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Immuno-geography of synovial lining and macrophage function #RACE3


About This PhD Project

Project Description

Supervisory team
Hub 1: Oxford – Prof. Irina Udalova (Lead Supervisor)
Hub 2: Glasgow – Mariola Kurowska-Stolarska
Hub 3: Birmingham – Andrew Filer

Project Description: The synovial lining represents the immuno-mechanical barrier that separates synovial tissue, cartilage and bone from the synovial cavity. The synovial membrane is very sensitive to mechanical stress, imposed by injury, obesity, misalignmenta and inflammation. The spatially confined structure of the synovial joint makes it vulnerable to
inflammatory exudate formation and creates a self-sustaining inflammatory cycle. Despite much research in the field of articular inflammation, functional immuno-geography of the synovial joint remains elusive. To address this question, the project will use the state-of-the art imaging and genomic technologies as well as novel in vivo models of inflammatory diseases. Recent single cell analysis of human tissues demonstrated a significant heterogeneity within these cell populations, but functions of immune cell subsets at anatomically discrete locations remain elusive. For example, resident macrophage might initiate the recruitment of neutrophils or sense tissue damage and extracellular lipid accumulation, while monocyte derived macrophages produce bulk of inflammatory mediators. Thus, in this project the project will use advanced whole tissue imaging of mouse and human biopsies to reconstruct the synovial membrane structure across the whole joint, perform spatial genomics and proteomics on synovial macrophage populations and genetically ablation of key enzymes regulating bioactive lipid synthesis.

Skills developed: cellular immunology; multi-dimensional confocal imaging; state-of-the-art spatial transcriptomics; bioinformatic training including coding in R for RNA seq data analysis; in vivo mouse physiological models

References

1. Zhang et al. Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry. Nat Immunol. 2019 Jul;20(7):928-942.
2. Udalova et al. Macrophage heterogeneity in the context of rheumatoid arthritis. Nat Rev Rheumatol. 2016 Aug;12(8):472-85
3. Kurowska-Stolarska et al. RMD Open. 2017 Dec 6;3(2):e000527. doi:10.1136/rmdopen-2017-000527.
4. Jaitin et al. Lipid-Associated Macrophages Control Metabolic Homeostasis in a Trem2-Dependent Manner. Cell. 2019 Jul 25;178(3):686-698.

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