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A functional investigation of the inducible nitric oxide synthase (NOS2) association with Ankylosing Spondylitis


About This PhD Project

Project Description

Nuffield Dept of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre – University of Oxford
And jointly at Wellcome Trust Centre for Human Genetics, Old Road Campus – University of Oxford

Project Outline


Ankylosing spondylitis (AS) is a severe inflammatory arthritis of the spine affecting about 200,000 individuals in the UK. Extensive genome-wide association studies (GWAS) indicate that more than 100 genes influence susceptibility to the condition, including NOS2, which encodes inducible nitric oxide synthase1. Understanding the molecular mechanisms behind this association is a major challenge that could give important insights into the pathogenesis of AS and how to treat it.

Our group has pioneered new technologies and statistical methods to investigate the genetic associations of AS and is now intent on discovering their functional consequences. The NOS2 association with AS extends over ~30kb upstream of the gene with a large cluster of single nucleotide polymorphisms (SNP) exhibiting genome-wide significant association (p<10-10). In this project you will first fine map these NOS2 associations using data from the International Genetics of AS (IGAS) consortium1 and the latest UK GWAS to identify the most relevant functional SNPs. These results will be correlated in silico with data on the epigenetic regulatory landscape at the locus for disease-relevant cell types to identify likely regulatory elements. You will then conduct targeted studies to characterise the likely functional influences of individual SNPs within these sequences and their potential relevance to AS. These methods will include allele-specific assays of protein-DNA interactions in vitro and in vivo (i.e. Mobility Shift Assays and Chromatin Immunoprecipitation), Luciferase Reporter Assays to assess gene promoter/enhancer activity, Chromosome Conformation Capture to study chromatin organisation and its physical interactions, DNA pull-down/Mass Spectrometry to examine the protein components of regulatory complexes, and the use of gene editing (CRISPR/Cas9) to dissect the potential active regulatory elements in the region. We have substantial experience on these statistical and laboratory techniques from our previous analyses of the IL23R/IL12RB2, RUNX3 and TNFRSF1A loci2-4 together with genome-wide using approaches such as eQTL mapping5,6. In this DPhil project you will elucidate the functional relevance of NOS2 polymorphisms associated with AS, gaining experience in genetics, functional genomics and biochemistry techniques, with the goal of identifying new pathological pathways associated with the condition as a prelude to identifying new drug targets.

This DPhil prize scholarship is funded by Versus Arthritis (https://www.versusarthritis.org/) (3 years with the option for supplemental funding for year 4 if required) which will cover the stipend and tuition/college fees at UK/EU rate, as well as £10,000 per year for running expenses.

Details of the Research Group


Dr Matteo Vecellio is a Versus Arthritis Career Development Fellow with experience in epigenetics and cellular/molecular biology. His work focuses on the functional investigation of genetic variants associated with AS.

Professor Julian Knight is Professor of Genomic Medicine and Director of the Genomic Medicine and Statistics Doctoral Training Programme. He leads a research programme in the functional genomics of AS.

Professor Paul B Wordsworth is Emeritus Professor of Clinical Rheumatology who has led GWAS of ankylosing spondylitis and rheumatoid arthritis for more than 20 years.

Dr Carla J Cohen is a postdoctoral researcher with experience in molecular biology and epigenetics.

Training


In the first few months DPhil students within NDORMS receive formal structured teaching across a wide range of musculoskeletal disciplines. You will also benefit from training and expertise in wet lab molecular genetic techniques and cutting-edge genomic technologies that take advantage of high throughput sequencing, and current bioinformatic and statistical analysis through the WHG. This will be complemented by weekly in-house seminars with group leaders and by group meetings with other local AS researchers. There are daily relevant external seminars not only across the Headington biomedical campus but also the wider University. The medical sciences division offers a comprehensive range of tailored training courses (for example through the Skills Training Programme of the Medical Sciences Doctoral Training Centre https://www.medsci.ox.ac.uk/study/skillstraining) and seminars and also offers career mentorship. Pastoral support is further enhanced through a College Advisor for every student. Oxford employs a system that allows students to engage with academics on the progress of the project at every year of study and NDORMS runs a rigorous mentoring systems for its DPhil students. All students will have a thesis committee and the co-applicants will be the named supervisors for the student. Dr Vecellio, Professor Knight and Professor Wordsworth work with Versus Arthritis and are involved in many patient/public engagement programmes, in which the student could also participate.

Person specification:


Applications are invited from candidates who hold or expect to obtain a First or Upper Second Class Honours Degree in genetics or in a relevant subject such as biochemistry, molecular biology or statistics. Molecular and cell biology skills, good knowledge of genetics and statistics, and programming skills in R or python would be highly relevant.

Value of the award:


The Studentship pays the College and University fees and has a generous stipend of £21.300-£22.169 for the three years (tax-free).

Application process:


Applicants must apply online for the D.Phil in Musculoskeletal Sciences. Queries relating to application should be directed to our Graduate Studies Officer (). Please direct any project-specific queries to Dr Matteo Vecellio ().

The DPhil will commence in October 2019.

Closing date: Applications are to be received by 12:00, noon on 30th August 2019.

References

1. International Genetics of Ankylosing Spondylitis Consortium (IGAS), Cortes A, et al. Nat Genet. 2013 Jul;45(7):730-8
2. Roberts AR, Vecellio M, et al. Ann Rheum Dis. 2016 Dec;75(12):2150-2156.
3. Vecellio M, Roberts AR, et al. Ann Rheum Dis. 2016 Aug;75(8):1534-40.
4. Watts L, Karaderi T, et al. Genes Immun. 2019 Feb;20(2):167-171.
5. Osgood JA and Knight JC. Brief Funct Genomics 2018;17, 308-318.
6. Fairfax BP et al., Science 2014; 343, 1246949

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