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  • Project No: MRC iCASE
  • Intake: MRC iCASE

Supervisor: Prof. Mark Coles

Co-Supervisor: Prof. Christopher Buckley

ABOUT THE PROJECT

Commercial partner: Mestag Therapeutics Ltd, 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 IMIDs and cancer using human culture systems, combing scRNAseq and imaging with functional analysis.

One of the key signalling pathways in human inflammatory disease and tumours is cytokines utilising the gp130 receptor complexes. IL-6, IL-11, CT-1, OSM and CNTF all utilise the GP130 receptor complex driving a complex set of cross talk between different fibroblast and macrophage populations in human disease. Despite the known function of IL6 in inflammation and has a key role in a pathological positive feedback loop driving fibroblast pathologies the relative role of other IL6 superfamily members is less clear. In contrast IL11R which shares the GP130 receptor has recently been shown to drive tissue repair.

In this DPhil project we will use a cycle of analysis (scRNAseq (BD Rhapsody), and multiplex imaging (CellDive)) and experimental perturbations including novel G/10XP130 targeting agents and CRISPR/Cas9 targeting of primary human cells to:

  • Analyse human synovial tissue function using 3D culture systems incorporating synovial primary human fibroblast and macrophage subsets with human vasculature to dissect the cross talk between these two cell types through GP130 receptor complex to address cross talk in rheumatoid arthritis.
  • Compare cross talk in human tumours using 3D spheroids of high Gleason grade human prostate stromal subsets, macrophages and PC3M cells (established 3D model in the lab) to determine how targeting this pathway can be used to treat cancer.
  • Validated outcomes using primary biopsy culture system using compressed tone sections from human tissue biopsies.

Through this work we identify how the gp130 / IL6R superfamily functions in the context of fibroblasts in inflammatory pathologies and cancer.

Apply using course: DPhil in Molecular and Cellular Medicine.