Role of Transferrin Receptor 2 in Iron Homeostasis

转铁蛋白受体 2 在铁稳态中的作用

• 批准号: 6937051
• 负责人: Robert E Fleming
• 金额: $ 34.55万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6937051
• 关键词: dietary iron; dietary trace element; gene expression; gene mutation; genetically modified animals; homeostasis; iron disorder; laboratory mouse; liver cells; northern blottings; nutrition related tag; peptides; plasma; tissue /cell culture; transferrin receptor; western blottings

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.

描述（由申请人提供）：铁稳态紊乱是全世界最常见的营养问题之一。由于人体没有调节铁排泄的生理机制，体内平衡完全取决于膳食铁吸收与铁利用和储存的紧密联系。循环的肝肽铁调素似乎是这一过程的中心调节剂。然而，肝细胞感知血浆铁和调节铁调素表达的方式仍然未知。与经典的 Tf 受体 (TfR1) 一样，最近发现的第二种 Tf 受体 (TfR2) 介导细胞对 HoloTf 的摄取。我们认为 TfR2 在肝细胞中的作用是充当循环 HoloTf 的肝细胞传感器，以及铁调节肽铁调素表达的调节剂。这一假设得到了我们对非功能性 TfR2 小鼠模型（TfR2 YaaSX 纯合小鼠）的观察结果的支持。该提案的广泛目标是定义和表征 TfR2 在铁稳态中的作用。我们有四个具体目标： 1) 识别并表征 TfR2 在肝细胞摄取 holoTf 中的参与。 2) 定义TfR2在调节hepcidin肝细胞表达中的作用。 3) 通过 TfR2 v245x 小鼠肝细胞中野生型 TfR2 的细胞特异性和可调节恢复来区分 TfR2 的肝细胞作用。 4)确定TfR2 M172K突变引起的功能缺陷的分子基础。 这些研究将鉴定和表征 TfR2 作为肝细胞铁传感器的作用，及其参与铁调素表达的调节。这些知识将增加我们对铁稳态的理解，并可能提出治疗铁过载和分布不良疾病的新方法。