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(BBSRC NWD) Deciphering the role of adaptor protein complexes in mast cell activation

Funding
Funded
Study mode
Full-time
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Start date
Subject area
Biological and Biomedical Sciences
How to apply
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Overview

Mast cell activation is central to the physiological development of tissue vasculature, but pathologically contributes to allergy, anaphylaxis, mast cell activation syndrome and mast cell cancers. Mast cell activation mechanisms are conserved in mammalian species, contributing to allergy in domesticated animals including over 10% of cats and dogs, 20-40% of horses, and over 20% of people in the UK. Therefore, understanding the fundamental mechanisms regulating mast cell biology would benefit animal and human health across the life course. This project will characterise a critical step in the activation cycle of mast cells.

About this opportunity

Background

Mast cell activation results in the rapid release of inflammatory mediators from granules, including histamine and proteases via degranulation (exocytosis). Importantly, mast cells can be activated repeatedly, without loss of viability and therefore require endocytosis to recycle membrane and to retrieve granule-associated proteins.

The adaptor protein complexes orchestrate cargo selection and vesicle formation, critical for intracellular trafficking to specific cellular compartments. In other immune cell types, the adaptor complex AP-2 transiently associates with endocytic sites and is required for re-internalisation of transmembrane proteins following exocytosis. Mast cells express components of all five AP complexes, however, the role of these proteins in trafficking following degranulation is unknown. Initially this project will focus on the role of AP-2 in appropriate re-internalisation of granule membrane proteins and associated cargo, a critical biological process.

The overall aim of the project is to define the requirement for AP complexes in endocytosis and recycling of machinery necessary to sustain further mast cell exocytosis. This will involve three different approaches; 1) cell biology approaches will generate genetic mutants in a human mast cell line, and combine with single cell assays to study the function of AP-2 in mast cell endocytosis, 2) proximity labelling and mass spectrometry approaches will identify potential interactors with this complex, 3) computational modelling using AlphaFold-based methods will predict direct protein-protein interactors relevant to endocytosis and granule recycling.

Further reading

1. Salt-inducible kinases are required for the IL-33-dependent secretion of cytokines and chemokines in mast cells. NJ Darling, S Arthur, P Cohen, J Biol Chem (2021) 296: 100428
2. Salt-inducible kinase 2 regulates fibrosis during bleomycin-induced lung injury. M van Gijsel-Bonnello, NJ Darling, T Tanaka, S Di Carmine, F Marchesi, S Thomson, K Clark, M Kurowska-Stolarska, HJ McSorley, P Cohen, JSC Arthur, J Biol Chem (2022) 298: 102644
3. AlphaFold-driven discovery of ORP-PIP phosphatase interactions using new generation confidence scores. F Dall’Armellina, S Urbé, DJ Rigden, bioRxiv (2025) 2025.09.09.675126 [pre-print]
4. ABCFold:easier running and comparison of AlphaFold3, Boltz-1 and Chai-1. LG Elliott, AJ Simpkin, DJ Rigden, Bioinformatics Advances (2025) 5: vbaf153
5. The role of the AP-1 adaptor complex in outgoing and incoming membrane traffic. MS Robinson, R Antrobus, A Sanger, AK Davies, DC Gershlick, J Cell Biol (2024) 223: e202310071
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Who is this for?

Applicants must have obtained or be about to obtain a minimum Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in an appropriate area of science, engineering or technology.

International applicants

We are only able to offer a limited number of full studentships to applicants outside the UK. Therefore, full studentships will only be awarded to exceptional quality international candidates due to the competitive nature of this scheme.

International applicants must ensure they meet the academic eligibility criteria (including English language) before applying. Visit our English Language requirements page to find out more.

Equality, Diversity and Inclusion

Equality, diversity and inclusion is fundamental to the success of The University of Liverpool, and is at the heart of all of our activities. The full equality, diversity and inclusion statement can be found on our website

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How to apply

  1. 1. Contact supervisors

    The student will be embedded in the Biochemistry, Cell and Systems Biology department at University of Liverpool which hosts world class proteomics, genomics and computational facilities. The student will receive comprehensive training in all the required techniques for this project. The supervisory team are experts in mast cell biology and cell signalling (Darling lab), in AlphaFold-based methods and protein interaction predictions (Rigden lab), and in vesicle trafficking and spatial proteomics (Davies lab, Manchester).

    https://www.liverpool.ac.uk/people/nicola-darling

    https://www.liverpool.ac.uk/people/daniel-rigden

    https://research.manchester.ac.uk/en/persons/alexandra-davies/

  2. 2. Prepare your application documents

    Browse our BBSRC NWD in Bioscience projects and discover one you’re passionate about that matches your interests, ambitions and goals.

    Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application.

    How to Apply

    All applications should be submitted through the University of Manchester application portal.

    Apply directly via this link, and select BBSRC DTP PhD as the programme of study. You may apply for up to two projects from the programme via this scheme. To do so, submit a single online application listing both project titles and the names of both main supervisors in the relevant sections.

    Please ensure that your application includes all required supporting documents:

    • Curriculum Vitae (CV)
    • Supporting Statement
    • Academic Certificates and Transcripts

    Incomplete or late applications will not be considered.

    Applications should not be made through the University of Liverpool’s application portal.

    You must submit your application form along with the required supporting documents by the deadline date. You can select up to two projects on one single application, noting the title of each project from the advert and the supervisor name. This can include two projects from one institution or a project from each institution.

    Once you have completed your application, you’ll receive a confirmation email.

    Deadline: Sunday 7th December, midnight (UK time)

    Late or incomplete applications will not be considered.

    If you need help with this stage of the process, or have any queries regarding your eligibility (such as if you achieved unexpectedly low degree results due to extenuating circumstances), please contact the Liverpool BBSRC team for advice at 

  3. 3. Apply

    Finally, register and apply online. You'll receive an email acknowledgment once you've submitted your application. We'll be in touch with further details about what happens next.

    Once you have applied through the University of Manchester portal, and if you are successfully offered a studentship following a formal interview, you will be instructed to apply formally through the University of Liverpool. You must only do this once you have been instructed to do so.

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Funding your PhD

These studentships are available to UK and international applicants, and provide funding for tuition fees and stipend at the UKRI rate, subject to eligibility, for four years. This does not include any costs associated with relocation. This scheme is open to both UK and international applicants.

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Contact us

Have a question about this research opportunity or studying a PhD with us? Please get in touch with us, using the contact details below, and we’ll be happy to assist you.

Liverpool BBSRC team
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