Kennedy Trust Prize Studentships
Characterising Key Determinants of Fibroblast Function in Immune Mediated Inflammatory Disease
Immune mediated inflammatory diseases (IMIDs) including Rheumatoid arthritis (RA), inflammatory bowel disease and Sjogren’s syndrome result from interactions between innate and adaptive immune cells with stromal fibroblasts driving both inflammation and tissue damage. Although current therapeutic approaches that target key molecules (e.g. TNF) and cell types (e.g. B cells)have had a dramatic impact on the clinical features of disease disease in many patients these drugs do not fully control inflammatory process, have no effect on fibroblast driven pathologies and do not adequately control pain. Thus, there is an urgent need for a new understanding of common mechanisms underlying disease process in IMIDs.
We have recently used a combination of single cell RNAseq, high dimensional flow cytometry and multi-parameter immunohistochemistry coupled to functional assays to characterize stromal fibroblasts from mouse and humans to generate a gene expression map that provides the basis for novel therapeutic discovery for treatments targeting stromal fibroblast function in IMIDs. Further analysis of synovial fibroblasts identified they are not one homogenous population rather they comprise of four highly conserved populations between human and mice; three populations reside in the sublining layer fibroblasts and an anatomically distinct population in the lining layer of the synovium
In this research project, we will focus developing and utilising a combination of primary 3D in vitrohuman tissue models with animal disease models to identify, characterise and dissect the role of fibroblast specific pathways in the formation of IMID pathology using RA and Sjogrens syndrome as exemplar diseases. In parallel we will determine the expression of the identified genes in human patient biopsies using high dimensional CODEX fluorescent imaging platform and RNA expression using the BEACON and OASIS patient cohorts. Through generating an integrated understanding of gene expression function in tissue stromal fibroblasts in IMIDs we aim to generate new therapeutic targets to treat human IMIDs and accelerate tissue repair and regeneration.
The student will be based at the Kennedy Institute of Rheumatology with access to state of the are imaging, cytometry and genomics equipment; training will be provided in advanced imaging techniques (across a wide range of modalities), image analysis, bioinformatics and systems biology and molecular and cell biology techniques. The Buckley and Coles groups work together closely with joint lab space and group meetings. The student will attend weekly lab meeting, journal clubs and seminars in KIR and across the wider University. There will be opportunities for the student to present to the institute, department and to attend international research conferences to present the outcomes of their research. Additional training will be provided through a core set of lectures during the first term providing a solid foundation in a broad range of subjects including immunology, genetics, musculoskeletal biology, data analysis, and translational medicine.
- Croft A, Campos J, Jansen K, Turner J, Marshall J, Attar M, Savary L, Perlman H, Barone F, McGettrick H, Fearon D, Wei K, Raychaudhuri S, Lorsunsky I, Brenner M, Coles M, Sansom S, Filer A, Buckley CD, Pathologically distinct fibroblast subsets drive inflammation and tissue damage in arthritis, BioRxiv, https://doi.org/10.1101/374330, 2018.
- Mizoguchi F, Slowikowski K, Wei K, Marshall JL, Rao DA, Chang SK, Nguyen HN, Noss EH, Turner JD, Earp BE, Blazar PE, Wright J, Simmons BP, Donlin LT, Kalliolias GD, Goodman SM, Bykerk VP, Ivashkiv LB, Lederer JA, Hacohen N, Nigrovic PA, Filer A, Buckley CD, Raychaudhuri S, Brenner MB.Functionally distinct disease-associated fibroblast subsets in rheumatoid arthritis. Nature Communications. 2018 Feb 23;9(1):789.
- Rao DA, Gurish MF, Marshall JL, Slowikowski K, Fonseka CY, Liu Y, Donlin LT, Henderson LA, Wei K, Mizoguchi F, Teslovich NC, Weinblatt ME, Massarotti EM, Coblyn JS, Helfgott SM, Lee YC, Todd DJ, Bykerk VP, Goodman SM, Pernis AB, Ivashkiv LB, Karlson EW, Nigrovic PA, Filer A, Buckley CD, Lederer JA, Raychaudhuri S, Brenner MB.Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis. Nature. 2017 Feb 1;542(7639):110-114.
- Li Z, Hodgkinson T, Gothard EJ, Boroumand S, Lamb R, Cummins I, Narang P, Sawtell A, Coles J, Leonov G, Reboldi A, Buckley CD, Cupedo T, Siebel C, Bayat A, Coles MC+, Ambler CA+, Epidermal Notch1 recruits RORγ(+) group 3 innate lymphoid cells to orchestrate normal skin repair. Nat Commun. Vol.7:11394. 2016
Inflammation, immunology, stroma, rheumatoid arthritis, disease models, imaging
HOW TO APPLY
The department accepts applications throughout the year but it is recommended that, in the first instance, you contact the relevant supervisor(s) or the Directors of Graduate Studies who will be able to advise you of the essential requirements.
Interested applicants should have or expect to obtain a first or upper second class BSc degree or equivalent, and will also need to provide evidence of English language competence. The University requires candidates to formally apply online and for their referees to submit online references via the online application system.
The application guide and form is found online and the DPhil or MSc by research will commence in October 2019.
When completing the online application, please read the University Guide.
Contact: Professor Christopher Buckley, Kennedy Institute of Rheumatology, University of Oxford.