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Evaluation of the influence of chemical modifications on antigen presentation and T cell immunity


   Faculty of Health and Life Science

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  Dr Xiaoli Meng, Prof D Naisbitt, Prof A Jones, Dr A Benham  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

T-cells, the drivers of adaptive immunity, have great 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 by molecules called “human leukocyte antigens” (HLA). However, chemical compounds such as drugs can interfere with this process, resulting in the formation of neo-antigens which have not been seen by the immune system before, potentially harming self- tissues. In this project, we aim to better understand how neo-antigens are presented in the presence of certain chemicals, and how chemical associated neo-antigens are recognised by human T-cells. To achieve this, these peptide antigens will be eluted from the surface of HLA molecules on cells and tissues and subsequently characterised using mass spectrometry-based methods. Chemical compounds that have known genetic associations with specific HLA alleles will be used as model compounds to explore pathways of neo-antigen formation. Computational tools will be developed to analyse the large and complex datasets as they can be difficult to interpret using existing computational platforms. Finally, the potential T- cell immunity of identified neo-antigens will be assessed using human T- cells from healthy volunteers or patients with specific diseases.

The departments of Pharmacology and Functional & Comparative Genomics at the University of Liverpool in collaboration with the Department of Biosciences at Durham University present an exciting multidisciplinary PhD opportunity. This multi-centre and multi-disciplinary project is suited for a student with an interest in analytical chemistry/biochemistry/ computational biology/cell biology from a relevant degree background (e.g. biological sciences, medicinal chemistry, and immunology). The student will be trained in both immunopeptidomics and mass spectrometry 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 at the University of Durham to study the biochemical and cell biological mechanisms of antigen processing. Upon completion, the student will have first-hand training in a range of analytical techniques relevant to academia and industry alike.

The studentship should be commenced before the end of 2022.

HOW TO APPLY

Applications should be made by emailing [Email Address Removed] with:

·      a CV (including contact details of at least two academic (or other relevant) referees);

·       a covering letter – clearly stating your first choice project, and optionally 2nd ranked project, 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;

·      copies of your relevant undergraduate degree transcripts and certificates;

·      a copy of your passport (photo page).

A GUIDE TO THE FORMAT REQUIRED FOR THE APPLICATION DOCUMENTS IS AVAILABLE AT https://www.nld-dtp.org.uk/how-apply. Applications not meeting these criteria may be rejected.

In addition to the above items, please email a completed copy of the Additional Details Form (as a Word document) to [Email Address Removed]. A blank copy of this form can be found at: https://www.nld-dtp.org.uk/how-apply.

Informal enquiries may be made to [Email Address Removed]. The closing date for applications is Friday 8th July 2022 at 12noon (UK time).

Note on English language requirements for international applicants: All students applying to the University of Liverpool must demonstrate that they are competent in the use of the English language and satisfy the University’s requirements. Please see this page for more details on specific requirements: https://www.liverpool.ac.uk/study/international/apply/english-language/.


Funding Notes

Studentships are funded by the Biotechnology and Biological Sciences Research Council (BBSRC) for 4 years. Funding will cover tuition fees at the UK rate only, a Research Training and Support Grant (RTSG) and stipend. We aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of bursaries that will enable full studentships to be awarded to international applicants. These full studentships will only be awarded to exceptional quality candidates, due to the competitive nature of this scheme. Note that home (UK) candidates may also apply to this studentship.

References

Characterisation of naturally processed and presented drug-modified peptides that act as T cell antigens. (2020), Toxicol Sci
Definition of Haptens Derived from Sulfamethoxazole: In Vitro and in Vivo. (2019), Chem Res Toxicol
Modification of the cyclopropyl moiety of abacavir provides insight into the structure activity relationship between HLA-B*57:01 binding and T-cell activation. Allergy. 2019
MHCVision: estimation of global and local false discovery rate for MHC class I peptide binding prediction, Bioinformatics, 2021.
Reductive stress selectively disrupts collagen homeostasis and modifies growth factor-independent signalling through the MAPK/Akt pathway in human dermal fibroblasts. Molecular and Cellular Proteomics 2019, 18(6): 1123-1137.
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