(BBSRC DTP CASE) Understanding how macrophages restore immune health after infection

Inflammation is the response of the body to tissue danger. Macrophages sense danger signals derived from tissue damage or infection, and initiate the activation of the inflammasome, a molecular complex which triggers release of the cytokines interleukin(IL)-1β and IL-18, and a process of cell death called pyroptosis. This inflammatory process is required to initiate an immune response that eventually restores body homeostasis. Aging, and its associated diseases, are linked to the accumulation of danger signals such as extracellular ATP or amyloid beta fibrils that trigger chronic low-grade inflammation. In addition, aging is also associated to higher susceptibility to infection, possibly due to these immunological changes. Although all these threats can activate the inflammasome, the mechanisms that govern inflammasome activation are not well understood.

The ubiquitin system plays a crucial role in immune signalling by maintaining a fine balance between addition of ubiquitin and the removal of this post-translational modification by deubiquitinating enzymes (DUBs) and alterations of this balance has detrimental consequences for health. Ubiquitin and ubiquitin-like posttranslational modifications finely control immune responses to different danger signals (both sterile and pathogenic). The key question for this project is how deubiquitinases regulate the inflammasome and hence contribute to restoration of immune health.

Recent research in our lab has shown the importance of the ubiquitin system, in particular deubiquitinases for inflammasome activation. How the DUB landscape is altered in macrophages and how this contributes to inflammasome mediated immune responses remains unknown and will be explored during this PhD. This project will combine the use of human macrophages (cell line and blood derived) as well as inflammasome activation models. The project will require the candidate to learn a wide variety of skills including cell culture, molecular biology techniques (western blot, immunoprecipitation, postranslational modifications, gene editing by CRISR/Cas9), ELISA, imaging, model infections and data analysis. All of this will allow the PhD candidate to determine whether DUBs differentially regulate responses to sterile and infectious danger signals by controlling inflammasome activation.

This project is an exciting collaboration between the lab of Gloria Lopez-Castejon at the Manchester Collaborative Centre of Inflammation Research (MCCIR), Forma Therapeutics and the Oxford Drug Discovery Institute (ODDI). We are looking for talented, motivated and enthusiastic candidates that want to join this unique opportunity. The PhD candidate will spend several months at the ODDI allowing the student to benefit and gain invaluable experience from an academic and industrial environment.

https://www.research.manchester.ac.uk/portal/en/researchers/gloria-lopezcastejon(a7255a0f-d744-4d28-bf0e-c3c560c213d8).html

https://www.research.manchester.ac.uk/portal/david.brough.html

http://www.formatherapeutics.com/

http://aruk-oddi.medsci.ox.ac.uk/home

Entry Requirements
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.