PhD: Oligodendrocyte-microglial interactions

VIDA (Vascular and Immune contributors to DementiA) is a new multi-institutional partnership between Alzheimer’s Society and four world-leading research sites: the University of Manchester, University of Edinburgh, Imperial, and City St George’s University of London. With projects focussing on the importance of vascular and immune mechanisms in dementia, VIDA PhD students will become the next generation of much-needed dementia researchers, contributing to breakthroughs in dementia diagnosis and treatment.

VIDA students will embark upon a 4 year fully-funded PhD project at one of the four institutions above, with access to the state-of-the-art research facilities and interdisciplinary training available at all sites. Students at each site will come together as a cohort at several points during the programme, most importantly for an induction week at the beginning of the programme, followed by annual conferences and residential workshop retreats which will link in with other Alzheimer’s Society Doctoral Training Centres across the UK. Students will also participate in engagement schemes with the Alzheimer’s Society and beyond, sharing the impact of their research in the community. The programme also benefits from built in opportunities for placements with leading industrial partners, and bespoke training plans including schemes to develop teaching, mentoring, and grant writing skills.

Further Information

https://www.dementiaresearcher.nihr.ac.uk/vascular-and-immune-contributors-to-dementia/

https://www.alzheimers.org.uk/research/our-research/alzheimers-society-doctoral-training-centres/vascular-and-immune-contributors-dementia

Project Description

Stroke is a leading cause of death and disability. With the aging population and improved survival rates, more individuals face serious long-term consequences of stroke, including immediate or delayed cognitive impairment and a doubled risk of dementia [1]. Despite its clinical importance, the mechanisms leading to cognitive decline post-stroke are not well understood.

Initially, stroke causes focal cell death and a localised immune response. However, emerging evidence from PET imaging, post-mortem studies, and animal models shows that inflammatory responses extend throughout the brain, impacting remote regions anatomically connected to the primary site of damage [2]. These widespread inflammatory changes are linked to slowly evolving brain pathology, including damage to distant white matter tracts. Clinical imaging studies suggest that this widespread white matter damage is associated with long-term cognitive impairment [3].

Oligodendrocytes, glial cells located in white matter tracts, myelinate neuronal axons, which facilitates efficient communication and supports axonal health. Our preliminary data indicate that in the long-term response to experimental stroke in mice, a unique subtype of oligodendrocytes, termed ‘disease-associated oligodendrocytes,’ [4] appear in white matter regions remote from the primary lesion and exhibit a distinct inflammation-related gene expression profile. This project aims to explore these disease-associated oligodendrocytes and their interactions with microglia, the brain’s primary immune cells, through a combination of methods in experimental mouse models and human post-mortem tissue.

The first part of the project will involve bioinformatic analysis of single-cell data to examine the heterogeneity of disease-associated oligodendrocytes compared to homeostatic oligodendrocytes. We will utilize specialised bioinformatic tools to investigate ligand-receptor interactions between oligodendrocytes and microglia post-stroke. The second part will combine MRI imaging with spatial transcriptomics to determine the spatial locations of disease-associated oligodendrocytes and their relationships with gene changes in other brain cells.

Lastly, we will analyse human post-mortem tissue from individuals who died months to years after stroke, sourced from the Cognitive Function After Stroke (CogFAST) cohort, which includes cognitive data and neuroimaging. Using immunohistochemistry, we will assess the presence of disease-associated oligodendrocytes and their relationship with white matter integrity and cognitive status post-stroke.

Ultimately, this research aims to clarify the mechanisms underlying cognitive decline post-stroke, exploring whether disease-associated oligodendrocytes and their altered signalling with microglia could serve as potential therapeutic targets for protecting white matter. We also aim to equip students with specialized skills in dementia-related neuroscience, including molecular imaging and computational analysis, within a collaborative environment that advances dementia research and training.

• Dr Jill Fowler https://discovery-brain-sciences.ed.ac.uk/our-staff/research-groups/jill-fowler
• Dr Owen Dando https://sidb.org.uk/owen-dando/
• Prof Raj Kalaria https://www.ncl.ac.uk/medical-sciences/people/profile/rajkalaria.html

Entry Requirements

Applicants are expected to hold (or about to obtain) a minimum upper second class undergraduate honours degree (or equivalent) in a biomedical science or medicine.

How to Apply

Interested candidates must first make contact with the Lead Supervisor Dr Jill Fowler prior to submitting any formal application, to discuss their interest and suitability for the project. Informal enquiries can be sent via email to jill.fowler@ed.ac.uk

Candidates should then email sbms-postgraduate@ed.ac.uk to request an application form and to formal application guidance.