Toxic Effects of Anesthetics in Developing White Matter

麻醉药对白质发育的毒性作用

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要基于人类流行病学研究和动物研究的最佳证据美国食品药品监督管理局在啮齿动物和非人类灵长类动物中进行了警告重复和/或长时间暴露于第三个孕期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。这些短效药物的机制可能会产生长期后果，尚不清楚。几乎所有关于此主题的研究都是专注于神经元，但是脑电路的正确功能也很大程度上取决于其他细胞类型。在哺乳动物物种之间的胎儿和产后发育期间，少突胶质细胞（OLS）与少突胶质细胞前体细胞（OPC）并产生髓磷脂，该细胞可以隔离轴突以确保高前进性电信号的传输。因此，开发OLS代表一个高度合理的，很大程度上未开发的麻醉神经毒性的新型靶标。我们建议测试早期的中心假设发育性暴露于全身麻醉（GA）通过破坏髓磷脂来干扰大脑发育形成。首先，我们将通过确定哪些常用气体来评估该假设的总体影响干扰髓鞘，鉴定出髓鞘障碍和测试气体对人OL发育的影响。我们的初步数据表明气体干扰 OPC的功能，它是对发育至关重要的前体细胞池髓鞘。因此，我们将通过抑制生存率来检验气体在细胞水平上起作用的假设， 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气体通过抑制调节的DNA序列的甲基化在分子水平上发挥表观遗传作用髓鞘形成所需的基因的转录。为了解决这些问题，我们的研究将采用创新，尖端的实验神经科学工具，包括人类胚胎干细胞，条件转基因小鼠，体内实时成像和细胞消融的两光子，以及高吞吐量测序甲基组。预计该提案的实验将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元素，作为关键的一部分防御脱髓鞘疾病（如多发性硬化症和肌萎缩）的毁灭性影响横向硬化症，也是使脑外伤和中风等损伤恢复的关键特征。因此，我们的发现对于孕妇和幼儿而言将很重要，也对大量人口很重要患有髓磷脂相关病理的成年患者。对麻醉剂如何影响髓鞘的增强理解这里获得的形成将使研究人员能够设计评估麻醉和/或镇静剂风险的研究潜在脆弱患者的暴露，并测试预防性和治疗策略以减轻伤害对于那些有危险的患者。