lncRNA-Rik/miR-96/Sox6信号轴在七氟烷引起的神经发育毒性作用中的机制研究

Multiple and long time general anesthesia by using inhalation anesthetics for young children which influence the brain neural development and long-term cognitive function of infants and children has been widely concerned. There’re many kinds of neural development related gene expression changes during this process. But whether there’re the non-coding RNAs, the critical regulator of gene expression, participate in the regulatory process still remain largely unknown. In this study, we treated the young mice by clinical concentration 3% sevoflurane for a 3 consecutive days in 2 hours a day and performed the RNA-seq of the gene expression of hippocampus in mice. We found that the homologous LncRNA-Rik was significantly downregulated. Sevoflurane treatment or knock down of the LncRNA-Rik can restrain the neural differentiation drived from mouse embryonic stem cells. Overexpression of LncRNA-Rik can alleviate the effects of sevoflurane.LncRNA-Rik bind with the downstream miR–96 which showed homologous sequence of macaque .MiR-96 targeted Sox6 and inhibited its expression, thereby inhibiting mice neural differentiation in vitro. The inhibition of miR-96 can alleviate the effects of sevoflurane. We thought that sevoflurane inhibits neural differentiation through the LncRNA-Rik/miR-96 / Sox6 signal pathway, eventually lead to nerve damage in the process of brain development and cause cognitive dysfunction and other problems. We will further detect that whether donwregulation of LncRNA-Rik induced the cognitive impair in mice and whether overexpression of LncRNA-Rik can alleviate the influence of sevoflurane on cognitive impairment. We also will study the sevoflurane influencing the neural differentiation from human embryonic stem cells to determine the function of LncRNA-Rik/miR-96/Sox6 signal axis. This study will provides the novel drug target for relieving or eliminating the neural development impair caused by multiple and long time sevoflurane anesthesia.

多次或长时间手术过程中，全身麻醉药物对婴幼儿大脑早期发育和远期的毒性影响是临床关注的焦点。但因机制并不明，影响了进一步的靶向治疗研究。预实验中发现，临床浓度七氟烷连续3天，每天2小时麻醉小鼠，其海马中LncRNA-Rik显著下调。七氟烷处理或敲低lncRNA-Rik均抑制小鼠体外神经分化。过表达LncRNA-Rik能缓解七氟烷的毒性。LncRNA-Rik可与下游人鼠同源的miR-96结合。miR-96靶向Sox6而抑制小鼠体外神经分化。我们认为七氟烷通过可能存在的LncRNA-Rik/miR-96/Sox6信号轴抑制小鼠神经分化，故将探索七氟烷是否通过调节该信号轴影响人的体外神经分化（人存在同源lncRNA-ECONEXIN），检测敲低LncRNA-Rik的小鼠认知功能，和过表达lncRNA能否回救七氟烷毒性作用。本研究将揭示七氟烷的神经发育毒性机理，并为该领域提供新的研究策略和治疗靶点。

本项目主要围绕麻醉手术造成大脑神经毒性，以及影响病人预后等方面开展研究。. 首先，我们针对国际广泛关注的全身麻醉药物对早期发育过程中产生神经毒性造成远期认知损伤的临床研究，以及美国FDA对全身麻醉药物的警告等问题研究全身麻醉药物七氟烷对神经发育的抑制作用及其机制。我们发现：七氟烷导致出生6天小鼠的大脑中lncRNA Rik-201/Rik-203表达降低。而敲除lncRNA Rik-201/Rik-203后，小鼠胚胎头部发育异常。进一步发现：lncRNA Rik-201，Rik-203分别通过调节miR-96，miR-467a-3p而靶向Sox6以调节胚胎干细胞向神经分化的过程。该研究不仅揭示了新的调节神经分化的lncRNA以及相关机制，而且指出了全麻药物神经毒性的机制之一，为未来治疗麻醉药物神经毒性提供理论基础。. 同时，针对麻醉药神经毒性和老年患者术后谵妄的关系问题，我们发现临床浓度的七氟烷通过上调小胶质细胞中ATP酶抑制因子1（ATPIF1）的表达，促进炎症因子分泌，激活caspase-3。ATPIF1的上调降低了可由小胶质细胞分泌并作为重要信号分子的ATP的合成。胞外补充ATP缓解七氟烷或ATPIF1过表达引起的小胶质细胞炎症反应和caspase-3激活。动物实验表明，腹腔注射ATP显著减轻七氟烷诱导的焦虑行为和记忆损伤。本研究表明：补充ATP可能是缓解POD的潜在临床治疗方法。. 另外，我们围绕麻醉领域另一重要问题，即不同麻醉药物对肿瘤病人术后转移复发影响的问题，针对最具争议的静脉麻醉药物丙泊酚开展研究并发现：丙泊酚可能通过GABAAR–TRIM21–Src信号通路调节结肠癌细胞向血管内皮细胞的黏附作用，促进循环肿瘤细胞在血管中对血管内皮细胞的黏附和进一步的定植，以最终促进肿瘤转移。该研究促进了临床对进一步研究丙泊酚麻醉下行结肠癌手术的临床实践讨论，为进一步优化术中用药提供了理论支持。.以上研究围绕麻醉学临床实践和科研的重要问题，揭示了麻醉在大脑、肿瘤中的作用及复杂机制，增强了麻醉学与神经科学、肿瘤学甚至其他相关学科的交叉合作，为共同解决麻醉手术造成的不良问题提供新的研究视角和理论支持。

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