Dissecting the fibrotic landscape in Dupuytren’s disease
- Project No: #OxKEN-2021/9
- Intake: OxKEN
Fibrotic diseases account for up to 45% of deaths in industrialised countries, yet there are few effective therapies. Important limiting factors are a lack of well characterised patient samples across the stages of disease, from the early to treatment refractory stages, as multiply passaged cells from limited samples usually from patients with late stage disease are not representative of the complex disease milieu, and animal models fail to recapitulate all the important aspects of the disease processes. To develop effective therapeutics in fibrosis we need to have a detailed understanding of the entire cellular ecosystem across tissues and the subtypes and functional properties of fibrotic stromal cells in particular.
Patients with localized fibrotic diseases are a rich source of readily accessible early stage tissue. Dupuytren’s disease is a common and progressive fibroproliferative disorder of the palmar and digital fascia of the hand and, in Western populations affects 12% of those aged 55 years, increasing to 29% of people 75 years and older. The initial clinical presentation is the appearance of a firm nodule in the palm that expands into fibrous collagenous cords that case irreversible flexion contractures of the fingers. Dupuytren’s nodules, which represent the early stage of the disease, are a highly cellular fibrotic ecosystem and are an important model to examine developing fibrosis in humans. Leveraging our ability to access a plentiful supply of clinical samples from patients with Dupuytren’s disease we have demonstrated the key role of immune-stromal cell crosstalk in driving the disease (Izadi et al., 2019). Furthermore, our identification of key signalling pathways (Verjee et al., 2013) has translated through an ongoing phase 2b clinical trial of anti-TNF therapy in Dupuytren’s disease (Nanchahal et al., 2018). We have also constructed a molecular taxonomy of stromal cells in human fibrosis using single cell RNA sequencing (Layton et al., 2020). Our single cell atlas of the fibrotic milieu elucidated functionally distinct stromal cell types and states, including fibroblast and myofibroblast subsets that mediate discrete pro-fibrotic functions. In addition, we developed functional and live cell imaging assays to functionally validate cellular biomarkers defined in the next generation sequencing.
This project will focus on the complex multicellular network in Dupuytren’s disease to gain a complete molecular prospective of how discrete cell types contribute to fibrosis. Building on our discoveries of the stromal and immune cell populations present in human samples, a central goal of this project will be to characterize the vascular niche in fibrosis and define the precursors of mural cells such as myofibroblasts, the key effector cells in all fibrotic disorders. It will be powered by the integration of advanced next generation sequencing techniques, such as single cell RNA-seq and ChIP-seq, with established functional assays. Our expertise in computational biology (Croft et al., 2019; Layton et al., 2020) will support the construction of a comprehensive single cell atlas of fibrosis and prioritise potential novel therapeutic targets.
Musculoskeletal science, Dupuytren’s disease, fibrosis, translational research, single cell RNA-sequencing
The successful candidate will benefit from supervision by a surgeon scientist with a focus on translational musculoskeletal science alongside a clinician scientist with expertise in computational biology and translational research. In addition, you will be supported by two junior supervisors with expertise in computational and cell biology, live imaging and molecular biology techniques.
You will be based in the modern building and laboratories of the Kennedy Institute of Rheumatology, a world-leading centre in the fields of cytokine biology and inflammation, with a strong emphasis on clinical translation. There is support available from post-doctoral scientists and lab managers in our groups. In summary, you will be working with:
- Cutting-edge musculoskeletal and fibrosis biology and next generation sequencing techniques available in-house, including tissue culture, cell sorting and single cell RNA-sequencing analysis, spatial transcriptomics and imaging
- Emphasis on translational work: findings from human samples using advanced genomics techniques will enable a high impact on future therapeutic development
- Well-established DPhil programme with defined milestones, ample training opportunities within the University and Department, and access to university/department-wide seminars by world-leading scientists
- Highly collaborative environment with expertise ranging from molecular and cell biology, live cell imaging and computational biology/genomics analysis. You will also have the opportunity to participate in several other collaboration within the University of Oxford and worldwide.
- Croft, A.P., J. Campos, K. Jansen, J.D. Turner, J. Marshall, M. Attar, L. Savary, C. Wehmeyer, A.J. Naylor, S. Kemble, J. Begum, K. Durholz, H. Perlman, F. Barone, H.M. McGettrick, D.T. Fearon, K. Wei, S. Raychaudhuri, I. Korsunsky, M.B. Brenner, M. Coles, S.N. Sansom, A. Filer, and C.D. Buckley. 2019. Distinct fibroblast subsets drive inflammation and damage in arthritis. Nature 570:246-251. doi: 10.1038/s41586-019-1263-7.
- Izadi, D., T.B. Layton, L. Williams, F. McCann, M. Cabrita, A.I. Espirito Santo, W. Xie, M. Fritzsche, H. Colin-York, M. Feldmann, K.S. Midwood, and J. Nanchahal. 2019. Identification of TNFR2 and IL-33 as therapeutic targets in localized fibrosis. Science Advances 5:eaay0370. doi: 10.1126/sciadv.aay0370.
- Layton, T.B., L. Williams, F. McCann, M. Zhang, M. Fritzsche, H. Colin-York, M. Cabrita, M.T.H. Ng, M. Feldmann, S.N. Sansom, D. Furniss, W. Xie, and J. Nanchahal. 2020. Cellular census of human fibrosis defines functionally distinct stromal cell types and states. Nature Commununications 11:2768. doi: 10.1038/s41467-020-16264-y.
- Nanchahal, J., C. Ball, D. Davidson, L. Williams, W. Sones, F.E. McCann, M. Cabrita, J. Swettenham, N.J. Cahoon, B. Copsey, E. Anne Francis, P.C. Taylor, J. Black, V.S. Barber, S. Dutton, M. Feldmann, and S.E. Lamb. 2018. Anti-Tumour Necrosis Factor Therapy for Dupuytren's Disease: A Randomised Dose Response Proof of Concept Phase 2a Clinical Trial. EBioMedicine 33:282-288. doi: 10.1016/j.ebiom.2018.06.022.
- Verjee, L.S., J.S. Verhoekx, J.K. Chan, T. Krausgruber, V. Nicolaidou, D. Izadi, D. Davidson, M. Feldmann, K.S. Midwood, and J. Nanchahal. 2013. Unraveling the signaling pathways promoting fibrosis in Dupuytren's disease reveals TNF as a therapeutic target. Proceedings of the National Academy of Sciences, U S A 110:E928-937. doi: 10.1073/pnas.1301100110.