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MRC DiMeN Doctoral Training Partnership: Breaking up the fight: Defining the spatial requirements for therapeutic modulation of signalling through FcγRIIa


Project Description

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 about half of rheumatoid arthritis (RA) patients, for example, 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 an important transducer of the inflammatory response that 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 (Robinson et al., 2018).

We wish to use the pipeline to identify specific protein based recognition molecules for FcγRIIa, which is expressed widely among myeloid cells and has been described as transducing pro- and anti-inflammatory signals in response to IgG Fc in complexed and monomeric forms (Ben Mkaddem et al., 2014). Therapeutic modulation of FcγRIIa signalling outcome has been suggested as a promising prospect for the treatment of autoimmunity, yet there are no licensed therapies that directly block FcγRIIa or its proximal signalling pathways. We postulate that differential signalling through FcγRIIa may be therapeutically inducible with the application of molecular spacers designed to mimic ligands that induce inhibitory signalling.

We aim to define the spatial requirements of activatory and inhibitory signalling through FcγRIIa, and to control receptor spacing to promote the desired therapeutic effect. A multidisciplinary approach is required to achieve our aims. There are many factors to consider in the design of molecular spacers for FcγRIIa, including specificity, linker rigidity, valency, molecular weight, immunogenicity and reporter assays. Co-supervisors from three different faculties at Leeds represent an established collaboration with the capacity and skills to deliver the project.

The candidate will 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 immune cells in real time using a novel microfluidic cell capture system. Distance threshold for the induction of inhibitory and activatory signalling will be determined, leading to a definition of the spatial requirements for therapeutic modulation of FcγRIIa.

Training:
This project will provide training in a diverse range of techniques including X-ray crystallography, protein biochemistry, molecular biology, cell biology and biophysics. The studentship will be based on the main University of Leeds campus in the Discovery and Translational Science Department of LICAMM.

Informal enquiries to Dr Jim Robinson ()

Links to supervisor profiles pages:
https://medhealth.leeds.ac.uk/profile/700/656/james_ian_robinson
http://www.astbury.leeds.ac.uk/people/staff/staffpage.php?StaffID=AG
https://physicalsciences.leeds.ac.uk/staff/198/dr-michael-webb

Benefits of being in the DiMeN DTP:
This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.
We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.
Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards
Further information on the programme can be found on our website:
http://www.dimen.org.uk/

Funding Notes

Studentships are fully funded by the Medical Research Council (MRC) for 3.5yrs
Includes:
Stipend at national UKRI standard rate
Tuition fees
Research training and support grant (RTSG)
Travel allowance
Studentships commence: 1st October 2019.

To qualify, you must be a UK or EU citizen who has been resident in the UK/EU for 3 years prior to commencement. Applicants must have obtained, or be about to obtain, at least a 2.1 honours degree (or equivalent) in a relevant subject. All applications are scored blindly based on merit. Please read additional guidance here: View Website
Good luck!

References

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.

Ben Mkaddem S, Hayem G, Jonsson F, Rossato E, Boedec E, Bousetta T, El Benna J, Launay P, Goujon JM, Benhamou M, Bruhns P, Monteiro RC. 2014. Shifting FcγRIIA-ITAM from activation to inhibitory configuration ameliorates arthritis. Journal of Clinical Investigation 124:3954-3959.

Bondza S, Foy E, Brooks J, Anderson K, Robinson J, Richalet P, Buijs J. 2017. Real-time characterization of antibody binding to receptors on living immune cells. Frontiers in Immunology 8:455

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