Identification of novel therapeutic pathways for lung fibrosis and repair

Although many tissues have the capacity to repair following injury, the majority heal by fibrosis. Discovery of new targets is hampered by the lack of early-stage disease human tissue and the failure of animal models to recapitulate all aspects of clinical disease. Lung fibrosis remains a major unmet need and shares some features with other fibrotic conditions such as Dupuytren’s disease, where we have access to a plentiful supply of early-stage tissue that facilitates the functional validation of key potential pathways. Fibrosis following injury can also be reduced by upregulating repair mechanisms. Most tissues, including the lung, have the capacity to repair through conserved pathways that target endogenous stem and progenitor cells. However, in the lung there is increasing evidence that chronic or repeated injury leads to the persistence of progenitor cells that play a key role in the development of fibrosis.

This project will focus on the factors that lead to the persistence of the pathogenic progenitor cells and their cross-talk with other cells that leads to the development of fibrosis.

KEYWORDS

Fibrosis, repair, progenitor cells, signalling pathways

TRAINING OPPORTUNITIES

The successful candidate will benefit from dual supervision by a surgeon scientist with a focus on translational medicine and an expert in matrix biology and fibrosis. You will be based in the purpose-built labs at The Kennedy Institute of Rheumatology, a world-leading centre in the fields of cytokine biology and inflammation, with a strong emphasis on clinical translation. The project will use a combination of human samples and murine models. There is support available from post-doctoral scientists in our groups and lab managers to become proficient in cell and molecular biological techniques, including flow cytometry, mass cytometry, mass spectrometry, immunofluorescence, tissue culture, microscopy, in vivo imaging and animal disease models.

KEY PUBLICATIONS

Buckley, CD and Midwood KS. Tracing the origins of lung fibrosis. Nature Immunology 2024.

Williams LM, McCann FE, Cabrita M, Layton T, Cribbs A, Knezevic B, Fang H, Knight J, Zhang M, Fischer R, Bonham S, Steenbeck LM, Yang N, Sood M, Bainbridge C, Warwick D, Harry L, Davidson D, Xie W, Sundstrom M, Feldmann M, Nanchahal J. (2020)

CREBBP/EP300 regulation of collagen VI is a key determinant of the myofibroblast phenotype in human fibrosis. Proceedings of the National Academy of Sciences. 117(34): 20753-20763

Layton TB, Williams L, McCann F, Fritzsche M, Colin-York H, Cabrita M, Ng MTH, Feldmann M, Sansom S, Furniss D, Xie W, Nanchahal J. (2020)

Cellular census of human fibrosis defines functionally distinct stromal cell types and statesNature Communications. 11: 2768

Identification of TNFR2 and IL-33 as therapeutic targets in localized fibrosis. Izadi D, Layton TB, Williams L, McCann F, Cabrita M, Espirito Santo AI, Xie W, Fritzsche M, Colin-York H, Feldmann M, Midwood KS, Nanchahal J. Sci Adv. 2019 Dec 4;5(12):eaay0370. doi: 10.1126/sciadv.aay0370.

Lee G, Espirito Santo A, Zwingenberger S, Cai L, Vogl T, Feldmann M, Horwood N, Chan J, Nanchahal J (2018)

Fully-reduced HMGB1 accelerates healing of multiple tissues by transitioning stem cells to GAlert.Proceedings of the National Academy of Science, USA. 115(19): E4463-72 

THEMES

Tissue remodelling and repair, Translational medicine, Molecular, cell and systems biology, Physiology, cellular and molecular biology

CONTACT INFORMATION OF ALL SUPERVISORS

jagdeep.nanchahal@kennedy.ox.ac.uk

kim.midwood@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.