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The role of fibroblast subsets in inflammatory arthritis

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  • Full or part time
    Dr A P Croft
  • Application Deadline
    No more applications being accepted
  • Funded PhD Project (UK Students Only)
    Funded PhD Project (UK Students Only)

Project Description

Research interests/description of main research theme:

Background

Rheumatoid arthritis (RA) is a chronic immune mediated inflammatory disease that is characterized by persistent inflammation leading to progressive joint damage(1). Whilst the introduction of biological disease modifying anti-rheumatic drugs targeting either leucocytes or their derived products has led to a step change in the management of RA, 30-40% of patients do not respond to such therapies, regardless of the mechanism of action of the drug used. These observations suggest the existence of additional pathways of disease persistence that remain to be identified and targeted therapeutically(2).

The synovial membrane is the primary site of pathology in RA and consists of a mesenchymal tissue composed mainly of fibroblasts that form the lining of the joint cavity. These synovial fibroblasts are key effector cells in joint pathology and act to amplify tissue inflammation and damage through the production of chemokines and cytokines which drive the recruitment, retention and differentiation of infiltrating inflammatory cells. We hypothesize, that as a result of chronic inflammation, fibroblasts become ‘transformed aggressors’ and contribute to disease persistence by driving inflammation locally within the joint.

We have recently described distinct subsets of fibroblasts within the inflamed synovium with non-overlapping effector cell functions(3). Importantly, we identified fibroblast subsets located within the sub-lining domain of the synovium with immune-modulatory functions. These subsets are selectively expanded in the synovia of patients with RA and act to amplify joint inflammation(3-5). Whilst their global effect is pro-inflammatory, the individual contribution of each of these immune effector fibroblast subsets to the inflammatory process and their specific interactions with leucocytes during the development and maintenance of chronic joint inflammation is unknown.

The aim of this project is to determine the immune effector function of individual fibroblast subsets in resting and inflamed conditions and elucidate their role in determining the outcome of joint inflammation (persistence versus resolution).
To achieve this aim we will perform a detailed analysis of the phenotypic changes in these fibroblast subsets during the course of joint inflammation using integrated tissue analysis platforms, including: single cell transcriptomics and multiparameter spatial protein and RNA analyses (geoMX Digital Multiplex Spatial Transcriptomic Profiling) to define the fibroblast pathotype (phenotype, number and location of fibroblast subsets in the synovial membrane) at the cellular and tissue level.

To determine the functional significance of these changes on the severity and persistence of joint inflammation we will adoptively transfer specific fibroblast subsets into joints of mice at different stages of inflammation using experimental models of chronic arthritis. Finally, we aim to characterise the gene regulatory pathways underlying specific patterns of gene expression in these individual fibroblast subsets using the ATAC (Assay for Transposase-Accessible Chromatin) to profile open chromatin accessibility signatures these cells under resting and inflammatory conditions.

Our group has extensive expertise in stromal cell biology, single cell genomics and digital imaging platforms. The group is located in Rheumatology Research Group within the Centre for Translational Inflammation Research, part of the Rheumatoid Arthritis Pathogenesis Centre of Excellence a partnership between the Universities of Oxford, Glasgow, Birmingham and Newcastle (RACE; http://www.race-gbn.org/). The student will have access to state-of-the-art technologies across the RACE centres and will work in close collaboration with Prof Chris Buckley’s team based at the Kennedy Institute at the University of Oxford. This combined expertise will provide critical mass to ensure the success of this project.


Person Specification

We are looking for an outstanding student with a strong background in immunology, ideally with a background in stromal cell biology and mouse models of disease. They should have a commitment to research in inflammation and hold or realistically expect to obtain at least an Upper Second Class Honours Degree in a relevant subject.

How to apply

Informal enquiries should be directed to Dr Adam P Croft

Applications should be directed to Adam P. Croft (email [Email Address Removed]). 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.

Funding Notes

This post is funded by the Kennedy Trust for Rheumatology Research

References

1. Conigliaro, P. et al. Challenges in the treatment of Rheumatoid Arthritis. Autoimmun Rev 18, 706–713 (2019).
2. Filer, A. The fibroblast as a therapeutic target in rheumatoid arthritis. Curr Opin Pharmacol 13, 413–419 (2013).
3. Croft, A. P. et al. Distinct fibroblast subsets drive inflammation and damage in arthritis. Nature 570, 246–251 (2019).
4. Mizoguchi, F. et al. Functionally distinct disease-associated fibroblast subsets in rheumatoid arthritis. Nat Commun 9, 789 (2018).
5. Croft, A. P. et al. Rheumatoid synovial fibroblasts differentiate into distinct subsets in the presence of cytokines and cartilage. Arthritis Res. Ther. 18, 270 (2016).



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