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The development of a data science pipeline to assess the influence of chemical compounds on the HLA immunopeptidome


Project Description

T-cells, the drivers of adaptive immunity, have gained increased interest for their therapeutic potential. However, there are still many unknowns about how they are activated. It is well understood that T-cells respond to antigens which have been processed and presented as antigenic peptides upon human leukocyte antigen (HLA). However, chemical compounds such as drugs can interfere with this process resulting in the formation of neo-antigens, redirecting their cytotoxic potential towards self-tissues. The field of immunopeptidomics has arisen whereby these peptide antigens can be eluted from the surface of HLA on cells and tissues and subsequently analysed using high resolution mass spectrometry. Initial data shown with some chemicals demonstrate unique pathways of neo-antigen formation including the presentation of an altered HLA-peptide repertoire, the presentation of peptides covalently modified with chemical compounds and the presentation of novel spliced peptides derived from proteasomal processing. While mass spectrometric technology may be sensitive enough to detect these neo-antigens, these large and chemically complex datasets can be difficult to interpret using existing computational platforms. Thus, the aim of this project is to generate an end-to-end pipeline to generate mass spectrometric data and develop computational tools to analyse the data. Chemical compounds with genetic associations with specific HLA alleles will be used as model compounds where in-vitro T-cell data has already provided some understanding of likely pathways of neo-antigen formation.

The departments of Molecular & Clinical Pharmacology and Functional & Comparative Genomics at the University of Liverpool in collaboration with the Department of Biological Sciences at the University of Durham present an exciting multidisciplinary PhD opportunity. This multi-centre and multi-disciplinary project is suited for a student with an interest in analytical chemistry/ computational biology from a relevant degree background (e.g. biological sciences, medicinal chemistry). The student will be trained in both immunopeptidomics and mass spectrometric methods in parallel with learning how to code bespoke scripts using the ‘R’ programming language. Furthermore, some wet-lab training will also be provided in genomics and T-cell culture methods. Finally, the student will have an opportunity to spend three months in Adam Benham’s lab at the University of Durham to study the chemical mechanisms of antigen processing. Upon completion, the student will have had first-hand training in a range of analytical techniques relevant to academia and industry alike.

HOW TO APPLY
Applications should be made by emailing with a CV (including contact details of at least two academic (or other relevant) referees), and a covering letter – clearly stating your first choice project, and optionally 2nd and 3rd ranked projects, as well as including whatever additional information you feel is pertinent to your application; you may wish to indicate, for example, why you are particularly interested in the selected project(s) and at the selected University. Applications not meeting these criteria will be rejected.
In addition to the CV and covering letter, please email a completed copy of the Additional Details Form (Word document) to . A blank copy of this form can be found at: https://www.nld-dtp.org.uk/how-apply.
Informal enquiries may be made to

Funding Notes

This is a 4 year BBSRC studentship under the Newcastle-Liverpool-Durham DTP. The successful applicant will receive research costs, tuition fees and stipend (£15,009 for 2019-20). The PhD will start in October 2020. Applicants should have, or be expecting to receive, a 2.1 Hons degree (or equivalent) in a relevant subject. EU candidates must have been resident in the UK for 3 years in order to receive full support. Please note, there are 2 stages to the application process.

References

Modification of the cyclopropyl moiety of abacavir provides insight into the structure activity relationship between HLA-B*57:01

Exosomal Transport of Hepatocyte-Derived Drug-Modified Proteins to the Immune System. Hepatology. 2019 doi: 10.1002/hep.30701. [Epub ahead of print]

Dapsone- and nitroso dapsone-specific activation of T cells from hypersensitive patients expressing the risk allele HLA-B*13:01. Allergy. 2019;74:1533-1548

β-Lactam hypersensitivity involves expansion of circulating and skin-resident TH22 cells. J Allergy Clin Immunol. 2018;141:235-249

The Effect of Inhibitory Signals on the Priming of Drug Hapten-Specific T Cells That Express Distinct Vβ Receptors. J Immunol. 2017;199:1223-1237

Strong anion exchange-mediated phosphoproteomics reveals extensive human non-canonical phosphorylation. Embo j, e100847 (2019)

Critical assessment of approaches for molecular docking to elucidate associations of HLA alleles with adverse drug reactions, Mol Immun 2018, 101:488-499 (2018)

Evaluation of Parameters for Confident Phosphorylation Site Localization Using an Orbitrap Fusion Tribrid Mass Spectrometer. Journal of Proteome Research 16, 3448-3459 (2017)

Allele frequency net 2015 update: new features for HLA epitopes, KIR and disease and HLA adverse drug reaction associations. Nucleic Acids Research, 43, D784-788 (2014)

Definition of the Nature and Hapten Threshold of the β-Lactam Antigen Required for T Cell Activation In Vitro and in Patients. J Immunol. 2017; 187, 200

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