Autoantibody-mediated inflammatory diseases are characterised by a proinflammatory feedback loop which leads to the destruction of tissues, prolonged pain, fatigue and subsequent reduction in life quality. Individual biological therapies are efficacious in ~50% of rheumatoid arthritis (RA) patients and are expensive (>£10,000/per patient/per annum). Approximately 400,000 people in the UK have RA. New effective treatments are urgently required.
In the context of autoimmunity, autoantibody engagement with activating Fc gamma receptors (FcγRs) is a key factor driving the inflammatory response and is an important feature of disease pathogenesis and maintenance, making FcγRs attractive targets for therapeutic blockade. Yet structural homology between human FcγR types presents significant challenges for their specific blockade. We have built a multidisciplinary FcγR inhibitor discovery pipeline which we have used to describe novel ways to specifically target FcγRIIIa/CD16a (Robinson et al., 2018).
We aim to define the spatial requirements of activatory and inhibitory signalling through FcγRIIa/CD32a, using patient-derived immune complexes, to validate the concept of therapeutic modulation. A multidisciplinary approach is required to achieve our aims. Co-supervisors from four different faculties at Leeds, including a clinician, represent an established collaboration with the capacity and skills to deliver the project.
You will be based in the School of Medicine and work with structural and chemical biology co-supervisors to determine the FcγRIIa binding positions of our protein based recognition molecules using X-ray crystallography, and to chemically link them together in a range of spacer formats. These spacers will be tested using our novel reporter assays that measure activatory and inhibitory signalling in live cells in real time using a novel microfluidic cell capture system in the presence and absence of a variety of immune complexes.
The two main objectives of this project are:
1. Develop novel strategies to modulate FcγRIIa signalling, developing prototypic therapeutics
2. Determine if their efficacy differs with different types of immune complexes
This project will provide training in a diverse range of techniques including X-ray crystallography, protein biochemistry, molecular biology, cell biology and biophysics. The scholarship will be based on the main University of Leeds campus in the Discovery and Translational Science Department of LICAMM in the School of Medicine.
You will join a multidisciplinary team of scientists, including clinicians, structural and chemical biologists and biophysicists across four Faculties with a growing track record of successful innovative research delivery. Using existing artificial binding proteins you will work closely with the primary supervisor to develop cutting-edge cellular and biophysical methods to induce and measure activatory and inhibitory signalling through FcγRIIa. Co-supervision with a chemical biologist will provide you with the skills to synthesise binding protein multimers. These will be used to demonstrate therapeutic potential in cellular systems using patient-derived immune complexes through co-supervision with a consultant rheumatologist, and detailed molecular structures will be determined through co-supervision from leading structural biologist in the field. Biophysical analyses will take place in the Molecular and Nanoscale Physics Research Group under the co-supervision of Professor Steve Evans.
You should hold a first degree equivalent to at least a UK upper second class honours degree in relevant subject..
The LICAMM International PhD Academy minimum requirements for candidates whose first language is not English are:
• British Council IELTS – score of 7.0 overall, with no element less than 6.5
• TOEFL iBT – overall score of 100 with the listening and reading element no less than 22, writing element no less than 23 and the speaking element no less than 24.
How to apply:
To apply for this project applicants should complete a Faculty Scholarship Application form using the link below https://medicinehealth.leeds.ac.uk/downloads/download/78/fmh_scholarship_application_form_2018_2019
and send this alongside a full academic CV, degree certificates and transcripts (or marks so far if still studying) to the Faculty Graduate School at [email protected]
We also require 2 academic references to support your application. Please ask your referees to send these references on your behalf, directly to [email protected]
by no later than Monday 13 January 2020.
If you have already applied for other scholarships using the Faculty Scholarship Application form you do not need to complete this form again. Instead you should email [email protected]
to inform us you would like to be considered for this scholarship project.
Any queries regarding the application process should be directed to [email protected]
Informal enquiries to Dr Jim Robinson ([email protected]
Robinson JI, Baxter EW, Owen RL, Thomsen M, Tomlinson DC, Waterhouse MP, Win SJ, Nettleship JE, Tiede C, Foster RJ, Owens RJ, Fishwick CWG, Harris SA, Goldman A, MacPherson MJ, Morgan AW. 2018. Affimer proteins inhibit immune complex binding to FcγRIIIa with high specificity through competitive and allosteric modes of action. Proceedings of the National Academy of Sciences of the United States of America 115:E72-E81.