A cellular atlas of human bone to understand the relationship between femeroacetabular impingement and hip osteoarthritis

RESEARCH OUTLINE

This innovative full-time 3 year DPhil post, funded by the Chan Zuckerberg Initiative (CZI), provides a unique opportunity to contribute substantially to the laboratory and computational research of the Ancestrally Diverse Musculoskeletal Atlas based at the Botnar Research Centre, University of Oxford. This is a partnership with the Human Cell Atlas and Chan Zuckerberg Initiative. This ground-breaking consortium works across seven international sites and utilises next generation sequencing to produce cellular maps of healthy muscle, tendon and bone, including ancestrally diverse samples from Zimbabwe, The Gambia, India, Turkey, Oman and Argentina.

We are looking for a DPhil student to build on our existing expertise in connective tissues to develop, optimise and deliver cellular maps of adult bone, both in the laboratory and computationally. Bone is the most abundant tissue of our musculoskeletal system and is commonly affected by painful and disabling diseases or injury, including fractures and osteoarthritis. While the musculoskeletal system shows notable ethnic diversity we know very little about how ancestry effects bone biology. Osteoarthritis (OA) is a major cause of loss of quality of life globally, with the hip particularly prone to disease. Hip OA is commonly preceded by a femoroacetabular impingement in which additional bone growth occurs on either the femoral head or acetabulum of the hip - preventing smooth movement and causing pain. Hip OA itself is characterised by further bony changes (including sclerosis) alongside loss of cartilage and additional bone growth (osteophytes). However, treatments for both femoroacetabular impingement (FAI) and hip OA are limited, partly due to a lack of understanding of the abnormal bony biology that occur in these conditions, alongside a paucity of data on the cellular composition of healthy bone of the femoral head and acetabulum.

You will build reference datasets of healthy bone and compare these to pathological conditions including FAI and OA to build understanding of disease mechanism(s) and identify treatment targets. As part of this DPhil you will process bone samples collected from the clinical team and generate libraries within the laboratory, carry out imaging validation and computationally analyse your data. You will work as part of a dynamic team of clinicians, engineers, computational biologists, epidemiologists, and biologists, who will provide an exciting range of training opportunities.

The outline for the DPhil will include:

1. Development of robust methods for single cell resolution analysis of bone. You will compare and contrast single cell and single-nuclei ATACseq of mineralised bone and its periosteum using both in vitro models of mineralisation and of healthy adult bone.
2. Deliver an ancestrally diverse and temporal atlas of healthy human bone. You will use optimised methods to generate a single-cell resolution atlas of healthy bone collected by our clinical collaborators, will annotate these maps to identify cell subsets that change with ageing and use spatial methods (e.g. CellDive imaging) to validate subsets and derive their locations.
3. Identify potential cellular drivers of FAI and hip OA. You will use optimised methods to develop single cell atlases of FAI and hip OA and compare these to healthy reference datasets to identify potential cell subsets or pathways that may drive disease. Using in-house in vitro models, you will assess the importance of these identified subsets in driving pathological changes.

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 computational and laboratory methods

Desirable

Wet laboratory and/or computational analysis experience

SUPERVISORY TEAM

The supervisor team will include Associate Professor Sarah Snelling (cell biologist and the principal investigator of the CZI Ancestry network), Dr Adam Cribbs (computational biologist), Dr Mathew Baldwin (orthopaedic clinical lecturer and computational biologist), Associate Professor Philippa Hulley (cell biologist with expertise in bone biology and in vitro models of human bone) and Mr Vikas Khanduja (Orthopaedic Surgeon specialising in hip arthroscopy, arthroplasty and sports surgery & Research Lead (Elective) in Cambridge University Hospitals). You will be based at the University of Oxford and will have the opportunity to visit and work in Cambridge with Mr Vikas Khanduja.

BENEFITS FOR THE STUDENT

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 enables and encourages research and education into the causes of musculoskeletal disease and their treatment. As well as the Botnar Research Centre, NDORMS encompasses the Kennedy Institute of Rheumatology and a specialist Trauma Research unit (Kadoorie). This enables and encourages research, training, and education into the causes of musculoskeletal disease and their treatment. All these centres work very closely and collaboratively together, making NDORMS, the biggest musculoskeletal research unit in Europe.

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, epigenetics, translational immunology, data analysis and the microbiome. 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.

Alongside departmental training opportunities listed above, we will ensure hands-on computational training to support analysis of single-cell RNAseq data and embedding within our international Tendon Seed Network and Ancestry Network providing the candidate with extensive laboratory guidance and support. The qualitative work within this project will be supported by long-standing collaborations with our population health and clinical trial unit partners. The student would be supported to shadow relevant clinical work and to attend clinical and basic science conferences to enrich their studies.

Finally, the student will be expected to regularly present data in Departmental seminars, the Soft Tissue Repair group & multi-team computational meetings. Attendance at National and International meetings will also be encouraged for which financial support is available.

HOW TO APPLY AND APPLICATION REQUIREMENTS

It is recommended that, in the first instance, you contact Associate Professor Sarah Snelling or the Graduate Studies Officer, Sam Burnell (Samuel.burnell@ndorms.ox.ac.uk), who will be able to advise you of the essential requirements.

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 2022.

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.

STUDENTSHIP DETAILS

This studentship provides a stipend of £18k per annum for 3 years, covers fees at the home level and provides consumable costs for the research. Any overseas applicants would need to cover the difference between home and overseas fees from alternative funding sources.

CLOSING DATE

Applications must be complete by noon on Friday 10th June 2022. 

INTERVIEW DATE

TBC