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  • Project No: #OxKEN-2022/4
  • Intake: OxKEN 2022

PROJECT OVERVIEW

Inflammatory bowel diseases (IBDs) are chronic relapsing disorders manifesting in the inflammation of the gastrointestinal tract (1). The complex multifactorial nature of IBD results in considerable heterogeneity in the cell types and molecular processes that drive inflammation across patients. This heterogeneity also affects response rates to medical therapy in IBD, which is now dominated by the use of biologics (e.g., anti-TNF). Indeed, biologics fail in more than half of the patients treated, suggesting that in many cases these medicines do not target the specific tissue inflammatory processes driving disease in an individual. To date patient stratification is limited to clinical symptoms and phenotype (Crohn’s disease, ulcerative colitis) which insufficiently captures the molecular and cellular nuances of tissue inflammation. 

To better understand the heterogeneity of tissue inflammation and therapy response, we recently integrated bulk and single-cell transcriptomics with molecular pathology to identify and define distinct tissular responses in IBD termed ‘pathotypes’ [4]. Such pathotypes represent a novel way to stratify patients based on distinct intestinal tissue ecologies which involve the remodelling of tissue resident stromal cell populations (fibroblasts) and the activation of innate (neutrophils) and adaptive immune cell compartments (T-cells, plasma cells) [4]. Despite this study, we still have an incomplete understanding of the diverse inflammatory tissue ecologies in patients with IBD, how they develop and how they could be therapeutically targeted. In-depth knowledge of these processes would allow us to select the most efficient biologic therapy for each patient, moving towards personalised medicine. Our findings highlight that fibroblasts and cytokine rewiring are key drivers in establishing the pathotype niches we identified so far [3,4]. 

Utilising existing data on molecular, cellular and histopathologic hallmarks of pathotypes in IBD patients, the DPhil student will establish disease-positioned mouse models to reflect these. Specifically, the role of cytokine- and fibroblast-driven pathology will be interrogated. This will include the longitudinal study of pathotype development, dissecting cell type specific contributions, and testing of potential new therapies. Most promising therapeutic approaches identified through the in vivo models will then be validated in ex vivo organ culture systems derived from IBD patients’ tissues, available through the Translational Gastroenterogy Unit at the John-Radcliffe Hospital. 

Overall, this translational project offers the opportunity to apply cutting-edge technologies such as disease-positioned mouse models, spatial transcriptomics, proteomics, digital pathology and pre-clinical organoid/experimental mouse models to address and overcome pressing unmet clinical needs in IBD.  

KEYWORDS

Inflammation, bowel, therapy, mouse, fibroblast 

TRAINING OPPORTUNITIES

The DPhil student will develop expertise in establishing and characterising mouse models, and testing therapies in pre-clinical in vivo models and patient-derived organ culture systems. In addition, the project will allow the DPhil student to build an excellent network of academic (Universities of Oxford and Cambridge) and industrial (Janssen) partners involved in the project. Specific training opportunities will include but are not limited to:  

  • Expert understanding in intestinal tissular ecologies and disease pathogenesis
  • Spatial transcriptomics (e.g., 10X Visium or GeoMx), proteomics (e.g., CellDive) 
  • Bioinformatic analysis of ‘omic data 
  • In vivo disease-positioned pre-clinical mouse models
  • Ex vivo patient-derived tissue culture models 
  • Presenting and networking with academic and industrial collaborators, including the opportunity of short stays
  • Designing, conducting and publishing experimental studies and reviews 
  • Attending and presenting at national and international conferences

 KEY PUBLICATIONS

  1. Uhlig H and Powrie F. Translating Immunology into Therapeutic Concepts of Inflammatory Bowel Disease. Annual Reviews Immunology 2018;36:755
  2. Friedrich M *, Pohin M *, Powrie F. Cytokine Networks in the Pathophysiology of Inflammatory Bowel Disease.Immunity 25th Anniversary Edition 2019;50(4):992. 
  3. West N *, Hegazy A *,  Owens B,  Bullers S,  Linggi B,  Buonocore S,  Coccia M,  Görtz D, This S,  Stockenhuber K, Pott J, Friedrich M,  Ryzhakov G,  Baribaud F,  Brodmerkel C,  Cieluch C,  Rahman N, Müller-Newen G, Owens R, Kühl A, Maloy K, Plevy S, Keshav S, Travis S, Powrie F. Oncostatin M drives intestinal inflammation in mice and its abundance predicts response to tumor necrosis factor-neutralizing therapy in patients with inflammatory bowel disease. Nature Medicine 2017; 23(5):579.
  4. Friedrich M *,  Pohin M *, Jackson MA *, Korsunsky I,  Bullers S,  Rue-Albrecht K,  Christoforidou Z,  Sathananthan D,  Ravindran R,  Peres RS,  Sharpe H,  Wei K,  Watts GFM, Mann EH,  Geremia A,  Thomas T,  Attar M, Oxford IBD Cohort Investigators, Roche Fibroblast Network Consortium,  McCuaig S,  Thomas L,  Collantes E,  Uhlig HH, Sansom SN,  Easton A,  Raychaudhuri S,  Travis SP, Powrie FM. IL-1-driven stromal-neutrophil interaction in deep ulcers definesa pathotype of therapy non-responsive inflammatory bowel disease. Nature Medicine (in press), bioRxv 2021 (https://doi.org/10.1101/2021.02.05.429804)

 

 

CONTACT INFORMATION OF ALL SUPERVISORS

Fiona Powrie - fiona.powrie@kennedy.ox.ac.ukpowrie.pa@kennedy.ox.ac.uk Phone: +44 (0)1865 612659

Matthias Friedrich - matthias.friedrich@kennedy.ox.ac.uk

Mathilde Pohin - mathilde.pohin@kennedy.ox.ac.uk