Smad7及相关的长链非编码RNA在术后认知功能障碍中的作用及机制研究

Postoperative cognitive dysfunction (POCD) is a common and severe complication of elderly patients during perioperative period, and there is a crucial need to clarify its pathogenesis. Through combined analysis of the Arraystar Mouse lncRNA/mRNA Microarray, we have identified upregulation of Smad7 and associated long noncoding RNA (lncRNA), which we named lncRNA-TS, in the hippocampus of mice with POCD. Our previous study also found that downregulation of Smad7 through perioperative intracerebroventricular injection of Smad7 siRNA had significantly reduced cognitive dysfunction after unilateral nephrectomy in aged mice. This indicates that Smad7 and associated lncRNA may play a crucial role in the development of POCD. In this project, we will perform the experiments at the molecular, cellular, and tissue levels. Increase of Smad7 and lncRNA-TS levels and their relationship with the POCD will be verified. Also, we will explore the possible mechanisms for the development of POCD mediated by Smad7 and lncRNA-TS. Moreover, means of regulation of Smad7 by lncRNA-TS and related molecular mechanisms will be determined in our designed experiments. Besides, clinical study regarding the role of Smad7 and associated lncRNA in the development of POCD will be conducted in elderly patients. The successful implementation of this project will help to provide novel ideas and theoretical basis for the exploration of mechanisms of POCD pathogenesis and potential preventive and therapeutic strategies.

术后认知功能障碍（POCD）是老年患者围术期的常见和严重并发症，亟需明确其发病机制。我们前期通过Arraystar Mouse lncRNA/mRNA Microarray的联合分析，初步确定了POCD老年小鼠海马组织中表达上调的Smad7及相关的长链非编码RNA（lncRNA），命名为lncRNA-TS；同时围术期下调Smad7 （siRNA干扰）可显著改善老年小鼠行单侧肾切除术后的认知功能，这提示Smad7及相关lncRNA可能参与介导了POCD的发生。本课题拟进一步从整体、细胞和分子不同层面，明确围术期因素引起Smad7和lncRNA-TS的表达变化及其与POCD的关系，探讨Smad7和lncRNA-TS介导POCD发生的可能机制，阐明lncRNA-TS调控Smad7的作用方式及分子机制，并进行临床探索性研究。本项目的成功实施将为POCD的发病机制及防治措施提供新的思路和理论基础。

术后认知功能障碍（POCD）是老年患者围术期的常见和严重并发症，POCD的具体发病机制尚不完全清楚。找到POCD 的关键调控因子，探索相关信号通路，发现切实有效的干预靶点，对于有效防治POCD的发生发展至关重要。我们通过对POCD组和对照组小鼠海马组织进行Arraystar mRNA和lncRNA芯片的联合分析，寻找到了具有重要作用的分子Smad7及其相关的长链非编码RNA-lncRNA-TS。我们提出，在老年小鼠单肾切除POCD模型中中枢神经系统lncRNA-TS表达上调，正向调控了相关基因Smad7的表达，进而导致中枢系统炎症级联反应、神经细胞凋亡和海马突触可塑性损伤，最终导致POCD的发生。在POCD的发病过程中，海马组织CA1区的TGFβ1 水平、Smad7及lncRNA-TS均显著升高，我们利用多种动物神经认知行为学实验、海马立体定位注射AAV病毒及CRISPR/Cas9等技术证实降低Smad7及lncRNA-TS的表达均可改善小鼠的认知障碍及炎症凋亡发生情况。此外，临床研究结果也显示心脏手术后老年患者外周血lncRNA-TS与术后认知功能密切相关。综上，我们发现Smad7及其相关lncRNA-TS可能通过导致中枢免疫系统失衡、炎症级联反应、神经细胞凋亡和海马突触可塑性损伤，进而介导POCD的产生。此研究将为POCD的发生机制研究提供的新的方向和理论基础。