Decoding carbohydrate regulation and interactions with cytokine systems to enable novel glycopharmaceuticals


   Faculty of Science

  , , ,  Sunday, June 30, 2024  Competition Funded PhD Project (Students Worldwide)

About the Project

The actions of many important cell communication proteins called cytokines are regulated by negatively charged, long chain carbohydrates (glycans), often through direct interactions. Understanding these protein-carbohydrate relationships are crucial in a multitude of diseases such as inflammatory and infectious diseases and cancers. This research will investigate such regulation and interactions to enable development of new activator or inhibitor pharmaceuticals which are urgently needed.

 

Cells have exterior surfaces that display numerous proteins and complex carbohydrates. Furthermore, these are often shed from the cell surface or secreted, alone or within the surface of tiny vesicles, into the extracellular environment. Such surface proteins and carbohydrates mediate communication between cells, which if malfunctioning can contribute to abnormalities such as cancers and inflammatory diseases. Additionally, surface carbohydrates and proteins are docking sites on human cells for pathogenic microbes, such as ‘superbug’ bacteria (e.g. methicillin-resistant staphylococcus aureus (MRSA)), and viruses (e.g. the Covid-19 SARS-Cov-2), facilitating infection. Antibiotic resistant bacteria are often considered a greater long-term global threat than Covid-19. Infection intersects with cell communication by involving the latter between human cells as part of immune defence and can also be associated with cancers. Molecular interactions are central to most processes in biology and underpin a lot of drug discovery, including increasingly successful macromolecule and cellular biotherapies (E.g. antibody or immune cell), as well as traditional small molecule. Understanding interactions between surface proteins and carbohydrates is critical for developing novel pharmaceuticals in an underexploited area.

 

This PhD will focus on selected protein families of cytokine communication systems and a family of carbohydrates called glycosaminoglyans, which include heparin (a pharmaceutical used to prevent blood clotting (anticoagulation) with an $8bn annual global market, considered a critical drug for an advanced healthcare system, but also one of the riskiest in use) and hyaluronic acids (used in skin cosmetics). These carbohydrates are highly negatively charged and exist as different, very complex and large diverse families, being long chains decorated with often highly variable carboxyls, sulfates and acetyls. They interact with at least 1000 proteins, many of eukaryotic cellular communication systems or involved in host cell attachment by microbes. Consequently these protein and carbohydrate families are areas of cutting-edge research in therapeutics.

According to the student’s interests, we will employ a cross disciplinary approach that combines interaction biochemistry, activity cell biology and analytical/’soft’ synthetic chemistry to investigate:

a) Interactions of these carbohydrates with several specific, key cytokines or their receptors using in vitro assays (such as microtitre plate reader and 19F-NMR, with thermostability and surface plasmon resonance approaches also available). 

b) Regulation of cytokine activity by these carbohydrates with keratinocyte and immune cell line response assays (e.g. Q-PCR transcript, flow cytometry, morphology microscopy and anti-microbial (e.g. MRSA) assays).  

c) Structural specificity of interactions and activity including using chemical modification of carbohydrates (involving ‘soft chemistry’ and NMR analysis).

The PhD student will join our School of Pharmacy & Biomolecular Sciences, at Liverpool John Moores University and work across laboratories within the Life Science Building and James Parsons Chemistry floor under supervision of Dr Andrew Powell (Andrew Powell | Liverpool John Moores University (ljmu.ac.uk), with assistance from Dr Kate Phillips, Dr Francesca Giuntini and others within the School, in addition to regularly liaising with and visiting Dr Ed Yates at the University of Liverpool regarding chemical modification and analytical biophysics. The student can also interface with other glycoscientists at other universities within the region. This reflects the PhD involving a cross disciplinary approach to best understand such important cell surface regulation involving proteins and carbohydrates.

Consequently they will receive exposure to and training in techniques of molecular interaction, protein and carbohydrate biochemistry, cell biology and analytical and ‘soft’ synthetic chemistry, using appropriate interaction approaches (e.g. plate reader, 19F-NMR, surface plasmon resonance optical biosensor/thermocycler thermostability), quantitation assays, structural analysis and cellular activity assays (e.g. plate reader, flow cytometry, Q-RT-PCR, microbial viability, microscopy). These are applicable to the field of protein-carbohydrate drug discovery, but also drug discovery in general (and some transferable to diagnostics and drug monitoring). 

In addition to holding a masters or strong first degree in a chemistry, biochemistry or biology type field, the ideal applicant will be able to demonstrate significant interest in and prior experience of macromolecules and cell surface/signalling biology. A good working knowledge of statistical analysis, strong organisational skills and the ability to work diligently both independently and collaboratively with a team would be advantageous. If English is not your first language and you are not an EU student, you will also need to provide evidence of competence in English language (e.g. IELTS 6 overall – all components > 5.5). Full training in molecular interaction, cell culture, chemical modification, biophysical analytical techniques, advanced statistical analysis and appropriate research methodologies will be provided by the supervisory team and through our Doctoral Academy, who offer a comprehensive development program for postgraduate researchers.

One of the top 3 cities to visit in the world according to the Rough Guide 2014, the UKs best large city break in a 2024 Which poll and the most cultural city in the UK by Group Leisure, Liverpool with its unique attractions, exciting events, world class sport offerings, unrivalled musical heritage and famously warm welcome is the ideal place to live.

The Faculty of Science and its three Schools: Biological & Environmental Sciences, Pharmacy & Biomolecular Sciences, and Sports & Exercise Science, have dedicated Diversity and Inclusion (DI) Groups. The individual School Diversity & Inclusion Coordinators and the Faculty Associate Dean for Diversity & Inclusion lead collective action to promote and embed a culture of equality, diversity and inclusivity. All Schools are awarded the Athena SWAN Bronze in recognition of their respective equality initiatives and action plans. Also, Schools have proactive diversity and inclusion groups that are aimed to support staff and students by addressing the inclusivity requirements that are unique to each School, in alignment with the LJMU Diversity & Inclusion policies. Applicants are invited to visit the Faculty of Science https://www.ljmu.ac.uk/about-us/faculties/faculty-of-science and follow the link to each School.

Biological Sciences (4) Chemistry (6)

Funding Notes

The selected applicant will be entered for the 2023/24 LJMU VC PhD Studentship competition.

If successful, the applicant will start in February 2024 and will receive three years funding covering tuition fees, UKRI-standard student stipend and research support. The VC PhD Studentship competition is open to both UK and International students, and applications from candidates from under-represented ethnic minority backgrounds are encouraged. Please see the VC PhD Studentship Website for further funding and eligibility details.


References

For an informal discussion about this opportunity please email Dr Andrew Powell A.Powell@ljmu.ac.uk for more information.

To apply, please email a CV and covering letter detailing your suitability for the project and contact details of two referees to Dr Andrew Powell A.Powell@ljmu.ac.uk by 30th June, 2024 to allow time for selection and interview.

Applicants must be available for interview in early July to allow time for final selection and submission of a final candidate application to the VC PhD Studentship competition by 29th July, 2024.

Register your interest for this project