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Research Fellow In Psoriatic Arthritis

Employer
University of Leeds
Location
Leeds, United Kingdom
Salary
£33,797 to £40,322 p.a.
Closing date
Apr 25, 2021
Are you an ambitious researcher looking for your next challenge?

Do you have a background in immunology/inflammation?

Do you want to further your career in one of the UK's leading research intensive Universities?

The spondyloarthropathies (SpA) include psoriatic arthritis (PsA) which is associated with psoriasis, the related arthropathy ankylosing spondylitis (AS) and arthropathy associated with Crohn's Disease, ulcerative colitis, reactive arthritis and acute anterior uveitis. Immunologically the SpA conditons are genetically and and therapeutically linked to TNF or IL-23/17 axis cytokine axes. The primary target tissue in the skeleton for inflammation in SpA is the enthesis which is the insertion point of ligaments or tendons.

There is a need for new therapy for SpA including PsA and AS. The multimodality mechanism of action of small molecule JAK inhibitors may offer a new strategy within SpA disease subgroups including PsA and AS and the entire SpA spectrum, where patients have more than one manifestation. Furthermore, the SpA group of diseases are associated with new bone formation that occurs in the post-inflammatory phase of disease and is thought to be mediated by unbalanced behaviors of bone resorbing osteoclasts and bone-progenitors, mesenchymal stem cells (MSCs). The effect of JAK1 inhibition on MSC-driven osteogenesis at the enthesis is therefore of considerable relevance. A great unmet need exists to decipher the role of the JAK-STAT pathway in enthesis biology and pathobiology. Upadacitinib, a specific JAK1 inhibitor showed good efficacy in 5 phase III trials and a very acceptable safety profile. Our understanding of JAK pathways at the enthesis is rudimentary and there is a need for a mechanistic understanding of how upadacitinib may modulate entheseal inflammation.

The McGonagle group is at the forefront of enthesis research and were the first group to define innate immunity in the normal human enthesis, namely group 3 ILC enthesis resident cells the presence of Th17 cells, Tc17 in the normal human enthesis. We have also reported on the biology of enthesis resident mesenchymal stem cells and how cytokines including IL-17A impact on in vitro osteogenesis.

This study is designed to test the overarching hypothesis that the benefits of JAK1 inhibition at the enthesis is consequent to the multifaceted inhibition of both innate and cell mediated adaptive immunity on the IL-23/17 and TNF cytokine axis and also a direct effect on enthesis stromal cells including MSCs. The research is a proof of concept studies on isolated and sorted cell populations following stimulation with various agonists including lipopolysaccharide, mannan and CD3/CD28 stimulation as recently reported in 2019 in the context of upadacitinib. The candidate will also evaluate the impact of mechanical stress on entheseal stromal cells and how this contributes to their activation. We will look for pathways including ERK that interact with JAK pathways and evaluate the impact of upadacitinib therapy on modulation of the induced entheseal mechano-inflammatory environment. The strategy will also look at enthesis resident MSC-driven new bone formation in vitro and evaluate the impact of upadacitinib therapy on this. This project is funded by Abbvie Inc.

To explore the post further or for any enquiries you may have, please contact:

Professor Dennis McGonagle

Tel: +44 (0)113 343 4747, Email: D.G.McGonagle.leeds.ac.uk

Please note: If you are not a British or Irish citizen, from 1 January 2021 you will require permission to work in the UK. This will normally be in the form of a visa but, if you are an EEA/Swiss citizen and resident in the UK before 31 December 2020, this may be your passport or status under the EU Settlement Scheme.

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