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A single-cell genomics based investigation of spondyloarthritis. (#202009)


About This PhD Project

Project Description

In our groups we are investigating the molecular basis of inflammatory arthritis1,2. In this project you will study ankylosing spondylitis (AS), a common and highly heritable form of arthritis which characteristically involves inflammation of the sacroiliac joints and spine. To understand the causes of this disease we are now applying the latest single-cell RNA-sequencing technology to patient biopsy samples. For your DPhil research, you will perform computational analysis of the resulting datasets in order to discover the cellular circuits, biological pathways and genes that are associated with disease.

This work is important as current therapeutics do not work in all patients and cannot induce disease remission. Inflammation in AS is known to involve the IL-23/IL-17 immune pathway3 but the molecular origins of the disease remain mysterious. The strong genetic association of AS with the human leukocyte antigen (HLA) class I molecule HLA-B*27 suggests that inflammation is triggered by an ‘arthritogenic’ peptide, but there is also evidence for several other models of disease pathogenesis4. This project will involve comparison of cells from patients with spondylitis with those from other forms of arthritis as well as from healthy joints (which we are generating as part of the Human Cell Atlas project).

Working closely with clinical and experimental colleagues you will have the opportunity to design follow-up experiments and test hypotheses using the latest functional genomics approaches such as CRISPR-based gene editing. Ultimately, the results of this research will provide a rational basis for the development of more effective therapeutics that target the causes, rather than the symptoms, of AS. This work is supported by funding from Versus Arthritis.

Training opportunities


The Kennedy Institute is a world-renowned research centre, housed in a brand new, state-of-the-art facility at the University of Oxford. The Botnar Research Centre 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. Students will become fluent in computational genomics and acquire an expert understanding of chronic inflammatory disease. Training will be provided in data science techniques including the writing of computational pipelines (see e.g. https://github.com/sansomlab/tenx) with Python, the use of Linux high-performance compute clusters, and statistical data analysis and visualisation with R. Students will have the opportunity to utilise machine learning approaches, to work closely with world-leading statistical geneticists, and will perform integrated analyses with “big data” from sources such as the Human Cell Atlas (https://www.humancellatlas.org/) and ImmGen projects. You will be expected to develop a close understanding of experimental research through regular attendance of wet-lab group meetings. You will have the opportunity to be closely involved in the generation of functional genomics data and to learn the various immunological techniques that are up and running in the Bowness lab. For more information on our work please visit our websites: https://www.kennedy.ox.ac.uk/research/computational-genomics (Sansom group), https://www.ndorms.ox.ac.uk/research-groups/immunology-of-Ankylosing-Spondylitis (Bowness group).

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. Students will attend regular seminars within the department and those relevant in the wider University. Students will be expected to present data regularly in the departmental PGR seminars, Sansom and Bowness group meetings and to attend external conferences to present their research globally.

Students will have access to various courses run by the Medical Sciences Division Skills Training Team and other departments. All students are required to attend a 2 - day Statistical and Experimental Design course at NDORMS.

Publications


Distinct fibroblast subsets drive inflammation and damage in arthritis. Adam P. Croft, et. al. Nature, 2019

Unique transcriptome signatures and GM-CSF expression in lymphocytes from patients with spondyloarthritis. Al-Mossawi et. al. Nature Communications, 2017

Progress in our understanding of the pathogenesis of ankylosing spondylitis. Simone D, Al Mossawi and Bowness P. Rheumatology (Oxford), 2018

HLA-B27. Bowness P. Annual Review Immunology, 2015

Related Subjects

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