indicates that the underlying cause is not simply hypertension but an inherent dysfunction in endothelial cells of the blood–brain barrier, which causes a maturation block on the oligodendrocytes of the white matter (Rajani et al. 2018). We showed that this rat model has a homozygous deletion mutation of the flippase ATP11B, which is sufficient to cause endothelial dysfunction, and that single nucleotide polymorphisms in ATP11B are associated with humans with sporadic cSVD. To better elucidate the effects of endothelial dysfunction in this disease, we characterised a novel ATP11B knock-out (ATP11BKO) transgenic rat to examine how well it reflects cSVD pathology.
Methods: We used histology, immunofluorescence and protein quantification to characterise classic markers of (1) endothelial dysfunction in brain tissue of ATP11BKO rats and (2) white matter changes including oligodendroglia maturation. Furthermore, we examined cultured endothelial cells both from ATP11BKO rats and human endothelial cells with knocked down ATP11B expression in vitro for signs of dysfunction and effects on oligodendroglia.
Results: Endothelial dysfunction is demonstrated in the ATP11BKO rat model with an increase in proliferation, mis-localisation of tight junction marker CLDN5 and increased levels of ICAM-1. Effects on oligodendroglia are shown by reduced maturation. We further demonstrate relevance to human disease by ATP11B knockdown in human endothelial cells, leading to similar dysfunction including proliferation, nitric oxide production and tight junction loss, and subsequent oligodendroglial maturation block.
Conclusion: The link between the blood–brain barrier and white matter changes in cSVD is poorly understood but understanding this may lead to potential new targets for therapies. The ATP11BKO rat will provide a novel platform to study endothelial dysfunction and may offer a new model of cSVD to trial new approaches to tackling this disease.
Reference
Rajani RM, Quick S, Ruigrok SR, Graham D, Harris SE, Verhaaren BFJ, et al. Reversal of endothelial dysfunction reduces white matter vulnerability in cerebral small vessel disease in rats. Sci Transl Med. 2018; 10(448):eaam9507.