Neurotoxic Effects of Volatile Anesthetics in C. elegans

描述（由申请人提供）：自发明以来，挥发性麻醉剂一直被认为是中枢神经系统的良性抑制剂。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，特别是在婴儿接受全身麻醉的护理方面。挥发性麻醉药现已被证明能引起发育中的大鼠脑中的细胞凋亡性神经元退化。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显示的那样（见研究设计），我们已经在模式生物秀丽隐杆线虫中建立了类似的效应。在本提案中，我们将确定负责在麻醉暴露后神经系统发育的神经毒性启动的基因。为了实现这一目标，我们将筛选线虫的全基因组RNAi文库，秀丽隐杆线虫。这些基因将被测试其调节麻醉引起的神经毒性的能力。我们假设，新的重大发现，以前未被怀疑的分子靶点，启动神经元变性将在线虫中被确定，他们将预测在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，即当研究跨系统发育时，导致细胞凋亡的相互作用将保持在高水平。我们假设，对控制麻醉诱导神经毒性的基因的鉴定将针对能够抑制这种现象的分子，并指导对儿童进行更安全的麻醉暴露的研究。

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.