This project is one of a number that are in competition for funding from the South West Biosciences Doctoral Training Partnership (SWBio DTP).
The DTP offers an interdisciplinary research training programme delivered by a consortium comprising the Universities of Bath, Bristol and Exeter, Cardiff University and Rothamsted Research, alongside six regional associate partners: Marine Biological Association, Plymouth Marine Laboratory, Swansea University, UCB Pharma, University of the West of England and SETsquared Bristol. The partnership has a strong track record in advancing knowledge through high quality research and teaching, in collaboration with industry and government.
All SWBio DTP projects will follow a structured 4-year PhD programme, combining traditional project-focussed studies with a taught first year which includes directed rotation projects.
The start date of the programme will be Monday 3 October 2022. Students are encouraged to attend Welcome Week at Bath (week commencing Monday 26 September 2022).
Lead supervisor: Prof Jean van den Elsen, University of Bath, Department of Biology & Biochemistry (email: [Email Address Removed])
Co-supervisors: Prof Paul Morgan (Cardiff University), Dr Maisem Laabei (University of Bath) and Dr Wioleta Zelek (Cardiff University)
Dr Alex MacPherson (UCB)
The complement system is a central component of innate immunity, a network of plasma proteins, which provides defence against infection and efficient removal of dead cells. Because of its complexity and destructive character, complement is tightly regulated by an array of fluid-phase and membrane regulators. Activation of complement is triggered in several ways, leading to the formation of enzymes, termed convertases, that cleave the central component C3 to C3a and C3b. C3b forms the nidus for formation of the C5 convertase, which in turn cleaves C5, the principal effector of the terminal portion of the complement cascade and subject of this proposal, into its fragments C5a and C5b. Once cleaved, the C5a fragment acts as a potent chemoattractant recruiting immune cells to sites of complement activation, whilst C5b contributes to the membrane attack complex (MAC) a molecular assembly involved in the efficient killing of microbial pathogens.
This project aims to gain a detailed molecular understanding of the aspects that control the cleavage of C5 by the C5 convertase enzyme complexes. For this purpose, we have developed a unique molecular toolkit comprised of a recombinant Llama anti-C5 VHH library (nanobodies) and a novel class of low molecular weight antibody fragments derived from cow antibodies, known as knob domain peptides, that have been developed by UCB-Pharma in collaboration with the University of Bath. This tool kit, in combination with our libraries of recombinant anti-C5 Fabs and known parasite-derived inhibitors of C5, will be available to the PhD student 1) to profile for C5 binders (Bath/UCB). Subsequently, 2) functional studies will be employed to assess inhibitory and non-inhibitory binders (UCB/Cardiff) and assign a putative mode of action. Finally, the most promising binders will be subjected to 3) structural analyses using X-ray crystallography (Bath) and computational methods.
The student will gain experience in a wide range of techniques across different disciplines and Universities, including protein biochemistry and X-ray crystallography (Bath/UCB), complement activity analyses (Cardiff) and computational techniques, particularly molecular dynamics simulation (UCB). We intend to use our molecular probes to gain a detailed mechanistic insight into the activation of C5, informing the development of targeted therapies for the treatment of inflammatory diseases resulting from complement dysregulation, including the acute respiratory distress syndrome linked to COVID-19. Results will be communicated in publications, and at conferences. Outcomes from the project will have immediate impact on the many academic and commercial groups working on complement therapies.
Applicants should have obtained, or be about to obtain, a First or Upper Second Class UK Honours degree, or the equivalent qualifications gained outside the UK, in a relevant subject. Applicants with a Lower Second Class degree will be considered if they also have Master’s degree or have significant relevant non-academic experience.
In addition, due to the strong mathematical component of the taught course in the first year and the quantitative emphasis in our projects, a minimum of a grade B in A-level Maths or an equivalent qualification/experience* is required.
* Physics A-level (grade B and above) or units in your degree with a significant mathematical component, e.g. maths, statistics, bioinformatics.
Applicants must ensure they highlight their Maths background within their application and upload any supporting evidence.
If English is not your first language, you will need to have achieved Academic IELTS 6.5 overall (with no less than 6.5 in any of the four skills). Find details of other acceptable tests and further information on our website.
Enquiries and Applications:
Informal enquiries are welcomed and should be directed to the lead supervisor.
Formal applications should be submitted on the University of Bath’s online application form for a PhD in Biosciences.
When completing the form, please identify your application as being for the SWBio DTP studentship competition in Section 3 Finance (question 2) and quote the project title and lead supervisor’s name in the ‘Your research interests’ section. You may apply for more than one project within the same application, but you should upload a separate (clearly labelled) personal statement for each one, outlining your interest and suitability for that particular project.
See our website for more information about applying for a PhD at Bath.
To be eligible for funding, you must qualify as a Home student. The eligibility criteria for Home fee status are detailed and too complex to be summarised here in full; however, as a general guide, the following applicants will normally qualify subject to meeting residency requirements: UK nationals and Irish nationals (living in the UK or EEA/Switzerland), those with Indefinite Leave to Remain and EU nationals with pre-settled or settled status in the UK under the EU Settlement Scheme). This is not intended to be an exhaustive list. Additional information may be found on our fee status guidance webpage, on the GOV.UK website and on the UKCISA website.