七氟醚麻醉致婴幼儿远期认知功能障碍的新机制：miRNA-30e介导的自噬研究

The mechanism of forward cognitive dysfunction caused by sevoflurane anesthesia in infancy is unclear. During our early study, we found that miR-30e was a highly homologous microRNA between human and rat, which was lower expressed in hippocampus of sevoflurane anesthetic young rat; the low expression of miR-30e in hippocampus could lead to forward cognitive disorder in rat; through the software analysis and our study, we found that the autophagy gene Beclin1 was the target gene of miR-30e, which was also highly expressed in hippocampus of sevoflurane anesthetic rat; literatures reported that the autophagy mediated by Beclin1 could influence the cognitive ability, which prompted that miR-30e might influence the cognitive ability of rat that was sevoflurane anesthetic in infancy through regulating the expression of Beclin1. The study will systematically demonstrate this scientific problem as follows: intending to observe the correlation between the expressions of miR-30e in different condition of sevoflurane anesthetic young rat and forward cognitive ability; estimating the influence of different expressions of miR-30e to the cognitive ability of sevoflurane anesthetic or normal young rat in vivo; demonstrating the mechanism of cognition through the influence of miR-30e to Beclin1 in hippocampal neuron. There is no report on the mechanism of cognitive ability in sevoflurane anesthetic young rat by the regulation of miR-30e to Beclin1, so this study will provide a new theory of preventing the forward harm of sevoflurane anesthesia in clinical.

婴幼儿期七氟醚麻醉致远期认知功能障碍的机制未明。我们前期发现，人鼠高度同源的miRNA-30e，差异低表达于七氟醚麻醉幼鼠海马；海马miRNA-30e表达沉默可致大鼠远期认知障碍；软件分析和实验发现自噬基因Beclin1为miRNA-30e靶基因，在七氟醚麻醉大鼠海马中也显著上调；文献报道Beclin1介导的自噬可影响认知功能，提示miRNA-30e可能通过调节Beclin1而影响幼年七氟醚麻醉大鼠远期认知能力。研究拟观察幼鼠七氟醚不同暴露条件下miRNA-30e表达与远期认知功能的相关性；在体评价miRNA-30e表达变化对七氟醚麻醉或正常幼鼠远期认知功能的影响；海马神经元层面论证miRNA-30e影响认知的Beclin1机制，来系统论证这一科学问题。miRNA-30e调节Beclin1影响幼年大鼠七氟醚麻醉远期认知的机制未见报道，研究将为临床七氟醚麻醉远期危害的防治提供新理论。

全世界每年有数以百万计的婴幼儿因手术需要接受麻醉治疗。婴幼儿阶段是神经系统发育的敏感期和高峰时期，与成人相比其中枢神经系统更容易受到麻醉的损害。这种因麻醉所引起的神经毒性反应将会对其智力发育、学习能力、以及成年后认知造成极大影响，因此已不仅仅是一个重要的医学问题，而且已成为一个广泛关注的社会问题。然而，七氟醚麻醉致婴幼儿远期认知功能障碍的发病机制至今尚未明确且治疗手段有限。.本课题主要就miRNA-30e在七氟醚麻醉致幼年大鼠远期认知能力障碍中作用，揭示其调控Beclin1表达致七氟醚麻醉幼年大鼠远期认知障碍的自噬机制。主要研究内容包括：（1）七氟醚异吸入麻醉认知障碍幼年大鼠海马组织中差异miRNAs；（2）miRNA-30e 和miR-155致幼年大鼠远期认知功能障碍探索；（3）miRNA-30e与Beclin1的相关性研究；（4）miRNA-30e调控Beclin1表达致七氟醚麻醉幼年大鼠远期认知障碍的自噬机制研究。此外，我们也研究了其围术期认知功能障碍相关性疾病的分子机制。.通过以上研究我们得出一些重要结果和关键数据：（1）人鼠高度同源的miRNA-30e，差异低表达于七氟醚麻醉幼鼠海马；海马miRNA-30e表达沉默可致大鼠远期认知障碍；（2）软件分析和实验发现自噬基因Beclin1为miRNA-30e靶基因，在七氟醚麻醉大鼠海马中也显著上调；（3）miRNA-30e可能通过调节Beclin1而影响幼年七氟醚麻醉大鼠远期认知能力。同时，我们也研究老年术后认知功能障碍（过氧化物酶体增殖物激活受体介导的过度炎症反应在认知功能障碍中发挥重要作用）、脓毒症相关性脑病（海马β-微球蛋白介导突触功能障碍负性调节脓毒症相关性脑病认知功能）及创伤应激障碍（微清蛋白中间神经元在创伤应激障碍中的关键细胞机制）的相关发生机制，已发表SCI论文3篇，实用新型专利2项。