lncRNAs and Anesthetic-Induced Developmental Neurotoxicity

项目总结

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.