How does metabolism change in brain endothelial cells in vascular dementia?

About the Project

An interdisciplinary PhD studentship is available between the groups of Prof Mathew Horrocks and Prof Anna Williams at the University of Edinburgh; School of Chemistry and the British Heart Foundation (BHF) Centre of Research Excellence.

https://edwebprofiles.ed.ac.uk/profile/dr-mathew-horrocks

https://edwebprofiles.ed.ac.uk/profile/anna-williams

Project

Cerebral small vessel disease (SVD) is common in the ageing population, increases risk of stroke and dementia and contributes to other dementias such as Alzheimer’s disease. We know that endothelial cells of the small brain blood vessels are affected early and drive the disease, affecting surrounding cells, including neurons and that these cells become hypoxic and their metabolism is altered. However, we do not understand how metabolism changes, whether some cells are more vulnerable than others or to what extent this is reversible.

Here, we will use cutting edge chemistry sensors and high-throughput imaging, coupled with machine learning analysis, to visualise and measure changes in cell metabolism in brain cells of a rat model of SVD. The transgenic Atp11bKO rat shows pathological, imaging and behavioural changes similar to human SVD. It shows early endothelial cell dysfunction in vivo and in vitro in both cultured cells and brain slices. We will use culture brain cells (e.g. endothelial cells/oligodendrocytes/astrocytes) and brain slices from these rats to study changes in metabolism – both metabolites and mitochondrial function - using single-molecule, super-resolution and high throughput (Opera Phenix) imaging. We will then try and reverse changes seen using drugs – both drugs known to change metabolism e.g. metformin, pioglitazone and informed by what we discover in our culture systems.

Hypothesis – metabolism is altered in brain endothelial cells (and surrounding cells) in SVD.

Aim 1 – Characterise the difference in metabolism in Atp11bKO endothelial cells in culture compare to controls using metabolic sensors and high throughput/super-resolution imaging.

Aim2 - Characterise the difference in metabolism in other Atp11bKO brain cells in the context of brain slice cultures compared to controls using similar tools, and compare these data with already available Omic datasets.

Aim3 – Use drugs, both known metabolic drugs and those discovered during the project, to determine if these changes can be reversed.

The student will learn to handle rats, derive primary cultures and brain slices, use of metabolic sensors and a range of microscopy approaches, drug manipulations of cells and functional assays, image analysis (AI) and statistics.

Applying

In the first instance, the initial application of cover letter and CV should be directed to:

Professor Mathew Horrocks: mathew.horrocks@ed.ac.uk

The position will remain open until filled. A closing date may be added at a later date.

The University reserves the right, in its sole discretion, to amend or withdraw any of the advertised scholarships, without further notice.

IMPORTANT

Before Submitting your cover letter and CV, please complete the online School of Chemistry Equality, Diversity & Inclusion Form for 26/27 Entry

The form will automatically generate a unique ‘Receipt Number’ that you must include in your cover letter.