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PKC-Θ AND PD-1 AS A THERAPEUTIC TARGET IN INFLAMMATORY ARTHRITIS

Supervisors: Professor Peter Taylor (Oxford), Professor Michael Dustin (Oxford), Professor Graham Ogg (Oxford) and Leon Carayannopoulos (Celgene) and Rolli Khattri (Celgene)

This project will apply advanced imaging and use of small molecule inhibitors to understand the role of PKC-θ in the pathobiology of inflammatory arthritis. In conventional T cells PKC-θ co-localises with the TCR and is necessary for downstream signals, whereas in regulatory T cells PKC-θ adopts a distal position and negatively regulates suppressive function. This study will examine the localisation and function of PKC-θ in conventional and regulatory T cells from patients with inflammatory arthritis or healthy controls. Insight provided by these studies will guide development of PKC-θ small molecule inhibitors as therapeutic agents. The co-inhibitory molecule PD-1 is upregulated on chronically stimulated T cells and delivers signals that inhibit T cell function. These studies will also evaluate the combination of PD-1 agonists and PKC-θ inhibitors as an approach to inhibit T cell responses.

UNRAVELLING PRO-FIBROTIC TNF SIGNALLING PATHWAYS IN DUPUYTREN'S DISEASE

Supervisors: Professor Jagdeep Nanchahal (Oxford), Dr. Dominic Furniss (Oxford), Professor Kim Midwood (Oxford) and Welin Xie (Celgene) and Jerry Horan (Celgene)

Dupuytren's disease is a fibrotic disorder of the hand in which the fingers progressively curl irreversibility into the palm. Recent studies showed TNF converts palmar fibroblasts from Dupuytren's patients into myofibroblasts that are responsible for matrix deposition and contraction in fibrotic disorders. The goal of this project is to identify pro-fibrotic TNF signalling pathways for development of highly specific therapeutics in Dupuytren's and other fibrotic disorders. Planned studies will investigate the molecular pathway through which TNF cooperates with canonical Wnt signalling to promote palmer fibroblast cell differentiation as well as the upstream regulators of TNF secretion. These studies will apply ex vivo models using samples from disease tissues. Data generated by these studies will complement a clinical trial of TNF inhibition for early Dupuytren's disease.

DEFINITION OF NEW DRUG TARGETS FOR FIBROSIS IN CROHN'S

Supervisors: Professor Alison Simmons (Oxford) and Kamal Puri (Celgene)

Fibrosis is a common complication of inflammatory bowel disease that is neither prevented nor reversed by current anti-inflammatory therapies. This project will apply new methodologies for isolation and molecular phenotyping of stromal cells from colonic or small bowel biopsies. This analysis will allow reclassification of intestinal stromal subsets and will provide insight into subset composition in IBD or IBD fibrotic tissues compared with healthy controls. In addition, stromal cells subsets isolated during different stages of disease will be examined for responses to innate stimuli to uncover molecules or pathways that contribute to the pro-fibrotic state. This project will advance mechanistic understanding of intestinal fibrosis in human disease and may reveal targets for development of biomarkers or new therapies.