未折叠蛋白反应在POCD及其向阿尔茨海默病转化机制中作用及干预研究

Along with the increase of aged population in China, the number of surgery in aged patients is also surging. However, aged patients are susceptible to suffering from postoperative cognitive dysfunctions (POCD), which may develop into alzheimer’s disease in the future. Nevertheless, the underlying mechanisms of POCD are unclear and the effective curative measurements are still lacking. Accumulating evidence has shown that unfolded protein response (UPR) plays significant roles in the development of numerous age-related neurodegenerative diseases. Our preliminary study found that the inhibition of unfolded protein response in in vitro aged neural stem cells (NSCs) model could attenuate isoflurane-induced decrease in NSCs proliferation. Therefore our program is intended to investigate the roles of unfolded protein response in the development of POCD in aged animals and explore the potential therapeutic targets on unfolded protein response for curing POCD and preventing against the transition of POCD towards alzheimer’s disease. Firstly, we will detect the alterations of different arms of unfolded protein response in multiple brain regions of aged animals after surgery. Secondly, we will illuminate the detailed roles of these alterations of unfolded protein response in the development of POCD. Finally, by regulating the key effectors of unfolded protein response, we will determine the best therapeutic time point and targets to cure POCD and prevent against the transition of POCD towards alzheimer’s disease. In summary，all the designed experiments are conducted to elucidate the role of unfolded protein response in the development of POCD and provide a new prospective for prophylaxis and medication of the POCD in aged population.

我国已进入老龄化社会，老年患者手术量不仅逐年增加，而且术后极易出现认知功能障碍（POCD），甚至远期转化为阿尔茨海默病。但老年患者POCD发生的确切机制尚不明确，有效预防治疗措施极为有限。文献报道，未折叠蛋白反应（UPR）在老年相关认知功能障碍疾病机制中发挥重要作用。本课题组前期研究发现，老年大鼠吸入异氟烷后，其海马与UPR相关信号通路显著激活且tau蛋白磷酸化加重，同时发现抑制未折叠蛋白反应（UPR）可逆转异氟烷麻醉所致老龄化神经干细胞增殖分化能力减退。因此，本项目拟从内质网、细胞、整体动物水平，探讨手术、麻醉后未折叠蛋白反应变化，揭示未折叠蛋白反应在POCD发生机制中的作用，并筛选出可能的干预靶点，探索预防和治疗手术麻醉所致POCD及POCD向阿尔茨海默病转化的新措施。该课题不仅有助于进一步揭示老龄患者术后POCD的发病机制，而且为早期预防和治疗这种严重神经并发症的新策略提供理论依据。

随着老龄化社会的到来，越来越多的老年患者经历麻醉和手术，而研究表明老年患者术后极易出现认知功能障碍（POCD），甚至远期转化为阿尔茨海默病，给社会，家庭和个人带来严重负担。本课题主要从内质网，细胞以及整体动物水平研究和探讨麻醉和手术后未折叠蛋白反应（UPR）改变情况，同时通过相应工具药物揭示未折叠蛋白反应在麻醉和手术所致认知功能障碍中的作用及机制，筛选出参与该过程的相关信号通路及干预靶点。结果表明，麻醉和手术会导致认知功能障碍，UPR过度激活，同时会促进凋亡和炎症反应的发生。通过相关工具药物的干预下调UPR中应激感受器PERK、IRE1的表达可降低UPR的过度激活，同时改善麻醉和手术所致认知功能障碍。以上研究进一步揭示了老龄患者POCD的发生机制，同时为POCD的早期预防和治疗提供了理论依据和新的思路。

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