CREB-NR2B反馈调控过程对脑衰老相关胰岛素抵抗与TGF-β信号通路紊乱对话的作用及其在术后认知功能障碍中的意义

Brain aging related insulin signaling and TGF-β signaling disorders and postoperative cognitive impairment (POCD) are closely related, but its mechanism remains to be further explored. Our pre-experiment showed that CREB can bind to the cAMP response element in the NR2B promoter region, and NR2B mRNA levels could be decreased by CREB siRNA. Based on the above results, combined with the fact that CREB expression is regulated by NR2B and CREB could be activated by insulin signaling and TGF-β signaling, we hypothesize that positive feedback control between CREB and NR2B may aggravate senescence aging related insulin resistance and TGF-β signaling disturbance, and then inhibit CREB-NR2B feedback regulation process, thus promote the occurrence of POCD. This study was to further confirm the transcriptional regulation of NR2B by CREB and its effect on insulin signaling and TGF-β signaling, to demonstrate whether CREB mediates the regulation of NR2B by brain aging-related insulin signaling and TGF-β signaling, and to explore the significance of CREB-NR2B feedback in POCD. These studies will explore the basis for the aging of POCD from the key nodes of the dialogue between insulin signaling and TGF-β signaling, and provide new experimental evidences for clinical prevention and treatment of POCD in the elderly.

脑衰老相关胰岛素及TGF-β通路紊乱与术后认知功能障碍（POCD）密切相关，但其作用机制仍待进一步探讨。我室预实验发现，CREB可结合NR2B启动子区的cAMP反应元件；沉默CREB则降低NR2B mRNA水平。基于上述结果并结合NR2B可调控CREB表达及胰岛素与TGF-β通路可激活CREB这些事实，我们假设：CREB与NR2B间存在正反馈调控，麻醉手术可加剧衰老相关胰岛素抵抗及TGF-β信号通路紊乱，进一步抑制CREB-NR2B反馈调控过程，进而促进POCD发生。本研究拟进一步证实CREB对NR2B的转录调控及其对胰岛素与TGF-β通路的整合作用，论证CREB是否介导脑衰老相关胰岛素及TGF-β通路紊乱对NR2B的调控，探讨CREB-NR2B反馈调控在POCD中的意义。这些研究将从胰岛素与TGF-β两条通路对话的关键节点探索POCD的衰老基础，为临床防治老年POCD提供新的实验依据。

术后认知功能障碍(POCD)以术后学习记忆下降为主要特征，老龄是当前POCD研究唯一明确的独立风险因素。脑衰老相关胰岛素及TGF-β通路紊乱与POCD密切相关，但其作用机制仍待进一步探讨。本研究采用长时程异氟醚或麻醉复合胫骨骨折手术构建的POCD小鼠模型以及原代海马神经元和HT22细胞系，探索麻醉手术对衰老相关胰岛素抵抗与TGFβ信号通路的影响，并分析其对POCD发生的作用及可能机制。结果发现：1.长时程异氟醚麻醉可引起并加重小鼠外周及中枢胰岛素抵抗；2. 采用二甲双胍调控胰岛素抵抗可改善异氟醚诱导介导的认知功能障碍；3.胰岛素及TGFβ信号通路的单独或联合干预可改善不同年龄POCD小鼠术后认知功能，CREB-NR2B反馈通路可参与其机制联系。这些研究从胰岛素与TGF-β信号通路探索POCD的衰老基础，为临床防治老年POCD提供理论基础和潜在的干预靶点。