Regulation and function of the transferrin receptor 2

描述（由申请人提供）：遗传性血色素沉着症（HH）是北欧血统人群中最常见的遗传性疾病。铁超载会损害特定器官，导致肝硬化、肝癌、糖尿病、心肌病和关节炎。肝脏是人体主要的铁感应器官。转铁蛋白是血液中主要的铁转运蛋白。主要在肝细胞和红细胞前体中表达的转铁蛋白受体2 （TfR2）的突变导致HH。Tfr2与另一种参与铁稳态的蛋白质HFE形成复合物。本提案中描述的实验将验证TfR2-HFE复合物提供一种检测铁负载Tf的传感机制，从而调节hepcidin的转录，hepcidin是一种负向调节铁从肠细胞和巨噬细胞外排的肽激素。另外，TfR2-HFE复合体可以建立hepcidin转录的基础水平。其他参与复合体和信号机制的蛋白质将被确定。这项研究的长期目标是了解关键蛋白质的突变是如何扰乱体内铁平衡的，从而揭示身体调节铁稳态的机制。

DESCRIPTION (provided by applicant): Hereditary hemochromatosis (HH) is the most common inherited disorder in people of Northern European origin. Iron overload results in damage specific organs leading to cirrhosis of the liver, liver cancer, diabetes, cardiomyopathy, and arthritis. The liver is a major iron-sensing organ in the body. Transferrin is the major iron transport protein in the blood. Mutations in transferrin receptor 2 (TfR2), which is predominantly expressed in hepatocytes and erythrocyte precursors result in HH. Tfr2 forms a complex with HFE, another protein involved in iron homeostasis. Experiments described in this proposal will test the model that the TfR2-HFE complex provides a sensing mechanism to detect iron-loaded Tf and thereby regulates the transcription of hepcidin, a peptide hormone that negatively regulates the efflux of iron out of intestinal cells and macrophages. Alternatively, the TfR2-HFE complex could establish basal levels of hepcidin transcription. Other proteins involved in the complex and in signaling mechanisms will be identified. The long-term goal of this research is to understand how mutations in key proteins disturb the iron balance in the body to reveal the mechanisms by which the body regulates iron-homeostasis.