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A computational investigation of inflammatory arthritis at the single-cell level (KTPS-Clinical-4)


Kennedy Institute of Rheumatology

, Friday, January 08, 2021 Funded PhD Project (Students Worldwide)

About the Project

Research in our groups (https://sansomlab.org, https://www.ndorms.ox.ac.uk/research-groups/immunology-of-Ankylosing-Spondylitis) is focused on understanding the molecular basis of immune-mediated inflammatory diesease1,2,3. In this project, you will undertake a bioinformatic investigation of ankylosing spondylitis (AS), a common and highly heritable form of inflammatory arthritis. To understand the causes of this disease, we are applying the latest single-cell genomics and spatial technologies to patient biopsy samples. For your DPhil research, you will perform computational analysis of the resulting datasets to discover the cellular circuits, biological pathways and genes that cause disease.

This work is important as current therapeutics do not work in all patients and cannot induce disease remission. Inflammation in AS, which characteristically affects the sacroiliac joints and spine, is known to involve the IL-23/IL-17 immune pathway4, 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 an ‘arthritogenic’ peptide triggers inflammation, but there is also evidence for several other models of disease pathogenesis5. This project will involve a computational 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 (https://www.humancellatlas.org/).

Working closely with clinical and experimental colleagues, you will also 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.

single-cell genomics; computational genomics; bioinformatics; arthritis; immunology

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.

References

(1) Distinct fibroblast subsets drive inflammation and damage in arthritis. Adam P. Croft, et. al. Nature, 2019
(2) IRF5 guides monocytes toward an inflammatory CD11c+ macrophage phenotype and promotes intestinal inflammation, Alastair L. Corbin et. al. Science Immunology, 2020
(3) Unique transcriptome signatures and GM-CSF expression in lymphocytes from patients with spondyloarthritis. Al-Mossawi et. al. Nature Communications, 2017
(4) Progress in our understanding of the pathogenesis of ankylosing spondylitis. Simone D, Al Mossawi and Bowness P. Rheumatology (Oxford), 2018
(5) HLA-B27. Bowness P. Annual Review Immunology, 2015

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