lncRNAs and Anesthetic-Induced Developmental Neurotoxicity

lncRNA 和麻醉诱导的发育神经毒性

• 批准号: 10382813
• 负责人: Xiaowen Bai
• 金额: $ 21.7万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10382813
• 关键词: 3-Dimensional; Acute; Address; Adverse effects; Affect; Age; Anesthesia procedures; Anesthetics; Animals; Brain; Cell Death; Child; Childhood; Data; Data Collection; Development; Dose; Electrophysiology (science); Equipment; General anesthetic drugs; Genetic Transcription; Goals; Human; In Vitro; Memory impairment; Molecular; Movement; Mus; Neonatal; Neurons; Productivity; Propofol; Research; Role; Safety; Slice; Structure; System; Tissues; United States Food and Drug Administration; Untranslated RNA; clinically relevant; developmental neurotoxicity; human stem cells; improved; induced pluripotent stem cell; insight; mouse model; neuron loss; novel; sevoflurane; stem cell model

PROJECT SUMMARY In 2016, the U.S. Food and Drug Administration warned that repeated or lengthy use of general anesthetics in children below the age of three might affect their brain development. This warning raises serious concerns regarding the safety of pediatric anesthesia. There are two main barriers in the research field of anesthetic- induced developmental neurotoxicity (AIDN): 1) So far, most of the evidence for AIDN was obtained from animal studies. The results from human studies remain inconclusive. 2) The mechanisms are largely unknown. The goal of this study is to address both of these barriers by using an in vitro system of three-dimensional (3D) human mini brains generated from induced pluripotent stem cells and mouse models to study novel mechanisms of long non-coding RNAs (lncRNAs). Human mini brains are more similar to developing human brains, both structurally and functionally, than the widely used 2D neurons. Our preliminary data provided the first evidence showing that clinically relevant doses of propofol and sevoflurane, two commonly used pediatric anesthetics, induced acute cell death in human mini brains. We also found that neonatal propofol exposure altered lncRNA expression profiles and caused multiple adverse effects in mice (E/I imbalance, neuronal death, and impaired memory function). Our exciting findings suggest that the abnormally expressed lncRNAs might contribute to AIDN. Thus, we will examine the role and mechanism of lncRNAs in AIDN such as abnormal neuronal activity and networks using both human mini brain and mouse models. The HyperCAM Alpha equipment would significantly improve our productivity and capacity by enabling high throughput, detailed data collection of our electrophysiological studies on 3D human mini brains and mouse tissue slices. This proposal is expected to provide new molecular and electrophysiological mechanistic insights into the neurodevelopmental consequences of pediatric anesthetic exposure. This will further aid in the development of more rational neuroprotective strategies related to pediatric anesthetic use, and movement towards a better assurance of safety for pediatric anesthesia use.

项目摘要 2016年，美国食品和药物管理局（FDA）警告说，在麻醉过程中反复或长时间使用全身麻醉药， 三岁以下的儿童可能会影响他们的大脑发育。这一警告引起了严重关切 关于小儿麻醉的安全性麻醉药研究领域存在两大障碍- 诱导的发育神经毒性（AIDN）：1）到目前为止，大多数AIDN的证据来自于 动物研究。人类研究的结果仍然没有定论。2)其机制在很大程度上是未知的。 本研究的目标是通过使用三维（3D）体外系统来解决这两个障碍。 从诱导多能干细胞和小鼠模型中产生的人类迷你大脑， 长链非编码RNA（lncRNA）人类的迷你大脑更类似于发育中的人类 大脑，无论是结构上还是功能上，都比广泛使用的2D神经元要好。我们的初步数据提供了 第一个证据表明异丙酚和七氟烷（两种常用的儿科药物）的临床相关剂量 麻醉剂，诱导人类微型大脑的急性细胞死亡。我们还发现新生儿异丙酚暴露 改变lncRNA表达谱并在小鼠中引起多种副作用（E/I失衡，神经元死亡， 记忆功能受损）。我们令人兴奋的发现表明，异常表达的lncRNA可能 有助于艾滋病。因此，我们将研究lncRNA在AIDN中的作用和机制，如异常的 使用人类迷你脑和小鼠模型的神经元活动和网络。HyperCAM Alpha 设备将通过实现高吞吐量、详细的数据， 收集了我们对3D人类迷你大脑和小鼠组织切片的电生理研究。这项建议 有望提供新的分子和电生理机制的见解， 小儿麻醉剂暴露的神经发育后果。这将进一步促进 与儿科麻醉剂使用相关的更合理的神经保护策略，以及朝着更好的 确保儿科麻醉使用的安全性。