Toxic Effects of Anesthetics in Developing White Matter

麻醉药对白质发育的毒性作用

• 批准号: 10372991
• 负责人: Cyrus David Mintz
• 金额: $ 36.03万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10372991
• 关键词: Ablation; Action Potentials; Address; Adult; Affect; Amyotrophic Lateral Sclerosis; Anesthesia procedures; Anesthetics; Animal Experimentation; Animal Model; Area; Axon; Behavior; Biological; Brain; Caring; Cell Death; Cell Transplantation; Cell physiology; Cells; Child; Childhood; Clinical Trials; Cognition; DNA; DNA Methylation; DNA Modification Methylases; DNA Sequence; Data; Demyelinating Diseases; Development; Disease; Electron Microscopy; Elements; Ensure; Epigenetic Process; Exposure to; Fetal Development; General Anesthesia; Genetic Transcription; High-Throughput Nucleotide Sequencing; Homeostasis; Human; Iatrogenesis; Image; Immunohistochemistry; Immunoprecipitation; Impairment; Injury; Intelligence; Laser Microscopy; Lead; Life; Methylation; Molecular; Multiple Sclerosis; Mus; Myelin; Nervous System Physiology; Nervous system structure; Neurocognitive; Neuroglia; Neurologic; Neurologic Deficit; Neurons; Neurosciences; Oligodendroglia; Pathology; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Population; Prevention strategy; Primates; Publishing; Recovery; Regenerative capacity; Repeat Surgery; Research; Research Design; Research Personnel; Risk; Rodent; Sedation procedure; Signal Transduction; Source; Stroke; Techniques; Testing; Third Pregnancy Trimester; Toxic effect; Toxicity Tests; Transgenic Mice; Traumatic Brain Injury; United States Food and Drug Administration; Vulnerable Populations; Work; adverse outcome; base; behavior test; brain circuitry; cell type; classical conditioning; cytotoxic; design; epidemiology study; epigenetic regulation; experimental study; gene delivery system; human embryonic stem cell; human stem cells; in vivo; infancy; injury recovery; innovation; methylome; model design; mouse model; multiphoton microscopy; myelination; neurotoxicity; nonhuman primate; novel; oligodendrocyte precursor; postnatal; postnatal development; precursor cell; pregnant; prevent; real-time images; restoration; sedative; tool; transmission process; treatment strategy; two-photon; white matter

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.

项目概要 基于来自人类流行病学研究和动物研究的最佳可用证据 在啮齿动物和非人类灵长类动物中进行的研究，美国食品和药物管理局已发出警告 在妊娠晚期和怀孕期间反复和/或长时间接触麻醉剂和镇静药物 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 可能产生长期后果仍不清楚。几乎所有先前关于该主题的研究都已 重点关注神经元，但大脑电路的正常功能也严重依赖于其他细胞类型。 在哺乳动物的胎儿和产后发育过程中，少突胶质细胞 (OL) 分化为 少突胶质细胞前体细胞 (OPC) 并生成髓磷脂，髓磷脂隔离轴突以确保高保真度 电信号的传输。因此，开发 OL 代表了一种高度合理且在很大程度上 尚未探索的麻醉神经毒性新靶点。我们建议检验早期的中心假设 全身麻醉 (GA) 的发育暴露会破坏髓磷脂，从而干扰大脑发育 形成。首先，我们将通过确定哪些常用的 GA 来评估该假设的总体影响 干扰髓鞘形成，识别由于髓鞘形成受损而导致的 GA 诱导的神经功能缺陷，以及 测试 GA 对人类 OL 发育的影响。我们的初步数据表明 GA 会干扰 OPC 的功能，OPC 是一组对发育至关重要的前体细胞 髓鞘形成。因此，我们将检验 GA 通过抑制存活在细胞水平发挥作用的假设， OPC 的增殖、分化和/或稳态相互作用。最后，我们将检验以下假设： GA 通过抑制调节 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，双光子体内实时成像和细胞消融，以及高通量测序 甲基化组。该提案的实验有望定义一种全新的麻醉机制 毒性。成人神经系统概括了髓磷脂发育的许多要素，作为神经系统的关键部分。 防御脱髓鞘疾病（如多发性硬化症和肌萎缩症）的破坏性影响 侧索硬化症，也是从脑外伤和中风等致残性损伤中恢复的一个关键特征。 因此，我们的研究结果对于怀孕患者和幼儿以及大量人群具有重要意义 患有髓磷脂相关病理的成年患者。加深对麻醉剂如何影响髓磷脂的了解 此处获得的信息将使研究人员能够设计评估麻醉剂和/或镇静剂风险的研究 对潜在易受影响的患者进行暴露，并测试预防和治疗策略以减轻伤害 对于那些处于危险中的患者。