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LEAD SUPERVISOR: Professor Mark Coles, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences

Co-supervisor: Professor Chris Buckley, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences

 Commercial partner: Mestag Therapeutics, Cambridge

 

Background: Fibroblasts are key regulators of chronic inflammation and tumours regulating the timing, type and duration of immune responses.  Fibroblasts are heterogenous with phenotypes varying between tissues and within pathology, ranging in function from maintaining chronic inflammation to promoting immunosuppression in malignancy. One key cellular partnership in both tissue homeostasis and pathology, is cross-talk between fibroblasts and macrophages subsets. This has a key role in driving forward feedback signals, thereby promoting resistance to disease therapy.  Despite the importance of fibroblasts in human disease this is an unexploited area with no clinically approved therapies directly targeting stromal function. One of the key research foci of the Coles and Buckley group is understanding human fibroblast – macrophage cross talk in Immune Mediated Inflammatory Disease (IMID) and cancer using human culture systems, combing multiplex imaging with spatial genonomics,  single cells RNA sequencing with functional assays. 

Aims: In this DPhil project, we will use multi-omics based approach (scRNAseq (10x) analysis, multiplex imaging (Cell Dive), high dimensional flow cytometry) to identify immunoreceptor tyrosine-based inhibitory motif (ITIM) domain expressing receptor expression in fibroblasts and then functionally determine how they regulate fibroblast function using CRISPR/Cas9 targetting of primary human fibroblasts specifically using:

1) Engineered 3D culture synovial joint system incorporating synovial primary human fibroblasts and macrophage systems that replicates key feature of arthritic disease and other IMIDs

2) A 3D cancer spheroid model of human colorectal and prostate cancer combining transformed epithelium with cancer associated fibroblasts (CAFs) with tumour macrophages

These outcomes will be validated in human biopsies using multiplex immunohistochemistry and then using tissue specific mouse gene knock-out models.  Together these datasets (in vitro and in vivo) will provide experimental validation of ITIM domain containing proteins in fibroblast function in human disease. 

Apply using course: DPhil in Molecular and Cellular Medicine

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