Supervisors: Anna Williams, Andrew Baker, Catalina Vallejos Meneses
Project Description :
Endothelial cells (EC) line all blood vessels and form a functional barrier between the blood and the adjacent tissue. The brain ECs in the brain microvasculature are specialised in that they form the blood-brain-barrier (BBB) which is a ‘tighter’ barrier than in other parts of the body to protect the brain from blood-borne immune cells and infectious agents. These brain ECs have now also been shown to communicate with brain cells controlling their function and health. When these ECs are damaged, by genetic or environmental effects, they change both their barrier function but also how they impact on surrounding brain cells. This contributes to diseases such as cerebral small vessel disease and Alzheimer’s disease.
To improve our understanding of this biology in health and disease, we need to understand a) how brain ECs are different from ECs in other parts of the body, b) how brain ECs change in health, ageing and disease (from genetic and environmental influences) and c) how can we use this information to inform differentiation protocols of ES/iPS cells into ECs which are truly functionally brain-like, for use in in vitro experiments.
To answer these questions, this project will:
1) Use bioinformatics to interrogate data deposited in public datasets (e.g. ENCODE), and from the Baker and Williams groups, some already generated and some will be generated. These will be microarray, RNAseq, single cell RNAseq and proteomic datasets.
2) Use human and experimental model cells and tissues to generate new datasets.
3) Use these data to improve differentiation protocols to generate ‘brain’ ECs from human ES or iPS cells
4) Use these data to try and model pathways which are activated when ECs become dysfunctional.
Training:
Bioinformatics on microarrays, bulk and single cell RNA sequencing, and proteomics, handling of tissues/ cells to generate such datasets, differentiation of ECs from ES/iPSCs, immunofluorescence and RNAscope for validation, examination of human tissue, confocal microscopy, image analysis.
References:
Rajani RM, Quick S, Ruigrok SR, Graham D, Harris SE, Verhaaren BFJ, Fornage M, Seshadri S, Atanur SS, Dominiczak AF, Smith C, Wardlaw JM, Williams A. Reversal of endothelial dysfunction reduces white matter vulnerability in cerebral small vessel disease. Science Translational Medicine 2018 Jul 4;10(448);
Eling N, Richard AC, Richardson S, Marioni JC, Vallejos CA. Correcting the Mean-Variance Dependency for Differential Variability Testing Using Single-Cell RNA Sequencing Data. Cell Syst. 2018 Aug 29. pii: S2405-4712(18)30278-3;
MacAskill MG, Saif J, Condie A, Jansen MA, MacGillivray TJ, Tavares AAS, Fleisinger L, Spencer HL, Besnier M, Martin E, Biglino G, Newby DE, Hadoke PWF, Mountford JC, Emanueli C, Baker AH. Robust Revascularization in Models of Limb Ischemia Using a Clinically Translatable Human Stem Cell-Derived Endothelial Cell Product. Mol Ther. 2018 Jul 5;26(7):1669-1684.
If you wish to apply for this project, please check this link and send your application to this email.
