自噬在术后认知功能障碍中的作用及机制研究

Postoperative cognitive dysfunction (POCD) causes the significant increase of mortality, and can seriously affect the quality of patients' life and their lives. it is a urgent thing to be solved. However, the mechanism of POCD has not yet been elucidated. Autophagy is a key catabolic process that degrades misfolded proteins and damaged organelles in cells, which is essential for cell homeostasis. Therefore, it appears to be more important for the nerve cells which are difficult to repair after injury. Our previous studies have demonstrated that autophagy activity reduces cerebral ischemic injury, showing that autophagy plays an important role for neuroprotection. Recent studies have reported that abnormal autophagy playing a crucial role in maturation of Alzheimer’s disease. In addition, we found that the expression of autophagy-related protein expression was decreased in hippocampus in rats undergoing POCD, and the activation of autophagy improved the cognitive impairment in rats after surgery, strongly suggesting that autophagy involves in postoperative cognitive impairment and may play a key role. Based on the previous studies, The present study aimed to investigate the regulatory role and possible molecular mechanism of autophagy in POCD, using siRNA interference technology and agonist, and the methods of functional analysis, morphology and molecular biology and so on. The present study will develop a new idea for the investigation of POCD. Moreover, it may provide a new theoretical basis for the clinical prevention and treatment as an effective target for POCD. These results have important theoretical and clinical significance.

术后认知功能障碍严重威胁患者的生命和生活质量，是亟待解决的科学问题，但发病机制远未阐明。自噬作为降解细胞内异常蛋白质、细胞器，维持细胞稳定的重要途径，对于损伤后难以修复的神经细胞尤其重要。2009年我们开始研究自噬在中枢神经系统中的作用，已证实诱导自噬能够减轻脑缺血再灌注损伤，表明自噬具有神经保护功能。近期有研究报道，自噬功能减退是阿尔茨海默病发病的重要机制，同时我们观察到，术后认知功能障碍大鼠海马组织中自噬相关蛋白的表达下降，诱导自噬可改善大鼠认知障碍，强烈提示自噬在术后认知功能障碍中起关键作用。本项目拟在前期研究的基础上，通过siRNA 干扰等技术，应用功能、形态、超微结构和分子生物学等综合方法，研究自噬对术后认知功能障碍的调控作用及分子机制。这将开拓术后认知功能障碍新的研究思路，为临床防治术后认知功能障碍提供新的理论依据，有效的作用靶点，具有重要的理论和临床意义。

术后认知功能障碍严重威胁患者的生命和生活质量，是亟待解决的科学问题，但发病机制远未阐明。自噬作为降解细胞内异常蛋白质、细胞器，维持细胞稳定的重要途径，对于损伤后难以修复的神经细胞尤其重要。2009年我们开始研究自噬在中枢神经系统中的作用，已证实诱导自噬能够减轻脑缺血再灌注损伤，表明自噬具有神经保护功能。本项目拟在前期研究的基础上，通过siRNA干扰等技术，应用功能、形态和分子生物学等综合方法，研究自噬对术后认知功能障碍的调控作用及分子机制。我们的研究结果发现：自噬活性降低是术后认知功能障碍重要发病机制之一，术后认知功能障碍老年大鼠海马组织神经元中自噬减少，purmorphamine （PUR）通过调节自噬抑制POCD；过表达AMPKα1通过诱导AMPK-SirT1信号以及促进神经元自噬抑制七氟醚诱导和手术诱导的认知功能障碍；而Sirt1则通过调节Nrf2/HO-1抗氧化通路参与了异氟烷诱导的认知功能障碍。本研究为术后认知功能障碍的分子机制提供新的思路和证据，为POCD的临床防治提供了理论依据。