About the Project

VIDA (Vascular and Immune contributors to DementiA) is a 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 focusing 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.

PhD studentships

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, including 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.

Project Background

Cerebral small vessel disease (SVD) is the leading cause of vascular dementia, and is characterised by white matter damage which correlates closely with the degree of cognitive impairment. SVD can be sporadic or inherited, and the most common inherited form of the disease is cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which is caused by a mutation in the NOTCH3 gene. While we have previously shown some of the ways in which vascular changes can affect white matter in both sporadic and inherited SVD, we still don’t fully understand how these changes occur. Additionally, much of this previous work has relied on rodent models of disease, which do not fully recapitulate changes seen in human patients. 

In this project, the student will use human induced pluripotent stem cell (iPSC) derived cells to investigate interactions between vascular cells and oligodendrocytes (myelin forming cells in the brain) to better understand white matter damage in vascular dementia. We hypothesise that vascular cells derived from CADASIL patient iPSCs secrete factors which alter oligodendrocyte behaviour and function, including downstream effects of oligodendrocytes on neuronal activity and microglia. By identifying the molecules involved in these interactions, we hope to ultimately be able to disrupt these pathways to prevent disease pathology.

The aims of the project are to:

• Develop a greater understanding of vascular and endothelial dysfunction in CADASIL, including changes in secreted molecules
• Elucidate the mechanisms underlying oligodendrocyte changes in CADASIL
• Identify secreted and other factors involved in mediating vascular induced oligodendrocyte changes in CADASIL, providing possible therapeutic targets to prevent white matter damage
• Elucidate the role of oligodendrocytes in mediating neuronal and immune cell changes in CADASIL

All of these aims will have high translational relevance through use of human patient-derived cells and human post-mortem tissue

The student will be trained in iPSC cultures; differentiation of endothelial cels, mural cells, oligodendrocytes, neurons and microglia from iPSCs; functional characterisation of oligodendrocytes, neurons and microglia (including immunocytochemistry, live cell imaging and image analysis); histology, immunohistochemistry and in situ hybridisation on human post-mortem tissue; and molecular biology techniques (including ELISAs and proteomics). The student will be based primarily in Dr Rajani’s group at the University of Edinburgh, with short amounts of time spent in Prof Wang’s group at the University of Manchester to train in iPSC-mural cell differentiation.

Key details

• Location UK DRI at Edinburgh
• Successful applicants will receive a generous stipend of £21,800 rising by £1,000 each year, and home fees will covered*. Funding is also provided for research expenses, career development and student travel/conference attendance.