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可以防止乙酰胆碱的分解，从而促进胆碱能神经信号的终止。这种跨门传播的关键作用是成功地利用它来保护农作物和动物免受寄生虫的侵袭。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/恐怖分子毒剂。受影响的人会戴上呼吸器，并接受肌肉松弛药和抗毒鼠药的治疗。利用模式生物秀丽线虫，我们确定了对长期暴露的复杂动态平衡反应，模拟了环境中毒。这意味着有支持的动态平衡机制，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型乙酰胆碱受体(NAChR)的超刺激，而nAChR是胆碱能神经传递的主要信号成分。我们确定了nAchR的不同突变，对内源性递质影响抗胆碱酯中毒和康复的结果的敏感性不同。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作用。这促进了改变乙酰胆碱受体敏感性的药理或分子药物成为治疗的新途径。学生将描述现有的/工程的受体突变体，旨在改变受体的敏感度。这将确定是促进还是抑制受体功能提供了治疗的最佳途径。越来越多的药物作为变构调节剂，改变受体对内源性递质的敏感性。我们将测试这一化学类别，以探索它们是否提供了一条治疗整个有机体的途径。然后，这些分子和药物操作将在分离的膈神经中进行研究，这是一种呼吸停止的哺乳动物模型。因此，模拟线虫抗胆碱酯酶缓解的分子和药理学操作将被翻译到哺乳动物的背景下，为一类重要的毒素提供新的治疗方法。

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.