Toxic Effects of Anesthetics in Developing White Matter

项目总结 基于从人类流行病学研究和动物研究中获得的最佳证据 在啮齿动物和非人类灵长类动物中进行的这项研究，美国食品和药物管理局发布了警告 在怀孕的第三个月和第三个月之间，反复和/或长期接触麻醉剂和镇静剂药物 生命的第三年可能会对大脑发育产生不利影响。这些短效药物的作用机制 可能产生的长期后果目前尚不清楚。以前几乎所有关于这一主题的研究都是 然而，大脑回路的正常功能也严重依赖于其他类型的细胞。 在哺乳动物的胎儿和出生后发育过程中，少突胶质细胞(OLs)与 少突胶质前体细胞(OPC)和产生髓鞘，它隔离轴突以确保高保真 电信号的传输。因此，发展在线学习是一种很有可能而且在很大程度上 未探索的麻醉剂神经毒性的新靶点。我们建议检验核心假设，即早期 发育过程中暴露于全身麻醉(GA)会破坏髓鞘，从而干扰大脑发育 队形。首先，我们将通过确定哪种常用气体来评估这一假设的总体影响 干扰髓鞘形成，识别由于髓鞘形成受损而导致的GA诱导的神经缺陷，以及 测试GAS对人类OL发育的影响。我们的初步数据显示气体干扰了 OPC的功能，这是一个前体细胞池，对发育至关重要 髓鞘形成。因此，我们将测试气体通过抑制存活在细胞水平上发挥作用的假设， OPC的增殖、分化和/或内环境平衡相互作用。最后，我们将检验假设 GAS通过抑制DNA序列的甲基化在分子水平上发挥表观遗传效应 髓鞘形成所需基因的转录。为了解决这些问题，我们的研究将采用创新的、 尖端实验神经科学工具，包括人类胚胎干细胞，条件转基因 小鼠，体内双光子实时成像和细胞消融，以及高通量测序 甲基组。这一提议的实验有望定义一种全新的麻醉机制 毒性。成人神经系统重述了髓鞘发育的许多要素，作为 防御多发性硬化症和肌萎缩症等脱髓鞘疾病的破坏性影响 侧索硬化症是从脑创伤和中风等致残性损伤中恢复的一个关键特征。 因此，我们的研究结果对孕妇和幼儿以及广大人群都具有重要意义。 患有髓鞘相关病理的成人患者。对麻醉药如何影响髓鞘的进一步了解 在这里获得的形成将使研究人员能够设计评估麻醉剂和/或镇静剂的风险的研究 潜在易感患者的暴露，并测试预防和治疗策略以减轻伤害 给那些处于危险中的病人。

PROJECT SUMMARY Based on the best available evidence derived from human epidemiologic studies and animal research conducted in rodents and non-human primates, the U.S. Food and Drug Administration has issued a warning that repeated and/or lengthy exposures to anesthetic and sedative drugs between the third trimester and the third year of life may adversely affect brain development. The mechanism by which these short-acting drugs could have long-term consequences remains unclear. Nearly all previous research on this topic has been focused on neurons, however proper functioning of brain circuitry is also heavily dependent on other cell types. During fetal and postnatal development across mammalian species, oligodendrocytes (OLs) differentiate from oligodendrocyte precursor cells (OPCs) and generate myelin, which insulates axons to ensure high-fidelity transmission of electrical signals. Therefore, developing OLs represents a highly plausible and largely unexplored novel target for anesthetic neurotoxicity. We propose to test the central hypothesis that early developmental exposure to general anesthesia (GA) interferes with brain development by disrupting myelin formation. First, we will assess the overall impact of this hypothesis by determining which commonly used GAs interfere with myelination, identifying GA-induced neurologic deficits that result from impaired myelination, and testing the effects of GAs on human OL development. Our preliminary data suggests that GAs interfere with the function of OPCs, which are a pool of precursor cells that are critically important for developmental myelination. Thus, we will test the hypothesis that GAs act at the cellular level by inhibiting the survival, proliferation, differentiation, and/or homeostatic interactions of OPCs. Finally, we will test the hypothesis that GAs exert an epigenetic effect at the molecular level by inhibiting methylation of DNA sequences that regulate transcription of genes required for myelination. To address these questions, our study will employ innovative, cutting-edge experimental neuroscience tools, including human embryonic stem cells, conditional transgenic mice, two-photon in vivo real time imaging and cell ablation, and high throughput sequencing of the methylome. The experiments of this proposal are expected to define an entirely new mechanism of anesthetic toxicity. The adult nervous system recapitulates many elements of myelin development as a critical part of the defense against the devastating effects of demyelination disorders such as multiple sclerosis and amyotrophic lateral sclerosis and as a key feature of recovery from disabling injuries such as brain trauma and stroke. Thus, our findings will be significant for pregnant patients and young children, and also for the large population of adult patients with myelin-related pathology. The enhanced understanding of how anesthetics affect myelin formation gained here will allow researchers to design studies assessing the risks of anesthetic and/or sedative exposures in potentially vulnerable patients and to test preventative and treatment strategies to mitigate harm to those patients who are at risk.