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.

TRAINING OPPORTUNITIES
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.