4-year PhD Studentship: Investigating the relationship and modelling the impact of neuroinflammation on cerebral vascular function in dementia using novel 3D models of the cerebral vasculature

Reduced blood flow and a breakdown of the protective blood-brain barrier (BBB) are major contributors to the development of cognitive decline and disease pathology in the early stages of dementia [1]. The causes of cerebral vascular dysfunction in dementia are still largely unclear but vascular co-morbidities such as diabetes exacerbate the problem. In our recently published study using human post-mortem brain tissue, we found that pro-inflammatory cytokines, specifically IL-15 and IL-17, are elevated in dementia and correlated strongly with markers of cerebral hypoperfusion and BBB leakiness, not only in people with dementia but also in non-demented controls. The relationship was present in the early stages of disease, was independent of classical disease markers (beta-amyloid and tau), and was exacerbated in the presence of vascular co-morbidities including systemic infection and hypertension [2]. We now want to build on recent studies [3,4,5] and our own pilot data indicating that vascular injury, including reduced cerebral blood flow, blood-brain barrier leakiness, and degeneration of supporting mural cells known as pericytes, are exacerbated in dementia patients with a history of diabetes mellitus.

Aims and Objectives

The student will explore the hypothesis that pro-inflammatory cytokine expression elevated in dementia and exacerbated in the presence of diabetes underpins cerebral vascular dysfunction within the brain.

The aims and objectives of the study are (i) to assess the relationship between markers of neuroinflammation and cerebral vascular pathology and dysfunction in dementia, in relation to diabetes, in human post-mortem brain tissue and (ii) to explore the underlying molecular mechanisms by modelling the impact of pro-inflammatory cytokines, particularly the effects mediated by IL-15 and IL-17, using novel 3D co-culture and bioengineered models of the human cerebral vasculature.

Methodology

The PhD student will explore the relationship between neuroinflammation and markers of cerebrovascular dysfunction in human post-mortem brain tissue to better understand the pathophysiological processes that underpin cerebral vascular dysfunction in dementia. The PhD studentship will provide training in neuroanatomy, neuropathology, and biochemistry and develop an understanding of disease pathogenesis in dementia. It will be led by Dr Scott Miners and supported by Professor Love at the Dementia Research Group.

The studentship will also explore the underpinning mechanisms involved in inflammatory-mediated cerebral vascular dysfunction in dementia using novel models of the cerebral vasculature under disease conditions e.g., hypoxia and hyperglycaemia. It will specifically investigate the effects of cytokines e.g.IL-15 and IL-17, in models of BBB breakdown and neurovascular signalling. This work will be led by Dr Scott Miners and supported by Dr James Armstrong, a leading expert in the bioengineering of in vitro models.

This project is cross-disciplinary and will provide the student with a breadth of techniques in a highly supportive environment in a field with huge potential growth. Both supervisors are newly appointed lecturers within the Bristol Medical School and so will benefit from the experience of co-hosting a PhD studentship.

Keywords

Alzheimer’s disease, diabetes, neuroinflammation, blood-brain barrier, cerebral hypoperfusion, neurovascular uncoupling

How to apply for this project

This project will be based in Bristol Medical School - Translational Health Sciences in the Faculty of Health Sciences at the University of Bristol.

Please visit the Faculty of Health Sciences website for details of how to apply