Translational genomics in critical care medicine.

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.