情志应激诱导多巴胺能神经元ferroptosis增加帕金森病“易感性”研究

帕金森病（PD）是遗传内因和环境外因作用下引发的神经退行性疾病，目前无有效治疗方法，病理机制不明确。我们前期研究发现科学问题：具有相同PD基因型的个体在不同的情志状态对PD的‘易感性’不同，并提出科学假说：情志应激引起“肝风内动”增加PD“易感性”的机制可能与其增敏多巴胺能神经元发生一种新型程序性细胞死亡——铁凋亡（ferroptosis）有关。本项目拟采用氧化脂质组学等先进技术，深入研究情志应激兴奋HPA轴引起激素和细胞内氧化水平的变化，进而诱导DJ-1通过调节TFR1/DMT1或SLC7A11/GPX4信号通路引起多巴胺能神经元发生Ferroptosis的生物学机制，并在此基础上采用mechanism-based design策略筛选能抑制多巴胺能神经元ferroptosis的中药方剂及活性成分。研究结果将丰富“情志致病”理论的生物学基础研究，为PD的防治策略和药物开发提供科学依据。

Parkinson's disease (PD) is a major neurodegenerative disease caused by the combination of genetic and environmental factors. Currently, there are no effective treatments or drugs to completely cure PD. Our previous studies found that individuals with the same PD genotypes possessed different susceptibility to PD under different emotional conditions. We hypothesize that emotional stress induced redox dysbalance sensitizes dopaminergic neurons to a novel type of programmed cell death – ferroptosis – and explore the mechanistic details involved. We will use respiratory metabolomics and oxidative lipidomics along with other advanced technologies to uncover the mechanisms through which emotional stress and activated HPA axis cause changes in the hormonal status, polyunsaturated lipid homeostasis, and intracellular redox balance, thereby inducing DJ-1 expression and ferroptosis in dopaminergic neurons. We will explore the signaling cascades in the ferroptotic program –TFR1/DMT1 or SLC7A11/GPX4. These mechanistic studies will be used to establish in vitro and in vivo model test-systems for screening of a variety of Chinese medicines or natural compounds as inhibitors of dopaminergic neuronal ferroptosis. The underlying molecular mechanisms will be explored for the most effective inhibitors. The results of this study will enrich the “emotional pathogenicity” theory and contribute to understanding of the specific pathological processes through which emotional stress promotes death of dopaminergic neurons and exacerbates PD. The results obtained will be used for the development of new prevention and treatment strategies against PD.