About the Project
You will be part of our collaborative working environment and have access to outstanding shared facilities such as microscopy and proteomics. Throughout your year, you will develop an advanced level of knowledge on your topic of interest as well as the ability to perform independent research in the topic area. Alongside basic science training in experimental design, data handling and research ethics, we will help you to develop skills in critical assessment and communication. This will be supported by workshops in scientific writing, presentation skills, ethics, laboratory safety, statistics, public engagement and optional applied bioinformatics.
The period of study is one year full-time or two years part-time research, which includes two months to write up the thesis. Please apply via the UCAS postgraduate application form: https://digital.ucas.com/courses/details?coursePrimaryId=c735d826-42b6-ca1f-50db-2a3ac6f68718
The innate immune system uses a broad variety of sensors to detect cues of infections (pathogen-associated molecular patterns, PAMPs) or signs of cell and tissue damage (danger-associated molecular patterns, DAMPs). Recognition of PAMPs and DAMPs usually results in the production and release of pro-inflammatory mediators. Often, the activation of sensors and their downstream effectors also results in lysis and death of the activated cell, which makes it paramount that this activation is tightly controlled. If control mechanisms fail and excessive immune cell death occurs, this has detrimental consequences for the host, such as septic shock or the development of autoimmune diseases. An example of such processes is activation of inflammasomes. Inflammasomes are multiprotein complexes, which – upon sensing of PAMPs or DAMPs – induce the release of IL-1b, a very potent pro-inflammatory cytokine (1). Inflammasomes are mostly studied in macrophages and much less is known in the most abundant human immune cell, the neutrophil. Neutrophils, rather than secreting IL-1b, undergo a special form of cell death when activated, they form neutrophil extracellular traps (NETs). NETs consist of DNA and protein; dying neutrophils expel them as web-like structures and thereby catch extracellular pathogens (2). Remarkably, we previously found that there is crosstalk between the molecular machinery mediating inflammasome activation in macrophages and NET formation in neutrophils (3).
This project therefore aims to study, what the differences are between inflammasomes in neutrophils and macrophages and if these differences affect the outcome of infections and inflammasome or NET-driven pathology. The project will use human cells and a combination of cell biological and genetic techniques to answer these important immunological questions from a mechanistic perspective. It will thereby contribute to our understanding of inflammation, infection and sterile pathologies and help to identify possible new drug targets to tackle such pathologies.
(1) Broz P., Dixit V.M. Inflammasomes: mechanism of assembly, regulation and signalling, Nat Rev Immunol, 16:417-20
(2) Sollberger G., Tilley D.O., Zychlinsky A. Neutrophil Extracellular Traps: The Biology of Chromatin Externalization Dev Cell, 44:542-553
(3) Sollberger G., Choidas A., Burn G.L., Habenberger P., Di Lucrezia R., Kordes S., Menninger S., Eickhoff J., Nussbaumer P., Klebl B., Krüger R., Herzig A., Zychlinsky A. Gasdermin D plays a vital role in the generation of neutrophil extracellular traps Sci Immunol, 3:eaar6689
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