吲哚胺2，3双加氧酶在术后认知功能障碍作用及机制的研究

术后认知功能障碍(POCD)严重影响术后患者恢复，增加死亡率，然而其发病机制仍不清楚。本课题组前期研究发现，麻醉手术后大鼠体内炎症因子，吲哚胺2，3-双加氧酶(IDO)表达增加，并与POCD的发生呈正相关。IDO是首个肝外催化色氨酸分解代谢的限速酶，与很多神经感染性疾病密切相关。本项目拟利用小鼠及原代培养神经元证明，麻醉手术导致的炎症因子释放，通过诱导IDO过表达，促进喹啉酸等神经毒性代谢产物及活性氧的积聚，介导线粒体通路相关的神经元凋亡，最终导致POCD的发生。进而分别利用基因和药理学方法使小鼠和神经元IDO低或过表达，观察IDO表达改变后，POCD发生率或神经元凋亡是否改变，从另一角度对IDO在POCD发病机制中的作用深入探讨。以上问题的解决将使我们从新的角度和深度揭示POCD的作用机制，启发我们通过抑制IDO过表达来防治POCD，为临床提供全新的、具有良好应用前景的治疗靶点。

Post-operative cognitive dysfunction (POCD) is one of the most common post-operative complications in older patients, and is associated with substantially increased morbidity, mortality, and cost of care. Many studies have demonstrated that pro-inflammatory cytokines, induced by anesthesia and/or surgery, can contribute to the development of POCD. However, the underlying mechanism by which the pro-inflammatory cytokines promote POCD development is unknown. Consistent with the notion that pro-inflammatory cytokines can increase expression of IDO, a rate-limiting enzyme of kynurenine pathway which converts tryptophan into kynurenine in extrahepatic tissues, our preliminary studies suggest that IDO can induce neurotoxicity, potentially through generation of its toxic metabolits, including quinolinic acid and 3-hydroxykynurenine. Collectively, the hypothesis of the proposed studies is that accumulation of IDO by inflammation produces neurotoxic metabolites, which result in ROS-associated mitochondrial pathway of neuron apoptosis, contributing to POCD pathogenesis and leading to impairment of learning and memory. We will use in vitro (primary neurons) and in vivo (mice) approach with both genetic and pharmacological tools to test the hypothesis and to determine the role of IDO in POCD. The outcomes from the proposed studies would significantly contribute to our understanding of the POCD neuropathogenesis, leading to targeted interventions of POCD in the future.