Functional Mechanisms of Genetic Risk Factors for Immune-Related Disease


   School of Medicine

  Prof Timothy Vyse  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Who are we?

We are a vibrant, outward-looking, multi-disciplinary research group interested in understanding how genetic risk factors can impact on both susceptibility to infection and to autoimmune disease.  We have a strong interest in comparing how genetic risk factors from different ancestries impact on risk of infection and in developing autoimmune disease.

The ImmunoGenetics group is headed by Prof Timothy Vyse, a clinical academic with world-leading expertise in the genetics of the autoimmune disease Systemic Lupus Erythematosus.  Each supervisor in the ImmunoGenetics group has an excellent track record in research and PhD supervision.  They each have a breadth of understanding and experience in guiding PhD students through their projects, including EU/world-wide international students. 

Systemic Lupus Erythematosus is a chronic, multi-system autoimmune disease, with increased disease severity in non-European ancestries and more females than males with lupus. The relapsing-remitting disease course makes it challenging to treat successfully. Approximately 140 risk loci have been mapped for SLE through genome-wide association studies (GWAS). We have shown that polygenic risk scores influence disease severity in a quantitative manner.  The projects listed below will utilise these data and other datasets as required to understand the mechanism of action and the functions of the identified risk loci.  

What projects are available?

How does the profile of genetic risk alleles from different ancestries affect gene expression profiles and epigenetic landscapes in immune cell subsets?

Can ancestral differences in Polygenic risk scores for autoimmune disease predict differences in severity and prognosis?

Correlation of genetic risk alleles for autoimmune disease with those for viral infection, including COVID-19.

Autoimmune Biomarkers: linking pathological mechanism for OX40-OX40L to cellular targeting for therapy - funded through an MRC DTP scheme https://kcl-mrcdtp.com/project/autoimmune-biomarkers-linking-pathological-mechanism-for-ox40-ox40l-to-cellular-targeting-for-therapy/

Scientific basis

We have a long-standing interest in two TNF superfamily genes, (OX40 and OX40L), as independent risk factors for SLE, as membrane-bound (mOX40) and serum (sOX40) proteins. The mechanism of production for sOX40 is unknown, but may involve alternative-splicing or cleavage by metalloproteinases (MMP). A co-stimulatory immune signal produced when OX40 binds to its unique receptor, OX40L, is an important regulatory factor for SLE (a disease of increased immune activity). We have both genetic associations and functional data to drive our interest in OX40. 

Techniques and skills

Multi-omic analysis of GWAS and scRNA-Seq datasets; multi-analyte immunoassay (MSD), multi-parameter flow cytometry (Cytek Aurora), cell culture, bioinformatics

What are we looking for?

Dedicated students with a first or 2.1 undergraduate degree or equivalent in statistics, computational biology, bioinformatics or biological science/medicine.

For international students, evidence of strong English Language Skills eg) IELTs overall score 6.5 with no less than 6 on individual elements.

 

How to apply?

If you meet the criteria listed above and are curious about the type of science we are doing, then please email Prof Vyse outlining the project you are interested in, your current English Language scores, and why you may be interested in joining our group.

Biological Sciences (4) Computer Science (8) Mathematics (25)

Funding Notes

The projects listed above are offered on the basis of self-funding, apart from the biomarkers project which will be funded through the View Website. View Website). The projects are open to applicants who already have funding or those who need to apply for funding sources. We are very happy to support applicants in writing funding applications or alternatively apply for a PhD Loan (View Website). Candidates must be able to meet admission criteria and tuition fee requirements of our department.

References

1. Morris DL, …. Cunninghame Graham DS, Bentham J, Chen R, …. Zhang XJ, Yang W, Cui Y, Vyse TJ. Meta-analysis of Chinese and European GWAS identifies 10 novel SLE associated loci and provides evidence for increased genetic risk of disease in non-Europeans. Nat Genet (2016) 48(8): 940-946.

2. Bentham J, Morris DL, Cunninghame Graham DS ….. Vyse TJ. Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus. Nat Genet. (2015) 47(12): 1457-64.

3. Kamitaki N, …. Morris DL, ….. Vyse TJ and McCarroll SA. Complement genes contribute sex-biased vulnerability in diverse disorders. Nature. (2020) 582(7813): 577-581.
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