Epigenetic targeting of fibroblasts as a novel therapeutic avenue for fibro-stenotic Crohn’s disease

project overview

An increasing number of people suffer from Crohn's disease (CD), not only in industrialised countries, but also in the Middle East, India, East Asia and Latin America. CD causes inflammation that spans all layers of the gastro-intestinal wall. In more than two-thirds of patients, the distal part of the small intestine (ileum) is affected. Up to 80% of these patients require surgery in their lifetime, because fibrosis – the excessive deposition of connective tissue – narrows the intestinal lumen. Rates of postoperative recurrence of fibrosis in CD are high (>80%), significantly reducing patients' quality of life and making the clinical management of CD challenging and costly. Commonly used medications to control inflammation in CD do not stop or reverse fibrosis, often rendering surgery the only option for intestinal obstruction. We therefore have to research the underlying causes of fibrosis progression, in order to provide better and alternative medical treatment options for patients.

Within this program, we will achieve this by:

• Focusing on the role of connective tissue fibroblasts, the dominant contributor to fibrosis in the tissue, and their interaction with immune and muscle cells;
• Using an animal model that mirrors fibroblast-driven progression of small intestinal fibrosis over time. This model also enables studying the effect on fibrosis progression when disrupting specific functions of fibroblasts;
• Studying the characteristics of pro-fibrotic fibroblasts, and specifically unexplored epigenetic changes that render it pro-fibrotic. In contrast to genetics, the 'code' (DNA) of the genome, epigenetics studies an additional layer of DNA modification ('histone code') which alters the accessibility of the genome for reading and writing;
• Assessing potential epigenetic modifiers to reverse pro-fibrotic fibroblasts back to normal fibroblasts.

Potential applications and benefits:

The overarching objective of this research is to generate fundamental insights into fibroblast-driven mechanisms of intestinal fibrosis, which can be leveraged for the rational design of anti-fibrotic drugs that are desperately needed. This is the translational interface between science and medicine.

As such, other researchers and clinicians will benefit from the generated insights into fibrosis pathogenesis, advancing our knowledge of this pathology and enabling the development of better advanced therapies. Within the proposed study, we will test the potential of targeting several fibroblast-specific pathways. In particular the epigenetic reversal of pro-fibrotic fibroblasts harbours great potential as a therapy once fibrosis is established. At the same time, the concept of an epigenetically-rewired pathologic fibroblast state is novel and will represent a major conceptual advance to the field. Furthermore, the study of fibrogenesis is pluripotential, since it applies to any organ in the body.
This study will lay the foundation for subsequent rational drug design in collaboration with pharmaceutical industry partners and bench-to-bedside translation initiatives. By doing this, we ensure that we are pursuing the most direct path to provide benefit for the patient in the clinic for this unmet need.

keywords

fibrosis, Crohn’s, epigenetic, fibroblast, therapeutic

training opportunities

Within this DPhil, you will have the opportunity to apply molecular and cellular in situ patient cohort phenotyping, pre-clinicial in vivo disease models, and in vitro screening and mechanistic assays, to study the role of epigenetics and fibroblasts in Crohn’s disease. This will include cutting-edge techniques such as: spatial transcriptomics (Nanostring GeoMx or 10X Visium) and proteomics (laser dissection mass spec proteomics); RNAseq, ATACseq and ChIPseq; in vivo diseas models (mouse) based on Cre-loxP genetic modification; CRIPSR-Cas9 cellular manipulation; high-throughput therapeutic compound screens.

You will be working in a highly interdisciplinary team consisting of basic researchers, gastroenterologists, GI pathologists and computational biologists across Oxford and Cambridge univiersities, as well as the Cleveland Clinic in the U.S. There will be further opportunities to carry out specific sub-projects through established collaborations with pharmaceutical industry (Bristol Myers Squibb, Pfizer, Janssen, UCB, among others). You will receive clise supervision by both a basic scientist and a clinician – an ideal setting to carry out a DPhil that focusses on bench-to-bedside translation.

key publcations

1. Friedrich M.*, Pohin M.*, Jackson M.A.*, Korsunsky I., Bullers S., Rue-Albrecht K., Christoforidou Z., Sathananthan D., Ravindran R., Peres R.S., Sharpe H., Wei K., Watts G.F.M., Mann E.H., Geremia A., Thomas T., Attar M., Oxford IBD Cohort Cohort Investigators, Roche Fibroblast Network Consortium, McCuaig S., Thomas L., Collantes E., Uhlig H.H., Sansom S., Easton A., Raychaudhuri S., Travis S.P., Powrie F.M. IL-1-driven stromal-neutrophil interaction in deep ulcers defines a pathotype of therapy non-responsive inflammatory bowel disease. Nature Medicine 2021; 27:1970. DOI: https://doi.org/10.1038/s41591-021-01520-5
2. Friedrich M.*, Pohin M.*, Powrie F. Cytokine Networks in the Pathophysiology of Inflammatory Bowel Disease. Immunity 2019; 50:992. DOI: 10.1016/j.immuni.2019.03.017
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 and predicts response to tumor necrosis factor–neutralizing therapy in patients with inflammatory bowel disease. Nature Medicine 2017; 23:579. DOI: 10.1038/nm.4307
4. Korsunsky I.*, Wei K.*, Pohin M.*, Kim E.Y.*, Barone F.*, Kang J.B., Friedrich M., Turner J., Nayar S., Fisher B.A., Raza K., Marshall J.L., Croft A.P., Sholl L.M., Vivero M., Rosas I.O., Bowman S.J., Coles M., Frei A.P., Lassen K., Filer A., Powrie F., Buckley C.D., Brenner M.B., Raychaudhuri S. Cross-tissue, single-cell stromal atlas identifies shared pathological fibroblast phenotypes in four chronic inflammatory diseases. Med 2022; DOI: 10.1016/j.medj.2022.05.002
5. Landerholm K., Reali C, Mortensen N.J., Travis S.P.L., Guy R.J., George B.D. Short- and long-term outcomes of strictureplasty for obstructive Crohn’s disease. Colorectal Disease 2020. DOI: 10.1111/codi.15013

contact information for all supervisors

Email: matthias.friedrich@ndm.ox.ac.uk

simon.travis@kennedy.ox.ac.uk