How do secreted phospho-proteins dictate fibroblast-neutrophil crosstalk in treatment resistant inflammatory bowel disease?

People who develop ulcerative inflammatory bowel disease (IBD) exhibit severe symptoms and do not respond to any current therapies.  Pathology is driven by a specific population of inflammatory fibroblasts, not found in healthy tissue but located specifically within the ulcer niche.  We identified a golgi resident protein kinase whose overexpression in these fibroblasts in people with IBD is linked to disease severity and lack of treatment response.  In human cellular and in vivo models of acute intestinal inflammation, kinase activity was required for development of the pathogenic fibroblast phenotype. Inflammation was sustained following kinase activation and tissue repair initiated, mediated by altered autocrine signalling within fibroblasts and paracrine effects on infiltrating neutrophils, before kinase expression was turned off.  However, fibroblasts from a subset of people with IBD lack the ability to switch kinase expression off, highlighting a potential cause of exacerbated inflammation and lack of tissue repair.  This project seeks to identify: i) the mechanisms by which off loops fail in IBD fibroblasts, ii) target kinase substrates in the inflamed intestine, and iii) how modification of key immune effectors including cytokines alters their inflammatory function. 

We will use genetic deletion of kinase expression in cellular and in vivo models of damage driven intestinal disease, applying spatial single cell transcriptomic analysis to uncover changes in cell network behaviour within ulcer niches and proteomic techniques to identify tissue relevant kinase substrates. In parallel, ex vivo assays will validate new substrate modification and the implications of phosphorylation of already known cytokine targets will be dissected using structure function analysis to characterize altered receptor binding and reporter assays to assess changes in downstream signalling pathways.  These data will inform novel candidate drug targets and/or points of intervention for people for whom there is a critical unmet need for effective new therapies.   

KEYWORDS

Inflammatory disease, extracellular matrix, cytokines, neutrophils, stromal biology

TRAINING OPPORTUNITIES

This project benefits from a supervisory team comprising experts in matrix biology, proteomics and immunology, and world leading gastrointestinal clinicians. The Kennedy Institute is a renowned research centre, located in the heart of the University of Oxford’s Old Road campus, housing fundamental and clinician scientists working on diverse aspects of immunology and inflammation. This project will combine state of the art spatial transcriptomics, cellular immunology, proteomics and tissue biology; training will be provided in a range of in vivo disease models and patient cohort tissue analysis, alongside immunological, bioinformatic, structural and molecular biology techniques. Students will join a vibrant postgraduate community at the Kennedy, that provides extensive peer and pastoral support for the duration of the project. The PhD programme includes a core curriculum of lectures and bespoke training covering aspects of science, data analysis, patient engagement, science outreach, entrepreneurship and beyond.  Students will join group meetings from each of the labs of the supervisory team and have the opportunity to network with world leading investigators from all walks of science at Institute seminars, workshops and careers events.  

KEY PUBLICATIONS

Buckley CD, Ospelt C, Gay S, Midwood KS. Location, location, location: how the tissue microenvironment affects inflammation in RA. Nat Rev Rheumatol. 2021 Apr;17(4):195-212. doi: 10.1038/s41584-020-00570-2.

Friedrich M, Pohin M, Jackson MA, et al. IL-1-driven stromal-neutrophil interactions define a subset of patients with inflammatory bowel disease that does not respond to therapies. Nat Med. 2021 Nov;27(11):1970-1981. doi: 10.1038/s41591-021-01520-5. 

Aschenbrenner D, Ye Z, Zhou Y, et al. Pathogenic Interleukin-10 Receptor Alpha Variants in Humans - Balancing Natural Selection and Clinical Implications. J Clin Immunol. 2023 Feb;43(2):495-511. doi: 10.1007/s10875-022-01366-7.

Chen YH, van Zon S, Adams A, Schmidt-Arras D, Laurence ADJ, Uhlig HH. The Human GP130 Cytokine Receptor and Its Expression-an Atlas and Functional Taxonomy of Genetic Variants. J Clin Immunol. 2023 Dec 22;44(1):30. doi: 10.1007/s10875-023-01603-7.

Gu Y, Bartolomé-Casado R, Xu C, Bertocchi A, Janney A, Heuberger C, Pearson CF, Teichmann SA, Thornton EE, Powrie F. Immune microniches shape intestinal Treg function. Nature. 2024 Apr;628(8009):854-862. doi: 10.1038/s41586-024-07251-0.

THEMES

Inflammation, Immunology, Tissue Biology, Translational Science

CONTACT INFORMATION OF ALL SUPERVISORS

kim.midwood@kennedy.ox.ac.uk

anna.hoyle@kennedy.ox.ac.uk

fiona.powrie@kennedy.ox.ac.uk

holm.uhlig@ndm.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.