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Can genetics-led immunologic investigation identify novel common regulators shared across immune-mediated inflammatory diseases? #NDORMS-2020/2


About This PhD Project

Project Description

Supervisors


Liye Chen: https://www.ndorms.ox.ac.uk/team/liye-chen
Paul Bowness: https://www.ndorms.ox.ac.uk/team/paul-bowness

Research Project Outline


Immune-mediated inflammatory diseases (IMIDs) are a group of incurable diseases that share inflammatory pathways and cause substantial personal and socioeconomic burdens. Current drugs do not always work and could comprise the immune system [1].

Genome-wide association studies (GWAS) have identified tens to hundreds of single nucleotide polymorphisms (SNPs) affecting the risk of developing each form of IMIDs [2, 3]. It has been recognized now that drug targets with genetic support are more likely to be therapeutically valid [4, 5]. However, to date, there is a plausible explanation for only a minority of genetic associations, which represents a substantial impediment to their translation into therapeutic options.

In this DPhil project, we will study the shared genetic risks across a group of clinically related IMIDs: ankylosing spondylitis (AS), Crohn's disease (CD), ulcerative colitis (UC), psoriasis, primary sclerosing cholangitis (PSC) [2, 6]. These conditions also have shared genetic associations and overlapped pathogenic mechanisms [3]. Whilst other cell types are clearly involved, this project will focus on T-cell and monocyte due to their key roles in pathogenesis of these 5 IMIDs [6, 7].

With training and support from CHEN and BOWNESS groups, you will undertake a genetics-led target prioritization approach integrated with gene knockdown validation in disease-relevant cellular assays to identify shared immune regulators across five common IMIDs (AS, CD, UC, psoriasis and PSC). Data generated will provide functional explanations for IMID-associated genetic loci, promote the understanding of the pathogenesis mechanism, and potentially identify novel therapeutic targets for the treatment of these IMIDs.

Research Aims


To achieve the overall goal of identifying novel immune regulators shared in IMIDs, the following specific aims will be addressed.
Aim-1: Identification of gene candidates regulating T-cells and/or monocytes in IMIDs through integration of GWAS and genomic datasets
Aim-2: Prioritization for genes most likely regulating T-cell and/or monocyte functions in IMIDs using transcriptomic datasets of disease-related cell subsets.
Aim-3: Validation of gene candidates through gene knockdown/overexpression in disease-relevant cellular assays
Aim-4: Mechanistic studies of validated genes (1-2)

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. Training will be provided in following aspects: 1) integration of GWAS findings with genomic datasets, 2) designing and performing disease-relevant cellular assays using primary T-cells and monocytes (techniques including ELISA, flowcytometry, qPCR and western blot), 3) gene knockdown and overexpression in primary T-cells and monocytes (techniques including standard molecular biology techniques, in-vitro mRNA translation and lentivirus production for gene knockdown and overexpression), 4) bulk and sing cell RNA-seq for mechanistic study of gene functions.

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 also be required to attend regular seminars within the Department and those relevant in the wider University. Students will be expected to present data regularly in Departmental seminars, lab meeting within Chen and Bowness groups and to attend external conferences to present their research globally, with limited financial support from the Department.

Students will also have the opportunity to work closely with the Julian Knight group (https://www.well.ox.ac.uk/people/julian-knight) which is a world-leading group in genetic and genomic research.

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 and run by the IT department (information will be provided once accepted to the programme).

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 Graduate Studies Officer, Sam Burnell (), 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 equivalentin a relevant subject and will also need to provide evidence of English language competence (where applicable). The application guide and form is found online and the DPhil or MSc by research will commence in October 2020.

Applications should be made to one of the following programmes using the specified course code:
D.Phil in Musculoskeletal Sciences (course code: RD_ML2)
D.Phil in Molecular and Cellular Medicine (course code: RD_MP1)

For further information, please visit http://www.ox.ac.uk/admissions/graduate/applying-to-oxford.

References

1. Winthrop, K.L., et al., Opportunistic infections and biologic therapies in immune-mediated inflammatory diseases: consensus recommendations for infection reporting during clinical trials and postmarketing surveillance. Ann Rheum Dis, 2015. 74(12): p. 2107-16.
2. David, T., S.F. Ling, and A. Barton, Genetics of immune-mediated inflammatory diseases. Clin Exp Immunol, 2018. 193(1): p. 3-12.
3. Ellinghaus, D., et al., Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci. Nat Genet, 2016. 48(5): p. 510-8.
4. Plenge, R.M., E.M. Scolnick, and D. Altshuler, Validating therapeutic targets through human genetics. Nat Rev Drug Discov, 2013. 12(8): p. 581-94.
5. Nelson, M.R., et al., The support of human genetic evidence for approved drug indications. Nat Genet, 2015. 47(8): p. 856-60.
6. Baker, K.F. and J.D. Isaacs, Novel therapies for immune-mediated inflammatory diseases: What can we learn from their use in rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, psoriasis, Crohn's disease and ulcerative colitis? Ann Rheum Dis, 2018. 77(2): p. 175-187.
7. Shi, C. and E.G. Pamer, Monocyte recruitment during infection and inflammation. Nat Rev Immunol, 2011. 11(11): p. 762-74.


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