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

研究神经毒剂效力的决定因素，以确定减轻环境毒素影响的新途径。

• 批准号: 2441792
• 金额: --
• 依托单位: University of Southampton
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2441792
• 关键词: Investigations; determinants; nerve; agent; potency

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.

氨基甲酸酯和有机磷酸酯防止乙酰胆碱分解，促进胆碱能神经信号的终止。这种跨门传播的重要作用是其成功用于保护作物和动物免受寄生虫侵害的基础。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剂/恐怖分子制剂。受影响的个人被放置在呼吸器上，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。这意味着存在可用于减轻中毒和/或改善暴露后恢复的基础稳态机制。抗胆碱能作用的核心是烟碱乙酰胆碱受体（nAChR）的超刺激，这是胆碱能神经传递的主要信号成分。我们确定了nAchR的不同突变，对内源性递质的敏感性不同，影响抗胆碱酯酶中毒和恢复的结果。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强保护。这促进了改变乙酰胆碱受体敏感性的药理学或分子药物作为新的治疗途径。学生将描述现有的/设计的受体突变体，旨在改变受体的敏感性。这将确定促进或抑制受体功能是否提供了最佳的治疗途径。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。我们将测试这类化学品，以探测它们是否提供了一种治疗整个生物体的途径。这些分子和药理学的操作，然后将研究在分离的膈神经，哺乳动物模型的呼吸停止。因此，在秀丽隐杆线虫中模拟抗胆碱酯酶缓解的分子和药理学操作将被翻译成哺乳动物环境，以平台对一类重要的毒素进行新的治疗。