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NDORMS DPhil & MSc by Research

Outline

Ankylosing Spondylitis (AS) is a common disabling arthritis of the spine affecting 200,000 people in the UK. It is highly genetic with more than 100 loci identified from genome-wide association studies so far. The recent Immunochip study (1) suggests that many of these genetic associations have important immunological or inflammatory implications but most of the primarily associated polymorphisms are in non-coding regions of the genome. The great challenges now are to understand the functional mechanisms behind these associations, to define the molecular and cellular pathological processes involved, and to translate these into potential new treatments.

Our recent studies have demonstrated (2) how the AS-associated SNPs located in a regulatory region upstream of the RUNX3 promoter, influence the binding of transcription factors, modify epigenetic markers and alter gene expression in monocytes and T-cells (2, 3).

Our primary goal is to decipher the precise mechanism(s) through which AS-associated SNPs at the RUNX3 locus alter gene expression and transcription in different cell types, highlighting the central role of both T-cells and monocytes in AS. Several new techniques will be applied to this project (a) DNA pull-down followed by Mass Spectrometry, (b) ChIP-qPCR and Chromosome Conformation Capture and (c) CRISPR-Cas9 gene editing.

We aim to define the full complement of cell types involved in AS, the aberrant regulatory gene networks behind the RUNX3 association, and to discover new potential molecular and/or cellular therapeutic targets. This programme of work also has the potential for application to many other AS-associated disease loci (4).   

Themes

  • Genetics
  • Ankylosing Spondylitis
  • Genomics
  • Musculoskeletal Disease

Details of the Research Group

The Student will carry on this project under the supervision of Dr Matteo Vecellio and Prof Paul Wordsworth in the Ankylosing Spondylitis genetics group at the Institute of Musculoskeletal Sciences at the Botnar Research Centre, which is an integral part of the Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences.  Dr Vecellio has recently secured a 5 years Arthritis Research UK Career Development Fellowship and Prof Wordsworth is an internationally recognised rheumatologist who has pioneered genome-wide studies in rheumatic diseases. The group has daily interactions with the Immunology group headed by Professor Paul Bowness, who share the same laboratory space, and with the team of Professor Julian Knight at the Wellcome Trust Centre for Human Genetics. Very productive collaborations have been established with the Kennedy Institute of Rheumatology, the Target Discovery Institute and the Wellcome Trust Centre of Human Genetics to support this project.

Training

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. The Nuffield Department off Orthopaedics, Rheumatology and Musculoskeletal Sciences hosts more than 300 scientists and 50 students. There is a well-established post-graduate training programme for students and post-doctoral scientists across the range of musculoskeletal disorders.

Specifically for this project training will be provided in different techniques including: publicly available Genome database (ENCODE, Roadmap) interrogation, RT-PCR, Electrophoretic Mobility Shift Assays, Chromatin Immunoprecipitation, Chromosome conformation Capture (3C), DNA pull-down assays and CRISPR-Cas9 gene editing. There will also be some opportunity for learning and applying genetic statistic techniques.

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 and data analysis. 

Students will attend weekly seminars within the department and those relevant in the wider University.

Students will be expected to present data regularly to the department, the Wordsworth group and to attend external conferences to present their research globally.

Students will also have the opportunity to work closely with the Immunology group headed by Professor Paul Bowness, the Functional Genomics of Immunity team of Professor Julian Knight at the Wellcome Trust Centre for Human Genetics.

How to Apply

The department accepts applications throughout the year but it is recommended that, in the first instance, you contact the relevant supervisor(s) or the Directors of Graduate Studies 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, and will also need to provide evidence of English language competence. The University requires candidates to formally apply online and for their referees to submit online references via the online application system.

The application guide and form is found online and the DPhil or MSc by research will commence in October 2018.

When completing the online application, please read the University Guide.

RELEVANT PUBLICATIONS

  1. Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci. International Genetics of Ankylosing Spondylitis Consortium (IGAS) et al. Nat Genet. 2013 Jul;45(7):730-8.
  2. The genetic association of RUNX3 with ankylosing spondylitis can be explained by allele-specific effects on IRF4 recruitment that alter gene expression. Vecellio M et al. Ann Rheum Dis. 2015 Oct 9. pii: annrheumdis-2015-207490.
  3. Two adjacent functional single nucleotide polymorphisms in a 5’ RUNX3 regulatory region are independently associated with ankylosing spondylitis. Vecellio M et al. Review in progress. 2017
  4. An ankylosing spondylitis-associated genetic variant in the IL23R-IL12RB2 intergenic region modulates enhancer activity and is associated with increased Th1-cell differentiation. Roberts AR, Vecellio M, et al.  Ann Rheum Dis. 2016 Feb 25. pii: annrheumdis-2015-208640

Project reference number #NDORMS-2018/13

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