Neurotoxic Effects of Volatile Anesthetics in C. elegans

描述(申请人提供)：从一开始，挥发性麻醉药一直被认为是良性的中枢神经系统抑制剂。然而，最近的研究严重挑战了这一教条，并在麻醉学领域引起了惊人的范式转变，特别是在全身麻醉下的婴儿护理方面。现已证实，挥发性麻醉剂可导致发育中的大鼠脑内神经细胞的凋亡性变性。初步数据表明，这种影响很可能也存在于人类身上。正如我们在初步数据中所显示的(见研究设计)，我们已经在模式生物秀丽线虫中建立了类似的效应。在这项提案中，我们将确定在发育中的神经系统中，麻醉药物暴露后引发神经毒性的基因。为了实现这一点，我们将从线虫线虫中筛选全基因组RNAi文库。这些基因将被测试它们调节麻醉剂引起的神经毒性的能力。我们假设，启动神经元退化的新的、以前未被怀疑的分子靶标的重大发现将在线虫中确定，并且它们将预测哺乳动物中类似的功能显著反应。现有数据支持这样一种信念，即当跨系统发育研究时，导致细胞凋亡的相互作用将保持在较高水平。我们假设，识别控制麻醉剂引起的神经毒性的基因将针对能够抑制这一现象的分子，并指导儿童更安全地接触麻醉剂的研究。 公共卫生相关性：挥发性麻醉剂已被证明在几种哺乳动物的中枢神经系统中引起神经毒性，可能包括人类。关于这种神经毒性效应是如何启动的，人们知之甚少。我们建议使用遗传方法在线虫线虫中识别在这种反应中重要的基因。

DESCRIPTION (provided by applicant): Since their inception, volatile anesthetics have been thought to be benign inhibitors of the central nervous system. However, recent studies have seriously challenged this dogma, and caused a startling paradigm shift in the field of anesthesiology, in particular in regard to the care of infants undergoing general anesthesia. Volatile anesthetics have now been shown to cause apoptotic neuronal degeneration in developing rat brains. Preliminary data indicate that this effect is likely to exist in humans as well. As we show in our preliminary data (see Research Design), we have established a similar effect in the model organism, C. elegans. In this proposal we will identify genes responsible for the initiation of neurotoxicity following anesthetic exposure in the developing nervous systems. To accomplish this we will screen a genome wide RNAi library from the nematode, C. elegans. These genes will be tested for their ability to regulate anesthetic induced neurotoxicity. We hypothesize that significant discoveries of novel, previously unsuspected molecular targets that initiate neuronal degeneration will be identified in the nematode, and that they will be predictive of similar functionally significant responses in mammals. Available data support the belief that interactions leading to apoptosis will be maintained at a high level when studied across phylogeny. We hypothesize that identification of the genes which control anesthetic induced neurotoxicity will target molecules that can inhibit this phenomenon and guide research for safer anesthetic exposure in children. PUBLIC HEALTH RELEVANCE: Volatile anesthetics have been shown to induce neurotoxicity in the central nervous system of several mammalian species, possible including humans. Little is known about how this neurotoxic effect is initiated. We propose to identify the genes important in this response using a genetic approach in the nematode, C. elegans.