This project is one of a number that are in competition for funding from the GW4 BioMed2 MRC Doctoral Training Partnership which is offering up to 20 studentships for entry in October 2023.
The DTP brings together the Universities of Bath, Bristol, Cardiff and Exeter to develop the next generation of biomedical researchers. Students will have access to the combined research strengths, training expertise and resources of the four research-intensive universities. More information may be found on the DTP’s website.
Supervisory Team:
- Prof Dylan Thompson (lead), University of Bath, Department for Health
- Prof Simon Jones, Cardiff University, Systems Immunity Research Institute
- Dr Francoise Koumanov, University of Bath, Department for Health
- Dr William Tillet, Royal National Hospital for Rheumatic Diseases (RNHRD) and University of Bath, Department of Life Sciences
The Project:
BACKGROUND: Recent studies using genetically modified (knock-out) mouse models demonstrate that adipose-derived adipsin (Complement Factor D) drives the aetiology and progression of both inflammatory arthritis (PMID: 31167128) and knee osteoarthritis (PMID: 32012117). Cross-sectional human studies indicate that elevated adipsin is associated with age-related inflammatory conditions such as macular degeneration, atherosclerosis, and cognitive impairment. We recently showed that adipose tissue displays profound pro-inflammatory transcriptomic changes and ~2-fold more immune cells per gram with ageing in humans, and this was associated with both increased adipsin secretion from adipose tissue explants, and elevated circulating adipsin concentrations (PMID: 33895996). Based on these prior observations, we hypothesise that adipose tissue inflammation leads to aberrant (raised) adipsin secretion and circulating concentrations, and that this influences the pathogenesis of inflammatory arthritis and osteoarthritis in humans.
PROJECT OVERVIEW AND KEY QUESTIONS: The overarching aim of this project is to examine the role of adipsin in inflammatory arthritis and osteoarthritis, and to determine whether it is possible to either manipulate the secretion of adipsin, and/or block adipsin action. The initial phases of the project will capitalise on samples already available across the project partners. The Royal National Hospital for Rheumatic Diseases (RNHRD) has a biobank of blood samples from (~1000) patients with different forms of inflammatory arthritis, as well as a much larger bank of clinical and individual-level patient data (>30,000). Targeted analysis of selected blood samples from this biobank will provide data to model the relationship between adipsin and different forms of inflammatory arthritis in humans for the first time. In parallel, the student will be able to access synovial fluid and biopsies from mouse models of rheumatoid arthritis provided by Cardiff (as well as associated transcriptomics data from RNA sequencing), to characterise and examine adipsin-related pathways in the inflamed joint. Subsequent experimental work will be shaped by the student, depending on their scientific and/or training-related preferences, and underpinned by findings from the above earlier studies. We see an opportunity to examine the cellular source of adipsin in specific groups of people (e.g., to examine ex vivo secretion/expression in the different cells that make up adipose tissue, including adipocytes, immune cells, and preadipocytes), and to examine the link between adipose tissue inflammation, adipsin secretion and disease activity. Adipose tissue explants can be cultured to examine whether adipsin secretion can be normalised or manipulated ex vivo – or whether the downstream action of adipsin can be inhibited. In addition, it would be possible to examine changes in adipsin secretion in patient populations receiving treatments that are likely to exert effects on adipose tissue inflammation, such as anti-TNF therapies. Alternatively, there would also be the opportunity to characterise adipsin secretion in vivo (e.g., studies of diurnal rhythm, effects of feeding and so on), or to develop/test non-pharmacological interventions that could be used to target adipose tissue in specific patient populations (e.g., exercise, weight loss, omega-3 supplementation).
TRAINING FOR THE STUDENT: This project is an excellent training opportunity. This includes technical training, such as the use of flow cytometry, qPCR, western blotting, and cell culture – plus the development of bioinformatics skills using curated datasets. There is also the opportunity to develop skills in the conduct of human studies, ranging from working with existing patient samples and datasets through to the development and implementation of new human intervention studies.
Requirements:
Applicants must have obtained, or be expected to obtain, a First or Upper Second Class UK Honours degree, or the equivalent qualifications gained outside the UK, in an area appropriate to the skills requirements of the project. Academic qualifications are considered alongside significant relevant non-academic experience.
Non-UK applicants will also be required to have met the English language entry requirements of the University of Bath.
Enquiries and Applications:
Informal enquiries are welcomed and should be directed to Prof Dylan Thompson on email address [Email Address Removed].
Formal applications must be made direct to the GW4 BioMed2 DTP using their online application form.
A list of all available projects and guidance on how to apply may be found on the DTP’s website. You may apply for up to 2 projects.
APPLICATIONS CLOSE AT 17:00 (GMT) ON 2 NOVEMBER 2022.
IMPORTANT: You do NOT need to apply to the University of Bath at this stage – only those applicants who are successful in obtaining an offer of funding from the DTP will be required to submit an application for an offer of study from Bath.
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