Kennedy Trust Prize Studentships
The role of tissue damage-associated lipids in triggering pathogenic neutrophil responses in inflammatory diseases
Neutrophils are well recognised for their ability to rapidly enter the site of tissue damage and microbial infection where they kill microorganisms by either ingesting them or releasing anti-microbial activities and facilitate wound repair. However they also cause immunopathology by overproducing anti-microbial activities that may lead to inflammatory and autoimmune diseases. We and others have shown that neutrophils are critical for the initiation and pathogenesis of inflammatory and autoimmune diseases, including inflammatory arthritis (1,2). How neutrophils respond to sterile tissue damage in the absence of infection is poorly understood, but both protein and lipid signals have been implicated in driving neutrophil entry into tissue (3).
The goal of this project is to define the relative contribution of tissue resident cells (synovial macrophages, fibroblasts) and infiltrating monocyte derived macrophages (MDMs) in the release of bioactive lipids that guide pathogenic neutrophil responses over the course of the inflammatory response (4). This will be done using a combination of immunological and biochemical techniques and by the generation of unique mouse models for cell-specific targeting of a key enzyme in the production of a range of lipid DAMPS, namely cytosolic calcium-dependent phospholipase A (cPLA2). Based on our preliminary data, we hypothesise that lipid production by MDMs is critical for neutrophil recruitment and activation, but we need to exclude other tissue resident cells in this process(5).
The outcome of this study is expected to lead to a better understanding of the cellular mechanisms behind the observed effects of cPLA2 inhibition in inflammatory arthritis, which may lead to more specific approaches for delivering cPLA2 inhibition. If for example MDMs were indeed critical producers of lipid DAMPS in inflamed synovium, inhibition of cPLA2 in circulating immune cells would help to focus the target effects of the cPLA2 inhibitors, and minimise homeostatic disruption to tissues thereby avoiding any significant side effects or complications.
- Weiss M, Byrne AJ, Blazek K, Saliba DG, Pease JD, Perocheau D, Feldmann M, Udalova IA. IRF5 controls both acute and chronic inflammation. Proceedings of the National Academy of Sciences. 2015, 112(35):11001-6.
- Blazek K, Eames HL, Weiss M, Byrne AJ, Perocheau D, Pease JD, Doyle S, McCann F, Williams RO, Udalova IA. IFN-lambda resolves inflammation via suppression of neutrophil infiltration and IL-1b-production. Journal of Experimental Medicine. 2015, 212(6):845-53
- Buckley CD, Gilroy DW, Serhan CN. Proresolving lipid mediators and mechanisms in the resolution of acute inflammation. Immunity. 2014, 40(3):315-27.
- Buckley CD, McGettrick HM. Leukocyte trafficking between stromal compartments: lessons from rheumatoid arthritis. Nature Reviews Rheumatology. 2018, 14:476–487.
- Udalova IA, Mantovani A, Feldmann M. Macrophage heterogeneity in the context of rheumatoid arthritis. Nature Reviews Rheumatology. 2016, 12(8):472-85.
The Kennedy Institute is a world-renowned research centre and is housed in a brand new state-of-the-art research facility. Training will be provided in techniques in a wide range of immunological (cell isolation, tissue culture, FACS, CyTOF), biochemical (enzyme-immunoassays (EIA), quantitative mass spectrometry (LC-MS/MS)) and imaging (immunofluorescence on tissue sections) approaches. Recently developed novel in vivomodels of inflammatory diseases will be extensively used and new models will be generated. A core curriculum of lectures will be taken in the first term to provide a solid foundation in a broad range of subjects including musculoskeletal biology, inflammation, epigenetics, translational immunology and data analysis. Students will attend weekly seminars within the department and those relevant in the wider University. Students will be expected to present data regularly to the department, the Genomics of Inflammation group and Arthritis Therapy Acceleration Programme and to attend external conferences to present their research globally. Students will also have the opportunity to work closely with members of the Rheumatoid Arthritis Pathogenesis Centre of Excellence (Glasgow/Birmingham/Newcastle) as well as Novonordisk Immunometabolism consortium (Oxford/Karolinska/University of Copenhagen).
Immunology; Molecular, Cell and Systems Biology; Genes, Genetics, Epigenetics and Genomics; Musculoskeletal Science
HOW TO APPLY
The department accepts applications throughout the year but it is recommended that, in the first instance, you contact the relevant supervisor(s) or the Directors of Graduate Studies who will be able to advise you of the essential requirements.
Interested applicants should have or expect to obtain a first or upper second class BSc degree or equivalent, and will also need to provide evidence of English language competence. The University requires candidates to formally apply online and for their referees to submit online references via the online application system.
The application guide and form is found online and the DPhil or MSc by research will commence in October 2019.
When completing the online application, please read the University Guide.