MRC CASE PhD studentship

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Supervisors: Dr Helen McGettrickDr Andrew Filer,  and Dr Miriam Bibel (Novartis, Basel)

Applications are invited for a prestigious and distinctive four year full time MRC CASE PhD Studentship starting in Autumn 2017. The PhD studentship is a collaborative project between the Institute of Inflammation and Ageing (IIA) at the University of Birmingham, UK and the ATI Translational Research Unit at Novartis, Basel, Switzerland, where the student will spend ~6 months training during the studentship.

Project Description

Regulation of leukocyte recruitment by fibroblast-endothelial interactions: Understanding the stromal switch from resolution to persistent inflammation
Rheumatoid arthritis (RA) is a major cause of disability affecting ~1% of the UK population. Biological treatments that target leukocytes or their cytokine produces have improved outcomes, but they do not reverse tissue damage nor do they cure disease. During the earliest stages of disease, conventional treatments are significantly more effective, but the reasons for this are not clear. Current evidence suggests that we may be able to improve control of disease further if we can better target the unique pathological processes occurring early on.

RA synovial fibroblasts are major contributors to joint damage and disease persistence, but have yet to be targeted therapeutically. Synovial fibroblasts actively regulate leukocyte recruitment through interactions with endothelial cells (EC) that line blood vessels (McGettrick et al., 2009). We have characterised a unique phenotype of synovial fibroblasts seen in early arthritis that distinguishes acute resolving arthritis (Res) from the early stages of RA (eRA). Res fibroblasts induce an immunosuppressive response in EC that limits the magnitude of leukocytes recruited to the joint (McGettrick et al., 2014; McGettrick et al., 2015). However this capacity is lost in eRA synovial fibroblasts (McGettrick et al., 2014; McGettrick et al., 2015). This change represents a phenotypic swtich from protective to pathological synoival fibroblast-endothelial cell interactions.

Thie aim of this PhD studentship is to interrogate the molecular mechanism underpinning the cellular cross-talk between the synovial fibroblasts and EC. To achieve this the student will have access to a unique resource of cellular material from the Birmingham Early Arthritis Cohort (BEACON), which will be analysed using high throughput analysis platforms (e.g. microarrays, RNAseq, proteomics, phosphokinase arrays, metabolomics) at Novartis, by flow based adhesion assays, live whole tissue imaging platforms, and chimeric mouse models of arthritis incorporating human synovial tissue and cells available at Birmingham.

The work will generate new insights into disease pathogenesis and provide novel targets for drug development. Ultimately, we aim to test whether mimicking the actions of Res SF or inhibiting those of ‘pathogenic’ eRA or RA SF can reset the balance of leukocyte recruitment, thus halting disease progression.

Person Specification

Applicants should have a strong background in cell biology and/or immunology. They should have a commitment to research in inflammation biology and rheumatology research and hold or realistically expect to obtain at least an Upper Second Class Honours Degree, or equivalent, in a relevant biological subject.

Funding Notes

Funded PhD (4 years): open to UK and EU Graduates. EU applicants are advised to check the level of funding they are eligible for using MRC guidelines: View Website

Applicants from EU countries other than the UK are generally eligible for a fees-only award. To be eligible for a fees-only award, an applicant must be ordinarily resident in a member state of the EU.

The student stipend will be funded at MRC CASE Studentship rates.

References

McGettrick, H. M., E. Smith, A. Filer, Kissane S, M. Salmon, C. D. Buckley, G. E. Rainger, and G. B. Nash. 2009. Fibroblasts from different sites may promote or inhibit recruitment of flowing lymphocytes by endothelial cells. Eur. J. Immunol. 39: 98-107.

McGettrick, H. M., A. Filer, K. Raza, G. B. Nash, and C. D. Buckley. 2014. Fibroblasts lose their immunosuppressive ability early in the development of rheumatoid arthritis: effects on lymphocyte recruitment. Ann. Rheum. Dis. 73: A19.

McGettrick, H. M., N. Naame, S. He, K. Raza, G. B. Nash, C. D. Buckley, and A. Filer. 2015. Functional pathways in endothelial cells are differentially regulated by fibroblasts from patients with RA and resolving disease. Ann. Rheum. Dis. 74: A57.

Closing date
Friday 31 March 2017

How to apply
Informal enquiries should be directed to Dr Helen McGettrick
Applications should be directed to Dr Helen McGettrick

To apply, please send:
• A detailed CV, including your nationality and country of birth;
• Names and addresses of two referees;
• A covering letter highlighting your research experience/capabilities;
• Copies of your degree certificates with transcripts;
• Evidence of your proficiency in the English language, if applicable.

Start date:
October 2017