Engineering Resolution – mRNA targeting of chronic inflammatory disease

mRNA based technologies have revolutionised vaccines and have the potential to modulate not just immunity to pathogens but also re-engineer immune responses to resolve chronic inflammatory disease. However, this potential has not been fully realised due to inefficiency in delivering mRNA to the specific cell types in tissues responsible for regulating the dynamics of immune response. We have shown that in immune mediated inflammatory disease (IMID), different localised fibroblast populations drive different processes: inflammation, tissue damage, but also disease resolution. We have previously identified proteins that regulate the state of fibroblasts. However, selectively targeting these cells is still an open challenge. In this PhD project, we will use a novel mRNA delivery system developed within the Stevens Group via polymer and lipid engineering. Will will use a suite of different methods to characterise the delivery system, including SPARTA (Single Automated Raman Trapping Analysis), a novel technology invented within the Stevens Group capable of analysing the molecular compositions of nanoparticles at the single particle level. By combining these technology, we will develop nanoparticles for the efficient transfection of tissue fibroblasts regulating disease progression in rheumatoid arthritis and inflammatory bowel disease. We will validate these nanoparticles using established models developed in the Coles-Buckley laboratory. The project will use a combination of human in vitro organoid systems, ex vivo human slice culture system, in vivo models, and chemical engineering to develop the mRNA-based approach to rewire inflammation in tissues. The student will spend time in both the Kennedy Institute of Rheumatology (Coles and Buckley groups) and Kavli Institute for Nanoscience Discovery (Stevens Group).

KEYWORDS

Nanoparticles, mRNA, arthritis, engineering, immunology

TRAINING OPPORTUNITIES

This DPhil studentship will lie on the intersection of bioengineering, tissue pathology, immunology and in vivo biology. The student will (depending on background - biological or chemical/engineering sciences) obtain training in tissue engineering, chemical engineering, immunological assays and in vivo biological systems.

KEY PUBLICATIONS

Croft AP, Campos J, Jansen K, Turner JD, Marshall J, Attar M, Savary L, Wehmeyer C, Naylor AJ, Kemble S, Begum J, Dürholz K, Perlman H, Barone F, McGettrick HM, Fearon DT, Wei K, Raychaudhuri S, Korsunsky I, Brenner MB, Coles M, Sansom SN, Filer A, Buckley CD. Distinct fibroblast subsets drive inflammation and damage in arthritis.  Nature. 2019 Jun;570(7760):246-251. doi: 10.1038/s41586-019-1263-7.

Blakney AK, Zhu Y, McKay PF, Bouton CR, Yeow J, Tang J, Hu K, Samnuan K, Grigsby CL, Shattock RJ, Stevens MM.  Big Is Beautiful: Enhanced saRNA Delivery and Immunogenicity by a Higher Molecular Weight, Bioreducible, Cationic Polymer.  ACS Nano. 2020 May 26;14(5):5711-5727. doi: 10.1021/acsnano.0c00326.

Korsunsky I, Wei K, Pohin M, Kim EY, Barone F, Major T, Taylor E, Ravindran R, Kemble S, Watts GFM, Jonsson AH, Jeong Y, Athar H, Windell D, Kang JB, Friedrich M, Turner J, Nayar S, Fisher BA, Raza K, Marshall JL, Croft AP, Tamura T, Sholl LM, Vivero M, Rosas IO, Bowman SJ, Coles M, Frei AP, Lassen K, Filer A, Powrie F, Buckley CD, Brenner MB, Raychaudhuri S.  Cross-tissue, single-cell stromal atlas identifies shared pathological fibroblast phenotypes in four chronic inflammatory diseases. Med. 2022 Jul 8;3(7):481-518.e14. doi: 10.1016/j.medj.2022.05.002

Ng MTH, Borst R, Gacaferi H, Davidson S, Ackerman JE, Johnson PA, Machado CC, Reekie I, Attar M, Windell D, Kurowska-Stolarska M, MacDonald L, Alivernini S, Garvilles M, Jansen K, Bhalla A, Lee A, Charlesworth J, Chowdhury R, Klenerman P, Powell K, Hackstein CP; ICECAP Consortium; Furniss D, Rees J, Gilroy D, Coles M, Carr AJ, Sansom SN, Buckley CD, Dakin SG. A single cell atlas of frozen shoulder capsule identifies features associated with inflammatory fibrosis resolution. Nat Commun. 2024 Feb 19;15(1):1394. doi: 10.1038/s41467-024-45341-9.

Penders J, Pence IJ, Horgan CC, Bergholt MS, Wood CS, Najer A, Kauscher U, Nagelkerke A, Stevens MM. Single Particle Automated Raman Trapping Analysis. Nat Commun. 2018 Oct 15;9(1):4256. doi: 10.1038/s41467-018-06397-6.

THEMES

Inflammation, Chemical Engineering, Immunology,

CONTACT INFORMATION OF ALL SUPERVISORS

mark.coles2@kennedy.ox.ac.uk

massimo.cau@dpag.ox.ac.uk

molly.stevens@dpag.ox.ac.uk

christopher.buckley@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 13^th January 2025.