铁调节激素在脑铁平衡中的作用及机制

AAbnormally increased iron in the brain has been demonstrated in a number of neurodegenerative diseases, including neurodegeneration with brain-iron accumulation-1 (NBIA-1), neuroferritinopathy, Parkinson's, Alzheimer's and Huntington's disorders. The concept that the increased brain iron functions as an initial cause of neuronal death and contributes to various neurodegenerative diseases has been widely accepted. In spite of years of study, however, currently very little is known about the mechanisms involved in brain iron homeostasis and therefore a key question of why iron is abnormally increased in the brain has not been answered. ..The objective of the project is to investigate the roles of hepcidin in brain iron homeostasis. Hepcidin is a newly discovered iron-regulation hormone. It has been well documented that the peptide is a central player in iron homeostasis in the peripheral tissues. The accumulated data show that hepcidin controls expression of iron transport proteins in enterocytes (iron absorption), liver cells (iron storage), macrophages (iron recycling) and bone marrow (iron utilization). Recent studies, including ours, demonstrated that the brain has the ability to express hepcidin. Based on this finding, the roles of hepcidin in iron homeostasis outside the brain and our preliminary study, we hypothesize that hepcidin may also be a central player in brain iron homeostasis. It might function an essential sensor that signals among different brain cells such as the endothelial cells of the blood-brain barrier (BBB), neurons and glial cells. Hepcidin, similar to its action in the intestine, may regulate expression of iron transport proteins in the endothelial cells of the BBB. It may also operate as a regulator to maintain iron balance in neurons and glial cells by controlling the expression of iron uptake and release proteins...To test the hypothesis, we will investigate: [1] Effects of hepcidin on iron transport across the BBB in vivo, [2] Effects of hepcidin on iron (Tf-Fe: transferrin-bound iron and NTPI: non-transferrin-bound iron) uptake and release as well as expression of iron uptake (TfR1: transferrin receptor 1 and DMT1: divlent metal transporter1) and release (Fpn1: ferroportin1 and Heph: haephastin) proteins in the cultured microvascular endothelial cells (BMECs) in vitro [3] Effects of hepcidin on iron (Tf-Fe and NTPI) uptake and release as well as expression of iron uptake (TfR1 and DMT1) and release (Fpn1 and Heph) proteins in neurons in vitro. The questions to be investigated are key aspects of physiology and pathophysiology of brain iron metabolism. The findings will provide key insights into understanding the mechanisms involved in brain iron homeostasis and the causes of abnormally increased iron in the brain as well as creating novel therapeutic approaches to disrupt the chain of iron-induced pathological events which occur in neurodegenerative diseases.

异常增加的脑铁至少是部份神经退行性疾病的起因。然而，目前仍不清楚为什么这些疾病脑铁会异常增加，也不清楚脑铁如何保持平衡。已有研究证明Hepcidin通过调控肠上皮细胞、巨噬细胞和骨髓细胞铁转运蛋白的表达，进而影响机体铁吸收，储存及利用，在保持脑外铁平衡发挥中心作用。也已证明，脑内能表达Hepcidin。根据这一事实和我们的初步研究，我们假设 Hepcidin亦有调控脑微血管内皮细胞，神经元和其他脑细胞铁转运蛋白表达的能力，进而影响血脑屏障铁转运和各种脑细胞铁摄取和铁释放，从而在保持脑铁平衡中也发挥中心作用。为证实以上假设，我们将研究Hepcidin对铁通过血脑屏障，脑微血管内皮细胞和神经元铁摄取和铁释放，及对相关铁代谢蛋白表达的影响及机制， 以期阐明Hepcidin在保持脑铁平衡的作用及机制，为研发防治铁相关神经退行性疾病新方法提供重要基础支撑。

异常增加的脑铁至少是部份神经退行性疾病的起因。然而，目前仍不清楚为什么这些疾病脑铁会异常增加，也不清楚脑铁如何保持平衡。已有研究证明 Hepcidin 通过调控肠上皮细胞、巨噬细胞和骨髓细胞铁转运蛋白的表达，进而影响机体铁吸收，储存及利用，在保持脑外铁平衡发挥中心作用。 也已证明，脑内能表达 Hepcidin。基于此，我们研究了Hepcidin 对铁通过血脑屏障，脑微血管内皮细胞和神经元铁摄取和铁释放，及对相关铁代谢蛋白表达的影响及机制， 研究发现，Hepcidin 亦有调控脑微血管内皮细胞，神经元和其他脑细胞铁转运蛋白表达的能力，进而影响血脑屏障铁转运和各种脑细胞铁摄取和铁释放，从而保持脑铁平衡中也发挥中心作用。同时阐明了Hepcidin 在保持脑铁平衡的作用及机制，为研发防治铁相关神经退行性疾病新方法提供重要基础支撑。