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

氨基甲酸酯和有机磷酸酯防止乙酰胆碱分解，促进终止胆碱能神经信号传导。这种跨门传播的重要作用支持了它成功地用于保护作物和动物免受寄生虫侵害。然而，这种治疗需要保护/遏制，因为抗胆碱酯酶是人类神经毒素。事实上，后者已经看到这些化合物被用作化学战/恐怖主义制剂。受影响的个体要戴上呼吸器，并用肌肉松弛剂和抗毒蕈碱剂治疗。使用模式生物秀丽隐杆线虫，我们确定了一个复杂的稳态反应长期暴露，模仿环境中毒。这意味着存在一种潜在的体内平衡机制，可以用来减轻中毒和/或改善暴露后的恢复。抗胆碱能作用的核心是对烟碱乙酰胆碱受体（nAChR）的超刺激，这是胆碱能神经传递的主要信号成分。我们在nAchR中发现了不同的突变，对内源性递质具有不同的敏感性，影响抗胆碱酯中毒和恢复的结果。此外，调节乙酰胆碱敏感性的乙酰胆碱受体的辅助亚基提供了强大的保护。这促进了药理学或分子药物，改变乙酰胆碱受体的敏感性，作为新的治疗途径。学生将描述现有的/工程的受体突变，旨在改变受体的敏感性。这将确定是否促进或抑制受体功能提供了最佳的治疗途径。作为变构调节剂和改变受体对内源性递质的敏感性的药物越来越多。我们将测试这类化学物质，以探索它们是否为整个生物体的治疗提供了一条途径。这些分子和药理学操作将在分离的膈神经（哺乳动物呼吸停止模型）中进行研究。因此，秀丽隐杆线虫抗胆碱酯酶缓解模型的分子和药理学操作将被转化为哺乳动物环境，为一类重要毒素的新治疗提供平台。

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.