Kennedy Trust Prize Studentships
Priming of the NLRP3 inflammasome in sterile inflammation
At the front line of immune defence lies the innate immune system, a component of which is the NLRP3 inflammasome—a multi-molecular sensing and signalling platform that recognizes the presence of infection or damaged tissue. While beneficial during infection, mutations in NLRP3 that cause over activation of this pathway can lead to multi-organ inflammatory episodes in patients with Cryopyrin-Associated Periodic Syndromes (CAPS). Overactive NLRP3 is associated with acquired inflammatory diseases such as gout, diabetes or Alzheimer’s. Hence, healthy individuals must have mechanisms in place to control inflammasome activity. Surprisingly, despite extensive research, we have very limited knowledge about how inflammasome signalling is controlled in healthy individuals. Recently, the inflammatory cytokine, TNF was identified as a critical priming signal for NLRP3 in ageing, and also in mouse models of heritable diseases caused by the NLRP3-activating mutations in CAPS, indicating a common NLRP3 priming mechanism in a diverse inflammatory settings. TNF is a known inflammatory signal associated with other NLRP3-associated maladies such as gout and Alzheimer’s disease. Notably, all known NLRP3-linked pathologies to date in humans are those of sterile inflammation, yet microbial stimuli (e.g., LPS) are used as a common experimental tool to study this pathway in the laboratory. Thus, we propose here to combine proteomics, imaging, biochemical and immunological assays to identify signalling pathways and posttranslational modifications that control NLRP3 activity downstream of TNF-mediated priming signal in primary mouse and human macrophages. We will then compare the findings with other known NLRP3 priming stimuli (microbial or not) to glean common principles that lie beneath inflammasome-mediated diseases and to identify therapeutic targets for the design of future interventions.
- Lamkanfi, M. & Dixit, V.M. Mechanisms and functions of inflammasomes. Cell2014,157,1013-1022 (2014).
- Boucher, D. et al, Bezbradica, J.S.and Schroder, K. Caspase-1 self-cleavage is an intrinsic mechanism to terminate inflammasome activity, Journal of Experimental Medicine, 2018,DOI:10.1084/jem.20172222
- Bezbradica, J.S, Coll, R.C. and Schroder, K. Sterile signals generate weaker and delayed macrophage NLRP3 inflammasome responses relative to microbial signals, Cellular & Molecular Immunology,2017, 14:118-126.
- Bezbradica, J. S., & Medzhitov, R. Integration of cytokine and heterologous receptor signaling pathways. Nature Immunology, 2009, 10: 333-339.
Immunology; Infection & immunity; Cell Signalling
The Kennedy Institute is a world-renowned research centre and is housed in a brand new state-of-the-art research facility. The project presents excellent training opportunities in a broad spectrum of immunological and biochemical approaches and in the use of the cutting edge technologies. Program will start with 20 lectures in year 1 to set the theoretical foundation in immunology and inflammation. Building on that foundation, we will use a combination of proteomics approaches, cell biology and imaging techniques (e.g. confocal microscopy), immunological assays (e.g. FACS, ELISA) and new mouse models to accomplish the aims of this project. Extensive collaborations with other research groups inside and outside of the Kennedy Institute will be developed. Project will particularly benefit from the co-supervision provided by Prof. Midwood who is an expect in signals associated with sterile inflammation and tissue damage. Student will attend weekly supervision and laboratory meetings, and departmental seminars. Student will also attend and present at external scientific conferences.
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.