基于ferroptosis调控通路的通腑养髓方对Wilson病模型TX小鼠神经元损伤的保护机制研究

Wilson disease (WD) is a treatable inherited disease characteristic by metabolic disorder of copper, however, many refractory WD patients with cerebral type acquired poor curative effects with decopper treatment and their working and living ability were badly damaged. Studies have confirmed that the unbalance of cellular iron homeostasis due to metabolic disorder of copper is an important mechanism for them and ferroptosis, an iron-dependent form of nonapoptotic cell death, was found to be in accord with the pathogenesis of neuron injury of WD. Because p62-Keap1-NRF2 is an important regulation pathway for ferroptosis, it is a potential therapeutic target for these patients.The applicant and his team members treated WD patients with cerebral type with Tongfu-Yangsui recipe on the basis of research results of the Syndrome Differentiation of TCM of WD and acquired perfect curative effects, the protection mechanisms of Tongfu-Yangsui recipe on neuron injury were studied subsequently. In this project, we assume that Tongfu-Yangsui recipe had the function of neuron protection which could block ferroptosis through p62-Keap1-NRF2 regulation pathways and carry out the following works: Study the protection mechanism of Tongfu-Yangsui recipe on neurons damage of TX mouse, a WD model, through inhibiting each steps of this pathway, ascertain concrete therapeutic targets of Tongfu-Yangsui recipe and explain the therapeutic mechanism of Tongfu-Yangsui recipe for WD patients with cerebral type from the perspective of modern medicine. Therefore, this project will have important implications for improving therapeutic effects and prognosis of WD patients with cerebral type and provide new therapeutic targets and the research ideas for the prevention and treatment of other nerve genetic degeneration diseases with traditional Chinese medicine.

Wilson病(WD)是可治性铜代谢障碍性遗传病，但许多难治性脑型WD患者驱铜疗效差，工作和生活能力严重受损。研究证实，铜代谢异常致细胞内铁稳态失衡是这些患者脑损伤的重要机制，铁依赖性ferroptosis与其损伤机制相契合，作为ferroptosis的重要调控通路，p62-Keap1-NRF2是潜在的治疗靶点。申请人团队根据WD中医辩证研究结果，创用通腑养髓方治疗脑型WD患者获得显效，并研究了通腑养髓方对神经元损伤的保护机制。基于此，本项目假设通腑养髓方通过调控p62-Keap1-NRF2通路阻断ferroptosis而具有神经元保护作用，分别抑制该通路的不同环节，研究通腑养髓方对WD模型TX小鼠神经元损伤的保护机制，明确其具体治疗靶点，从现代医学角度诠释通腑养髓方治疗脑型WD的疗效机制。本项目对提高脑型WD疗效、改善患者预后有重要意义，并为中医药防治其他神经遗传变性病提供新的治法思路。

Wilson病(WD)是可治性铜代谢障碍性遗传病，但部分难治性脑型WD患者驱铜疗效不佳，工作和生活能力严重受损。研究证实，铜代谢异常致细胞内铁稳态失衡是这些患者脑损伤的重要机制，铁依赖性铁死亡(ferroptosis)与其损伤机制相契合，作为铁死亡的重要调控通路，p62-Keap1-Nrf2是潜在的治疗靶点。.申请人团队根据WD中医辩证研究结果，创用通腑养髓方治疗脑型WD患者获得显效，并研究了通腑养髓方对神经元损伤的保护机制。基于此，本项目假设通腑养髓方通过调控p62-Keap1-Nrf2通路阻断铁死亡而具有神经元保护作用，研究通腑养髓方对WD模型TX小鼠神经元损伤的保护机制，明确其具体治疗靶点，从现代医学角度诠释通腑养髓方治疗脑型WD的疗效机制。本项目对提高脑型WD疗效、改善患者预后有重要意义。.本研究发现，铁死亡诱导的氧化应激性损伤是WD模型TX小鼠神经元损伤的重要机制，中药通腑养髓方可上调p62-Keap-Nrf2通路中Nrf2、NQO1、HO1、FTH1、HSPB27、GPX4、TfR及TRF的表达水平、下调P53的表达水平，并在一定程度上降低细胞内铁的含量，使得细胞内的氧化应激水平降低、细胞生存率提高而具有神经保护作用。.细胞及动物实验结果显示，Nrf2基因沉默可降低通腑养髓方治疗的TX小鼠脑内SOD及GSH表达量，增加MDA和GSSG表达量，下调p62-Keap1-Nrf2信号通路及铁代谢相关蛋白及基因Nrf2、NQO1、HO1、FTH1、HSPB27、GPX4、TfR及TRF的表达，表明调控铁死亡的p62-Keap1-Nrf2通路与WD神经元损伤的氧化应激分子机制密切相关，是潜在的治疗靶点。.本研究从分子水平初步阐明了通腑养髓方可调控p62-Keap1-Nrf2信号通路阻断铁死亡诱导的TX小鼠神经元损伤的机制，为从现代医学角度对中医通腑利湿、活血养髓法防治WD的治法提供理论依据，并为中医药防治神经遗传变性疾病提供新的治疗靶点和研究思路。

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