Identification and modification of the cellular and molecular mechanisms underlying unsuccessful knee replacements for osteoarthritis

Knee osteoarthritis (OA) is the most common form of arthritis, affecting 5.4 million people in the UK. It is characterised by loss of cartilage and inflammation and fibrosis of the synovial tissue that surrounds the joint. Treatments are limited, and 100,000 people undergo partial or total knee replacement surgery for knee OA each year. Unfortunately, up to 7 per cent of these replacements fail and require revision. Patients who require revision of partial knee replacements often have progression of OA, whilst unresolved pain and continued loss of function underlies revision and failure of total knee replacements. During joint replacement, the cartilage and ends of the bones are removed, but the synovial tissue remains. The synovium is a rich source of pain- and inflammation-mediators and is therefore likely to play a critical role in driving and modifying the response to knee replacement for OA.

This 3-year full-time DPhil post at the Botnar Institute will embed a student within a dynamic and interdisciplinary team. You will use next generation sequencing, metabolomics, and in vitro models to understand and modify the reasons for failure of knee replacements for OA. You will address a significant unmet clinical need, and deliver critical next-generation reference datasets of diseased synovium to the Human Cell Atlas.

Ultimately your DPhil will identify ways of improving outcomes for patients undergoing knee replacement for OA. You will: 

1. Write a critical literature review and/or systematic review on current understanding of the clinical and biological reasons for revision of knee replacements for OA
2. Process synovial tissue and fluid samples collected through our clinical team. Tissue and fluid will be obtained from OA patients undergoing unicompartmental knee replacement (baseline samples), revision of unicompartmental to total knee replacement (progression samples), and revision of total knee replacements (failure samples).
3. Delivery of an overarching transcriptional signature (bulk RNA-seq of synovial tissue) and metabolomic (synovial fluid) in progression and failure signatures. Interrogate the relationship of these signatures with patient demographics (e.g. sex, BMI) and clinical information (e.g functional scores, radiographic findings).
4. Identify critical cell types and pathways contributing to the progression and failure of knee replacements by producing single-nucleus RNA-seq and multiplex imaging datasets of synovial tissue, and analysing these datasets using computational pipelines.
5. Use in vitro/ex-vivo models, including explant culture, to modify the cellular and molecular mechanisms contributing to the progression and failure of knee replacements such as those involved with pain, vessel ingrowth, fibrosis, and hyperplasia.

References

NJR Editorial Board. National Joint Registry 16th Annual Report. Report No.: 16th Annual Report. National Joint Registry; London: 2019. Sep, p. 248. reports.njrcentre.org.uk. Available from: https://reports.njrcentre.org.uk/Portals/0/PDFdownloads/NJR%2016th%20Annual%20Report%202019.pdf.

Sanchez-Lopez, E., Coras, R., Torres, A. et al. Synovial inflammation in osteoarthritis progression. Nat Rev Rheumatol 18, 258–275 (2022). https://doi.org/10.1038/s41584-022-00749-9

Zhang L, Xing R, Huang Z, Ding L, Zhang L, Li M, Li X, Wang P and Mao J (2021) Synovial Fibrosis Involvement in Osteoarthritis. Front. Med. 8:684389. doi: 10.3389/fmed.2021.684389

SELECTION CRITERIA

Essential

A degree in a biomedical, medical or related subject 

Excellent communication skills

Experience of writing scientific essays, documents, or dissertations

Experience of working or studying within a research environment

Willingness to learn laboratory and computational methods

Desirable

Experience of processing human tissue samples

Laboratory and/or computational analysis experience of sequencing methods

Imaging experience

BENEFITS

The Botnar Research Centre – part of Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS) - plays host to the University of Oxford's Institute of Musculoskeletal Sciences, which leads research and education into the causes of musculoskeletal diseases and their treatments.

A core curriculum of lectures will be taken in the first term to provide a solid foundation in a broad range of subjects including musculoskeletal biology, inflammation and translational immunology. All students are required to attend a 2-day Statistical and Experimental Design course at NDORMS and participate at regular seminars/workshops within the Department/their research team. Students will have access to various courses run by the Medical Sciences Division Skills Training Team and other Departments. 

We will ensure hands-on laboratory and computational training and embedding within our international Tendon Seed Network and Ancestry Network. This will provide the candidate with laboratory and computational guidance and support both locally and internationally.  

Finally, the student will be expected to regularly present data in Departmental seminars, the Soft Tissue Repair group & multi-team computational meetings. You will work alongside the Versus Arthritis Centre for Osteoarthritis Pathogenesis and be invited to attend regular meetings with our collaborators on synovial biology at the Kennedy Institute of Rheumatology. Attendance at National and International meetings will also be encouraged, for which financial support is available.

HOW TO APPLY AND APPLICATION REQUIREMENTS

You should contact Associate Professor Sarah Snelling and the NDORMS Graduate Studies (graduate.studies@ndorms.ox.ac.uk). Interested applicants should have, or expect to obtain, a first or upper second-class BSc degree or equivalent in a relevant subject and will also need to provide evidence of English language competence (where applicable). The application guide and form is found online and the DPhil will commence in October 2024.

Applications should be made to the following programme using the specified course code (for online application): D.Phil in Molecular and Cellular Medicine (course code: RD_MP1).

Further information can be found here.