Investigating mechanisms regulating cGAS-STING signalling

Background: The innate immune system senses and responds to endogenous and exogenous danger signals in order to protect the host. cGAMP synthase (cGAS) detects viral double stranded DNA (dsDNA) in the cytosol leading to the activation of Stimulator of IFN Genes (STING) and production of type I interferons (IFNs) and inflammatory cytokines as part of an anti-viral inflammatory response. However, unwarranted activation by host dsDNA is implicated in a number of serious autoimmune and neurodegenerative conditions (e.g. Parkinson’s disease). Further, humans expressing gain-of-function mutations in STING exhibit a life threatening autoinflammatory disease termed, STING-associated vasculopathy with onset in infancy (SAVI). The precise mechanisms controlling STING responses however, remain poorly described. Project aim/s: In this study we will examine STING activation, trafficking and downstream signalling responses under a range of conditions, in the absence of potential novel regulating proteins identified in our lab through an unbiased proteomics screen. This work will help to better understand the mechanisms that control this vital immune pathway. Techniques to be utilised: This project will utilise a range of cutting-edge molecular, cell biology, high end imagaing and biochemical approaches (e.g. CRISPR/Cas9 gene editing, viral transduction) as well as standard techniques (Western Blotting, quantitative-PCR, DNA cloning) in models of inflammation to investigate, dissect and discover mechanisms that control regulation of STING signalling pathways.