自噬在镧所致中枢神经系统神经细胞损伤中的作用及其机制研究

Lanthanum possesses neurotoxicity and can impact cognitive function. However, the mechanism underlying these adverse effects is not completely clear. Our previous work has shown that the impairment and even death of nerve cells in central nervous system via excessive autophagy induced by lanthanum may be the cytologic foundation of learning and memory defect caused by this chemical. Autophagy can eliminate toxic proteins and damaged organelles accumulated from cytoplasm, and provide energy and feedstock for cytothesis and reconstraction by way of lysosome-dependent degradation pathway, and is generally considered to be a self-repair and survival mechanisim as cells facing to stresses. But the excessive autophagy can also cause cell impairment and even death. Mammalian target of rapamycin ( mTOR ) is the main regulator of triggering autophagy, and oxidative stress and intracellular Ca 2＋overload have the positive regulation effects on autophagy. This study plans to elucidate the mechanisms underlying excessive autoghagy of nerve cells through investigating the activation disorder of mTOR related signaling pathways, oxidative stress and Ca 2＋overload induced by LaCl3 by experiments in vivo and vitro, with making use of techniques in neuroethology, histopathology, biochemistry and molecular biology. The results of this study will provide new scientific evidence for searching the molecular targets of effective intervention against the toxic action in central nervous system caused by lanthanum.

镧具有神经毒性，影响认知功能，其机制尚未完全阐明。我们的前期工作提示，镧通过诱发过度自噬进而导致中枢神经系统神经细胞损伤甚至死亡可能是其损害学习记忆的细胞学基础。自噬可通过溶酶体依赖途径将胞质内堆积的有毒蛋白与受损细胞器降解，为细胞修复、重建提供能量与原料，通常被视为细胞面对有害应激的自我修复和存活机制。但自噬水平过高则会造成细胞损伤甚至死亡。哺乳动物雷帕霉素靶蛋白（mTOR）是自噬发生的主要调控者，氧化应激与细胞内钙超载对于自噬具有正向调控作用。本研究拟采用整体动物与体外细胞培养相结合的方法，应用神经行为学、组织病理学、生物化学与分子生物学等技术手段，阐明镧通过干扰mTOR相关信号通路活化状态、诱发氧化应激和钙超载导致神经细胞过度自噬的作用机制，为寻找有效干预镧所致的中枢神经系统毒作用的分子靶点提供新的科学依据。

镧具有神经毒性，影响认知功能，其机制尚未完全阐明。自噬是一种广泛存在于真核细胞内的溶酶体依赖降解方式，可清除胞质内堆积的有毒蛋白与受损细胞器，并为细胞修复、重建提供能量与原料，通常被视为细胞面对有害应激的自我修复和存活机制。但自噬水平异常则会造成细胞损伤甚至死亡。本研究采用整体动物与体外细胞培养相结合的方法，应用神经行为学、组织病理学、生物化学与分子生物学等技术手段观察了镧对于中枢神经系统神经细胞自噬的影响并探讨其与学习记忆损害之间的关系。结果证实镧既可造成mTORC1相关调控信号紊乱而抑制该复合物的活性、又可通过诱发氧化应激和钙超载活化其下游信号通路，导致自噬过度增强，神经细胞结构与功能受损，由此损害学习记忆。这些结果为深入阐释镧的神经毒作用机制、寻找有效干预的分子靶点提供了新的科学依据。