Role of Transferrin Receptor 2 in Iron Homeostasis

描述（由申请人提供）：铁体内平衡失调是世界上最常见的营养问题之一。由于没有调节人体铁排泄的生理机制，体内平衡完全依赖于铁吸收与铁利用和储存的紧密联系。循环的肝肽hepcidin似乎是这一过程的中心调节器。然而，肝细胞感知血浆铁并调节hepcidin表达的途径尚不清楚。与经典的Tf受体（TfR1）一样，最近发现的第二Tf受体（TfR2）介导细胞对holoTf的摄取。我们提出TfR2在肝细胞中的作用是作为循环holoTf的肝细胞传感器和铁调节肽hepcidin表达的调节剂。这一假设得到了非功能性TfR2小鼠模型（TfR2 YaaSX纯合小鼠）的支持。定义和表征TfR2在铁稳态中的作用是本提案的主要目标。我们有四个具体目标：

DESCRIPTION (provided by applicant): Disorders of iron homeostasis are among the most common nutritional problems worldwide. Because there are no physiologic mechanisms to modulate iron excretion in humans, homeostasis depends entirely upon tightly linking dietary iron absorption with iron utilization and storage. The circulating liver peptide hepcidin appears to be a central regulator of this process. However, the means by which hepatocytes sense plasma iron and modulate hepcidin expression remain unknown. Like the classic Tf receptor (TfR1), the recently identified second Tf receptor (TfR2) mediates cellular uptake of holoTf. We propose that the role of TfR2 in the hepatoeyte is to serve as a hepatocellular sensor of circulating holoTf, and modulator of expression of the iron-regulatory peptide hepcidin. This hypothesis is supported by observations in our mouse model with a non-functional TfR2 (TfR2 YaaSX homozygous mice) It is the broad goal of this proposal to define and characterize the role of TfR2 in iron homeostasis. We have four specific aims: 1) Identify and characterize the participation of TfR2 in the hepatocellular uptake of holoTf. 2) Define the role of TfR2 in modulating the hepatocellular expression of hepcidin. 3) Distinguish the hepatocellular role of TfR2 by the cell-specific and regulatable restoration of wild-type TfR2 in TfR2 v245x mouse hepatocytes. 4) Determine the molecular basis for the functional defect caused by the TfR2 M172K mutation. These studies will identify and characterize the role of TfR2 as a hepatocellular iron sensor, and its participation in the modulation of hepcidin expression. This knowledge will increase our understanding of iron homeostasis, and may suggest new approaches to the management of diseases of iron overload and maldistribution.