Neuroimmune regulation of rheumatoid arthritis

Background

Rheumatoid arthritis (RA) is an immune mediated inflammatory disease which constitutes a major global healthcare challenge as it causes significant disability and pain. The use of advanced high- throughput technologies have significantly improved our understanding of the stromal and immune cell compartments in the synovium in RA (Croft AP Nature 2019), however the role of innervation, and in particular peripheral nerve-associated glial cells (Schwann cells) remains understudied despite their emerging role in the regulation of inflammation in the gut and lung.

Preliminary data

Glial cells are crucial for the organisation, function and repair of neural tissues in the central nervous system. Our recent work (Progatzky F, Nature, 2021) and that of others has demonstrated crucial roles for enteric glia in epithelial barrier maintenance, host protection, immunity and tissue repair of the gut, both at steady state and in response to inflammatory challenge. These recent discoveries suggest that peripheral glia represent important regulatory nodes of immune responses which maintain and restore the function of tissues. 

Hypothesis

We propose that tissue resident glial cells of the synovium play important roles in the regulation of tissue immunity, both at steady state and during disease progression and persistence. This project aims to understand how synovial glia regulate immune homeostasis and inflammation and to determine underlying pathways that control their interaction with other synovial cells such as fibroblasts in health and disease.

Project plan

This project will employ state-of-the-art single cell RNA sequencing and cutting-edge 3D imaging techniques to define the glial landscape of the synovium both in humans and mice. To uncover the functional roles of glia in the context of synovial inflammation and tissue remodelling, tissue-specific glial in vivo targeting will be developed and employed in conjunction with mouse models of synovial inflammation and analysis of human tissue samples.

Importance

This project is uniquely capable of making fundamental and mechanistic insights into the contributions of glia to the pathogenesis of rheumatoid arthritis and in particular uncover the cellular basis that links inflammation and pain.

KEYWORDS

Neuroimmunology, inflammation, joint, rheumatoid arthritis

TRAINING OPPORTUNITIES

This interdisciplinary project synergises and integrates experimental approaches, tools and expertise in tissue immunology and neuroglial biology to uncover fundamental roles of peripheral glia in rheumatoid arthritis. It is therefore suitable for a candidate that has a keen interest in tissue biology and neuroimmune interactions and is passionate about discovering basic biological concepts. 

This project will provide high level training in cutting-edge imaging approaches (such as whole tissue visualisation using light sheet microscopy and quantitative and high-resolution confocal microscopy-based analysis), mouse in vivo functional genomics and inflammatory models as well as single cell sequencing and data analysis. Depending on project progress, advanced spatial transcriptomic approaches will also be employed. The physiological relevance of mechanistic and functional discoveries to human health and disease will be validated in human tissues samples. 

This project is bold, innovative, interdisciplinary and cutting-edge and is suitable for curious and creative candidates that are motivated by challenges and keen to perform experiments that significantly push the boundaries of current knowledge. Our research environment is supportive, friendly and inclusive. We will work with the candidate to develop their research skills and scientific independence and will ensure they get fully integrated in the diverse research environment of the institute. 

KEY PUBLICATIONS

Croft, A.P., et al., Distinct fibroblast subsets drive inflammation and damage in arthritis. Nature, 2019. PMID: 31142839 

Progatzky, F., et al., Regulation of intestinal immunity and tissue repair by enteric glia. Nature, 2021. PMID: 34671159

Davidson S et al Fibroblasts as immune regulators in infection, inflammation and cancer.

Nature Reviews Immunology, 2021. PMID: 33911232

Progatzky, F. and V. Pachnis, The role of enteric glia in intestinal immunity. Curr Opin Immunol, 2022. PMID: 35533467 

THEMES

Biological sciences, immunology, inflammation, tissue biology

CONTACT INFORMATION OF ALL SUPERVISORS

Email christopher.buckley@kennedy.ox.ac.uk

Email franze.progatzky@kennedy.ox.ac.uk

The Kennedy Institute is a proud supporter of the Academic Futures scholarship programme, designed to address under-representation and help improve equality, diversity and inclusion in our graduate student body.  The Kennedy and the wider University rely on bringing the very best minds from across the world together, whatever their race, gender, religion or background to create new ideas, insights and innovations to change the world for the better. Up to 50 full awards are available across the three programme streams, and you can find further information on each stream on their individual tabs (Academic futures | Graduate access | University of Oxford).

How to Apply

Please contact the relevant supervisor(s), to register your interest in the project, and the departmental Education Team (graduate.studies@ndorms.ox.ac.uk), who will be able to advise you of the essential requirements for the programme and provide further information on how to make an official application. 

Interested applicants should have, or expect to obtain, a first or upper second-class BSc degree or equivalent in a relevant subject and will also need to provide evidence of English language competence (where applicable). The application guide and form is found online and the DPhil or MSc by research will commence in October 2025. 

Applications should be made to the following programme using the specified course code.

D.Phil in Molecular and Cellular Medicine (course code: RD_MP1)

For further information, please visit http://www.ox.ac.uk/admissions/graduate/applying-to-oxford.

Interviews to be held week commencing 13th January 2025.