Repurposing IL-1 Inhibitors for the Treatment of Vascular & Mixed Dementia

Details

Heart disease is a major risk factor for dementia. We have previously shown that midlife heart disease leads to the breakdown of a key brain blood flow mechanism called neurovascular coupling (Shabir et al, 2022). These mice display elevated brain interleukin-1 (IL1) beta levels – a key inflammatory molecule. We hypothesised that targeting IL1 may prevent neurovascular decline and the onset of dementia. We have found preliminary evidence that using an IL1 inhibitor is able to prevent neuropathological damage associated with neuroinflammation, improve brain blood flow, and stabilise cognitive decline (unpublished data).

The aim of this PhD will be to assess the efficacy of Anakinra and other IL1 inhibitors in models of dementia at more clinically relevant timepoints. This interdisciplinary PhD will project will bridge cellular and molecular neuroscience, neurophysiology and cardiovascular biology. You will be hosted in the Division of Clinical Medicine (School of Medicine & Population Health; SMPH) and will work collaboratively with colleagues in the Division of Neuroscience (SMPH)/Sheffield Institute for Translational Neuroscience (SITraN) and the School of Psychology (Faculty of Science).

The PhD will begin by training of the relevant and necessary laboratory skills required to undertake this project. These include preclinical surgery, imaging, tissue extraction, immunohistochemistry, qPCR, transcriptomics and analysis methods. Necessary Home Office licensing required will be obtained in the first 3-4 months of the PhD. The work from this project will form a basis for trialling or repurposing IL1 inhibitors for patients with heart disease and/or dementia (translational neuroscience pillar of the Neuroscience Institute). As a proof of principle, we know IL1 inhibitors work in models of dementia, but we wish to investigate this further in different models at more clinically relevant timepoints. The work will also help elucidate mechanistic insights into how IL1 inhibitors work within these models (cellular and molecular mechanisms). Furthermore, we will trial these drugs in a mixed comorbid model of Alzheimer’s disease and atherosclerosis in which beta-amyloid plaques have been shown to be trebled. The hypothesis is that IL1 inhibition will lower amyloid in this mixed model.

During the PhD, the prospective student will have the opportunity to attend national and international conferences (e.g. ARUK, Brain, BNA etc.) to disseminate their research as well as network with fellow students. Attending monthly supervisory meetings as well as regular whole-lab meetings will be mandatory, and attendance to journal clubs and weekly seminars will be highly encouraged. The RTSG for this PhD will help cover training and travel costs throughout the PhD whereas most of the research and consumable costs will be provided by ongoing grants.

The focus of this interdisciplinary PhD studentship will be on translational neuroscience, one of the three pillars of the Neuroscience Institute, and will support research within the emerging Dementia Group at the University of Sheffield. This group is a collaboration between the Neuroscience Institute and the Healthy Lifespan Institute; the student will be an active member of both institutes. The student will be engaging with internal conferences for both these institutes which have different audiences. As part of the training, the student will also engage with public outreach in conferences such as “Dementia Futures”.

Interviews are likely to be held between 4 – 15 March. Students must be able to start by October 2024.

Applications are open to students from both the UK and overseas. We anticipate competition for these studentships to be very intense. We would expect applicants to have an excellent undergraduate degree in a relevant discipline. We would also expect applicants to have completed or be undertaking a relevant master’s degree to a similar very high standard (or have equivalent research experience).

Please ensure you pick the Department/Division of Neuroscience when filling in your application form, regardless of where your first supervisor sits.