A cellular atlas of human bone to understand the relationship between bone stromal cells and osteoclasts in giant cell tumour of bone?

RESEARCH OUTLINE

This full-time 3 year funded DPhil post will contribute substantially to the laboratory and computational research of the Ancestrally Diverse Musculoskeletal Atlas and the Tendon Seed Network based at the Botnar Research Centre, University of Oxford.

We are looking for a DPhil student to develop, optimise and deliver cellular maps of healthy and diseased 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, injury and both benign and cancerous tumours. To understand more about bone in disease, it is critical for us to decipher the cellular composition of bone in health. Defining the cellular factors that underlie bone homeostasis will provide crucial comparators for hypotheses to help delineate disease mechanism as well as providing reference datasets for evaluation of new treatments.

Giant Cell Tumour of Bone (GCTB) accounts for 4-5% of bone tumours and affect the lone bones of the arms and legs. Currently it is thought that malignant stromal cells drive the formation of the osteoclastoma, with a strongly abnormal and haemorrhagic vascular contribution. Although the majority of GCTB cases are benign, they often grow aggressively leading to pain, disability and destruction of surrounding bone, typically in people aged 20-45 years. In a small number of cases GCTB can be cancerous. Malignant Giant Cell Tumour of Bone (MGCTB) has a 5 year survival rate as low as 50%. Unfotunately, treatments for both benign and cancerous GCTB are limited, and replacement of damaged bone is challenging. Futhermore, the factors that cause GCTB to become cancerous remain unknown. This lack of knowledge is partly due to a lack of understanding of the cellular composition and interactions of healthy bone and GCTB and MGCTB bone.

You will build reference datasets of healthy bone, developing new methods to work with multinucleated osteoclasts, and compare these to GCTB and MGCTB bone. This will 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 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 and imaging methods of healthy adult bone from ancestrally diverse donors using fresh, frozen and formalin-fixed bone specimens.
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 imaging methods (e.g. CellDive imaging) to validate subsets and derive their locations.
3. Identify potential cellular drivers of benign and cancerous Giant Cell Tumour of Bone. You will use optimised methods to develop single cell and/or imaging atlases of GCTB and MGCTB 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

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 enables and encourages research and education into the causes of musculoskeletal disease and their treatment.

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 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.

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 you contact Associate Professor Sarah Snelling or 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 2023.

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 7th April 2023.

INTERVIEW DATE

Thursday 20^th April 2023.