七氟烷通过CircRNAs调控CREB信号通路改善新生大鼠脑缺血缺氧损伤所致精神发育迟滞的作用及机制研究

There is still lack of effective treatment of mental retardation (MR) resulting from neonatal hypoxic-ischemic brain injury (HIBI) in clinic. Sevoflurane improves HIBI-induced MR, however, the involved mechanism of which is still unclear. Our previous findings showed that sevofurane postconditions increased the expression of CREB in hippocampus, which was positively related to the improvement of MR. In addition, circRNAs accumulated during brain injury and their high stability could lead to a long-term effect in injured brain. So we hypothesize: sevoflurane improves HIBI-induced MR by down-regulating the relevant circRNAs, which then ameliorates the long-term inhibition of CREB in HIBI-induced MR. In our present study, the hippocampal neuron of neonatal OGD rats will be used to find the relevant circRNA affected significantly by sevoflurane postconditions. The regulation of circRNAs on CREB will be verified through transfection experiments of amplification and inhibition and the effect of circRNAs on MR will be confirmed in vivo. Through the viewpoint of circRNA, our study is aimed to investigate the involved mechanism by which sevoflurane improves HIBI-induced MR at a molecular and cellular level and confirm the regulation of CREB by circRNAs, which will provide a new therapeutic target on HIBI-induced MR.

新生儿脑缺血缺氧损伤（HIBI）所致精神发育迟滞(MR)，目前临床上仍缺乏有效的治疗方法。七氟烷可改善新生大鼠HIBI所致的MR，但该作用的调控机制仍不明确。前期研究发现，七氟烷后处理提高了海马区CREB的水平，而CREB的高表达与MR的改善作用明确相关。同时，circRNAs在脑损伤期间大量聚集，其高稳定性可带来长期的影响作用。因此，我们提出假说：七氟烷后处理通过下调新生大鼠HIBI相关circRNAs而减少对CREB表达的长期抑制，进而改善MR。我们拟通过OGD新生大鼠海马神经元验证与七氟烷作用关系密切的circRNAs，通过转染扩增和抑制实验验证相关circRNAs和CREB的调控关系，并在体证实其对MR的影响。本研究将通过circRNAs这个新视点，探讨七氟烷改善新生大鼠HIBI所致MR的机制；明确circRNAs对CREB表达的调控，寻找MR治疗的新靶点。

新生儿脑缺血缺氧损伤（HIBI）所致精神发育迟滞(MR)，目前临床上仍缺乏有效的治疗方法，尤其是对于其导致的青春期MR仍停留在康复治疗水平。深入研究新生儿HIBI和其所致的MR的分子生物学机制，并找到理想的防治方法极具现实意义。七氟烷可改善新生大鼠HIBI所致的MR，但该作用的调控机制仍不明确。前期研究发现，七氟烷后处理提高了海马区CREB的水平，而CREB的高表达与MR的改善作用明确相关。同时，circRNAs在脑损伤期间大量聚集，其高稳定性可带来长期的影响作用。我们通过OGD新生大鼠海马神经元验证与七氟烷作用关系密切的circRNAs，通过转染扩增和抑制实验验证相关circRNAs和CREB的调控关系，并在体证实其对MR的影响。本研究验证了经生物学分析预测的与新生大鼠HIBI密切相关并在七氟烷后处理下发生明显变化的circRNAs；明确了在新生大鼠OGD海马神经元和七氟烷后处理下的circRNAs、miR-132与CREB信号通路表达之间的调控关系,同时Notch信号通路和Wnt信号通路对细胞分化、老化和凋亡也具有重要的调控作用；明确了CREB信号通路在新生大鼠HIBI所致的MR发生和七氟烷后处理对MR的改善作用中的关键作用,即七氟烷后处理通过下调新生大鼠HIBI相关circRNAs而减少对CREB表达的长期抑制，进而改善MR。本研究通过circRNAs 这个新视点，获得了新生大鼠HIBI和七氟烷后处理的神经保护作用在基因层面的深入了解，发现与损伤和保护相关的“生物标记物”；弄清了 circRNAs、miRNAs 与 CREB信号通路表达之间的关系，及其与新生大鼠HIBI所致的MR和七氟烷的长期保护作用的关系。对新生脑HIBI所致MR的发生机制，描绘出一个连续的网络，同时为新生儿HIBI所致的MR的预防和治疗提供新的思路和靶点。