中药肝豆汤改良方调控PKR/eIF2α通路改善Wilson病模型TX小鼠突触功能障碍的机制研究

突触功能障碍是神经系统疾病的重要致病机制之一，研究证实高铜可激活PKR/eIF2α通路降低突触蛋白表达，诱导突触功能障碍，损伤认知功能。Wilson病(Wilson’s disease, WD)是一种可治性遗传性铜代谢障碍疾病，铜离子在脑内认知相关区域沉积是脑型WD患者出现认知功能障碍的主要原因。我们发现中药肝豆汤改良方可改善神经元损伤，减轻WD模型TX小鼠认知功能障碍，推测肝豆汤改良方可能调控PKR/eIF2α通路阻断高铜诱导的突触功能损伤，从而发挥神经保护作用。为此，本研究拟以TX小鼠为WD动物模型，基于PKR/eIF2α通路探究肝豆汤改良方改善高铜诱导突触功能障碍的作用靶点，旨在从干预突触功能障碍的角度为肝豆汤改良方治疗脑型WD患者认知功能障碍提供理论依据，为中医药治疗神经系统疾病提供新的研究及治疗思路。

Synaptic dysfunction is one of the important pathogenetic mechanisms of nervous system diseases. Evidence shows Chronic Cu exposure might activate PKR/eIF2α signaling pathway, reduce synaptic protein expression, induce synaptic dysfunction, and cause memory impairment. Wilson’s disease (WD) is an autosomal recessive inherited disorder of copper (Cu) metabolism. The main cause of cognitive impairment for WD patients is Cu accumulation. We reported that the TCM Modified Gan Dou decoction (MGDD) improved the neuron damage, and alleviated the cognitive function. Meanwhile, MGDD protect the neuron from Cu-induced cell death in the brain of rodent models of WD. Therefore, we assume that the presence of MGDD may inhibit Cu-induced synaptic dysfunction and subsequent neurotoxicity through decrease the activation of PKR/eIF2α signaling pathway. TX mice which are rodent model of WD will be used to study the regulatory mechanism of Modified Gan Dou decoction on synaptic dysfunction induced by high Cu through PKR/eIF2α signaling pathway. Therefore, this project will provide theoretical basis of Modified Gan Dou decoction for treatment of WD patient with cognitive impairment. Besides, this project may provide new therapeutic targets and the research ideas for the prevention and treatment of neurodegeneration disease and disease with cognitive impairment with Chinese medicine.