星形胶质细胞铜蓝蛋白对多巴胺能神经元铁代谢调控机制的研究

铜蓝蛋白(CP)调控机体铁代谢。全身CP基因敲除加重了小鼠帕金森病（PD）模型诱导中多巴胺能神经元的丢失。脑内CP主要由星形胶质细胞表达，但星形胶质细胞表达的CP对多巴胺能神经元铁代谢的影响尚未阐明。我们前期利用星形胶质细胞敲除CP基因的小鼠，研究发现小鼠脑微血管内皮细胞铁含量增加；在PD模型诱导中，CP基因敲除会更加削弱神经元多巴胺水平。我们推测：星形胶质细胞CP基因缺失导致了脑铁稳态失调，抑制血液的铁跨越血脑屏障而滞留在脑微血管内皮细胞，星形胶质细胞CP敲除影响了与神经元的相互联系，致使多巴胺能神经元的铁摄取和铁释放等相关分子发生变化。因此，我们拟从组织学水平、细胞水平和分子水平研究内皮细胞、星形胶质细胞调节多巴胺能神经元铁代谢的细胞和分子机制，以期揭示星形胶质细胞CP对多巴胺能神经元铁代谢的调控机制。研究结果将丰富脑铁代谢理论，对脑研究、预防和治疗神经系统疾病提供实验数据和理论支持。

Ceruloplasmin (CP) plays important roles in maintaining iron homeostasis. We previously found that global CP gene knockout (CP-/-) mice aggravated the loss of dopaminergic cells during the induction of Parkinson’s disease (PD). CP is mainly expressed in astrocytes of the brain, however, it remains a mystery how CP in astrocytes regulates the iron metabolism in dopaminergic neurons. Therefore, we generated astrocytes-specific CP gene knockout mouse, and found that conditional knockout of CP in astrocytes induced iron accumulation in microvascular endothelial cells and exacerbated the reduction of dopamine contents during the induction of PD mouse model. We speculated that CP gene knockout in astrocytes might destroy its regulation of brain iron homeostasis, which inhibited iron crossing from blood-brain barrier and led to iron retention in the endothelia, and which also disrupted the iron metabolism in astrocytes and the connection between astrocytes and dopaminergic neurons through altering the expression of iron uptake and iron release proteins in neurons. Therefore, we will investigate the cellular and molecular mechanisms underlying the regulation of iron metabolism in dopaminergic neurons by microvascular endothelial cells and astrocytes at histological, cellular and molecular levels in astrocytes-specific CP gene knockout mouse. Our results will reveal the regulatory mechanisms of CP in astrocytes on iron metabolism in dopaminergic neurons, which will enrich the theory of iron metabolism in the brain, and provide experimental data and theoretical basis for brain research, prevention and treatment of neurological diseases.