Using changes in the synovial microenvironment to define disease progression and treatment response in rheumatoid arthritis

PROJECT DESCRIPTION

The Human Cell Atlas will provide an encyclopedic list of the different cell populations comprising each tissue of the body. However, a navigable atlas requires geographical context. This project will define the extracellular networks that surround and support newly discovered cell subsets in the human joint and define how changes in the synovial microenvironment during rheumatoid arthritis drive disease, providing effective biomarkers and novel targets to prevent disease progression. The synovium is an anatomically complex tissue, populated at peak of inflammation by at least 18 different cell types, each specialized to fulfil distinct roles.  This project aims to understand: 1) how the extracellular networks surrounding and supporting synovial cells dictate site-specific behaviour in rheumatoid arthritis (RA), and 2) how these microenvironmental cues can be exploited to develop new ways to stratify disease and to treat people with RA.  

Skills developed: cellular immunology; matrix biology; state-of-the-art spatial transcriptomics; bioinformatic training including coding in R for RNA seq data analysis; patient cohort analysis using the TranSMART platform. 

 KEY REFERENCES

1. Hynes, R.O. and A. Naba, Overview of the matrisome--an inventory of extracellular matrix constituents and functions. Cold Spring Harb Perspect Biol, 2012. 4(1): p. a004903.
2. Amit, I., D.R. Winter, and S. Jung, The role of the local environment and epigenetics in shaping macrophage identity and their effect on tissue homeostasis. Nat Immunol, 2016. 17(1): p. 18-25.
3. Aungier, S.R., et al., Targeting early changes in the synovial microenvironment: a new class of immunomodulatory therapy? Ann Rheum Dis, 2019. 78(2): p. 186-191.
4. Croft, A.P., et al., Distinct fibroblast subsets drive inflammation and damage in arthritis. Nature, 2019. 570(7760): p. 246-251.