Neuromodulation of death in Caenorhabditis elegans (360G-Wellcome-214076_Z_18_Z)

The Nobel Prize-awarded discovery of programmed cell death while studying Caenorhabditis elegans nematode cell lineage revolutionised biomedicine. Although pervasive across living organisms and despite incredible potential applications, organismal death remains understudied, partly due to the lack of reliable death-markers. In nematode worms, death is marked by an impressive blue fluorescence burst, allowing us to study events that immediately precede death. Using this marker, we found that alteration of conserved neuromuscular pathways can delay worm death. Death fluorescence, whole-brain imaging at single-cell resolution, and a transparent model organism with fully-mapped brain wiring provide unique opportunities to study how neurological processes modulate death. We will (1) generate a collection of transgenic worm strains expressing ratiometric calcium-biosensors tissue-specifically to follow individual neurone/muscle activities, (2) develop a new fluorescence imaging platform to monitor in parallel death fluorescence and brain activity, (3) produce a temporal map of neuromuscular activity in the moments leading to death. This could help us understand how death occur, when it becomes irreversible, and how it can be targeted pharmacologically to improve organ collection and preservation, extend safety windows for major surgeries (particularly in elderly patients), or even reverse it to some extent.