This fully-funded MRC studentship is an opportunity for a talented student to perform exciting interdisciplinary research using new tools to capture, identify and image active proteolytic enzymes in osteoarthritis (OA). It has the potential to translate to better diagnostics and make significant steps towards personalised medicine and more targeted therapeutics to this painful disease.
The central pathology in OA is the destruction of the articular cartilage, a process driven by matrix metalloproteinases (MMPs). More recently, a role for serine proteinases has emerged in the proteolytic cascades leading to cartilage destruction (Wilkinson et al., 2019). Although OA pathology appears similar between patients, the relative importance of specific proteinases differs by individual and stage of OA. Unfortunately, total proteinase levels in an OA joint are of little use when characterising active disease. Many proteinases are complexed to inhibitors, degraded, or present as inactive precursors. Previously, we have identified serine proteinases capable of inducing cartilage destruction and uncovered how they interact with metalloproteinases and the cartilage extracellular matrix (Wilkinson et al., 2017a; Wilkinson et al., 2017b; Wilkinson et al., 2021; Falconer et al., 2019). There is, however, a clear unmet need to profile proteinase activity within the synovial joint and to determine how this changes with OA progression. Activity-based probes (ABPs) are chemical tools that covalently bind to proteinase active sites, via a reactive ‘warhead’ (or bait), only when a proteinase is active. The ABP can include a tag, such as biotin, for the capture and identification of proteinases, or a fluorophore to visualise proteolytic activity. This studentship will involve profiling human OA synovial fluid of different stages using ABPs, as well as the design of novel ABPs to study a specific proteinase previously associated with OA. We will also use fluorescent ABPs to visualise proteolysis in experimental models of disease.
The project will be supervised by Dr David Wilkinson (University of Liverpool) who is an expert in proteinases and cartilage destruction. The successful applicant will be based in the William Henry Duncan Building which houses state-of-the-art laboratories, dedicated tissue cultures, microscope and histology suites. The second supervisor, Dr Megan Wright (University of Leeds), will provide expertise and training in the design and synthesis of novel chemical probes and host the student for a research stay in her Chemical Biology Lab. Professors Patricia Murray and George Bou-Gharios (University of Liverpool) will provide expert supervision of in vivo fluorescence and models of OA, respectively. Together, the supervisory team will provide a positive and supportive environment. The student will join an inclusive, diverse, and engaged community, supported by the Liverpool Doctoral College and the ‘Discovery Medicine North’ cohort of over 140 PhD students.
This studentship will provide a breadth of first-class training in cutting-edge techniques and represents an opportunity to perform research to better understand, and ultimately treat, OA. The project is suitable for a holder of a BSc (2:1 or above) in Biochemistry, Biological or Natural Sciences, or a related discipline.
We encourage informal enquires to be made to [Email Address Removed].
Benefits of being in the DiMeN DTP:
This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle, York and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.
We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.
Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards
Further information on the programme and how to apply can be found on our website:
http://www.dimen.org.uk/how-to-apply/application-overview
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