Investigations of the determinants of nerve agent potency to define novel routes to mitigate the effects of environmental toxins.

Carbamates and organophosphates prevent the acetylcholine breakdown that facilitates termination of cholinergic nerve signalling. The essential role of this transmission across phyla underpins its successful use to protect crops and animals from parasites. However, such treatments require protection/containment, as anti-cholinesterases are human neurotoxins. Indeed, the latter has seen these compounds used as chemical warfare/terrorist agents. Affected individuals are placed on a respirator and treated with muscle relaxants and anti-muscarinic agents. Using the model organism C.elegans we identified a complex homeostatic response to protracted exposure that mimics environmental intoxication. This implies that there are underpinning homeostatic mechanism that could be used to mitigate the intoxication and/or improve post exposure recovery. At the core of the anti-cholinergic effects is the super stimulation of the nicotinic acetylcholine receptors (nAChR), the primary signalling component of the cholinergic nerve transmission. We identified distinct mutations in nAchR, with varying sensitivity to the endogenous transmitter affecting outcomes to anticholinesterse intoxication and recovery. Moreover, auxiliary subunits of the acetylcholine receptor that modulate acetylcholine sensitivity afford strong protection. This promotes pharmacological or molecular agents, which shift acetylcholine receptor sensitivity, as novel routes to treatment. The student will characterize existing/engineered receptors mutants designed to shift receptor sensitivity. This will establish if promoting or inhibiting receptor function provides the best route to therapies. There is a growing list of drugs that act as allosteric modulators and change sensitivity of receptor to endogenous transmitter. We will test this chemical class to probe if they provide a route to whole organism treatment. These molecular and pharmacological manipulations will then be investigated in the isolated the phrenic nerve, a mammalian model of respiratory arrest. Thus, the molecular and pharmacological manipulations that model anticholinesterase mitigation in C.elegans will be translated into a mammalian context to platform novel treatments to an important class of toxins.