Translational genomics in critical care medicine. (360G-Wellcome-223164_Z_21_Z)

My work during the Covid outbreak has shown that genetic associations with critical illness can predict therapeutic targets, and that therapies targeting the host response improve outcome in carefully-defined subgroups of critically ill patients. I propose to extend this work to bridge the gap between genetic discovery and therapeutic application. In doing so I will build on established infrastructure and lay the foundations of a system for rapid identification and assessment of candidate drugs for respiratory critical illness. To achieve this I will: \- \- Use genome-wide association studies to identify host genes associated with critical illness in viral pneumonia (Covid-19: 20,000 cases; influenza: 3000 cases). \- \- Identify targets using computational approaches including integrated functional genomics and Mendelian randomisation. \- Complete proof-of-principle analysis to test for differential genetic effects in new patient subgroups. \- \- Refine and test candidate causal variants in vitro. \- Establish technology for distal lung regional microdosing to validate targets in vivo in critically ill humans. At the end of this fellowship I will have established a programme of translational genomics in critical care medicine going from genomic discovery to experimental medicine in humans.