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

project overview

You will develop, optimise and deliver ancestrally diverse cellular maps of adult femoral bone, both in the laboratory and computationally. This project will be embedded within a partnership between the Human Cell Atlas and Chan Zuckerberg Initiative that utilise next generation transcriptomic sequencing to produce cellular maps of musculoskeletal tissues. A key aim of this partnership is to ensure cellular maps address important clinical questions and are globally relevant. To this end, the PhD student will work with teams at seven international clinical sites.

Bone is the major tissue of our musculoskeletal system and is commonly affected by femeroacetabular impingement (FAI) which leads to hip osteoarthritis (OA). Osteoarthritis (OA) is a major cause of loss of quality of life globally, with the hip particularly prone to disease. In FAI, additional bone growth occurs on the femoral neck - preventing smooth movement and causing pain. Hip OA itself is characterised by further bony changes ,including sclerosis, bone growth (osteophytes) and cystic change, alongside loss of cartilage. However, treatments for both femoroacetabular impingement (FAI) and hip OA are limited, partly due to a lack of understanding of the abnormal bone biology that occur in these conditions, alongside a paucity of data on the cellular composition of healthy bone of the hip joint.

The recruited student will build reference datasets of healthy bone, compare this 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 femoral. You will compare and contrast single cell and single-nuclei ATACseq to improve cellular annotation.
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 at the bone level. 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.

training opportunities

Alongside departmental training opportunities listed below we will ensure hands-on computational training to support analysis of single-cell RNAseq data. Embedding within our international Tendon Seed Network and Ancestrally Inclusive Musculoskeletal Network will also ensure laboratory guidance and support. Human primary bone organoid models containing functional sclerostin secreting osteocytes are available. A student would be supported to shadow relevant clinical work and to attend clinical and basic science conferences to enrich their studies –financial support is available for travel to conferences.

NDORMS hosts Oxford's Institute of Musculoskeletal Sciences, a centre for experimental medicine, the Kennedy Insititue of Rheumatology and a specialist trauma research unit. This 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, epigenetics, translational immunology, data analysis and the microbiome. All students are also required to attend a 2-day Statistical and Experimental Design course at NDORMS.Students will also be required to attend regular seminars within the Department and have access to a variety of other courses run by the Medical Sciences Division Skills Training Team https://www.medsci.ox.ac.uk/study/skillstraining and the wider University.

Finally,the student(s) will be expected to regularly present data in Departmental seminars, the Soft Tissue Repair group and within our linked goups internally and externally.

key publications

1. Ramos-Mucci L, Sarmiento P, Little D, Snelling S (2022). Research perspectives-Pipelines to human tendon transcriptomics. J Orthop Res. doi: 10.1002/jor.25315
2. Baldwin, M.J., Cribbs, A.P., Guilak, F. et al. Mapping the musculoskeletal system one cell at a time. Nat Rev Rheumatol 17, 247–248 (2021). https://doi.org/10.1038/s41584-021-00600-7
3. Naoki Nakano & Vikas Khanduja (2018) Femoroacetabular impingement: the past, current controversies and future perspectives, The Physician and Sportsmedicine, 46:3, 270-272, DOI: https://doi.org/10.1080/00913847.2018.1478151

keywords

Genomics, osteoarthritis, hip, sequencing, therapeutics

contact information for all supervisors

Sarah.snelling@ndorms.ox.ac.uk / https://www.ndorms.ox.ac.uk/team/sarah-snelling 

Matthew.baldinw@ndorms.ox.ac.uk / https://www.ndorms.ox.ac.uk/team/matthew-baldwin

Adam.cribbs@ndorms.ox.ac.uk / https://www.ndorms.ox.ac.uk/team/adam-cribbs

Philippa.hulley@ndorms.ox.ac.uk / https://www.ndorms.ox.ac.uk/team/philippa-hulley