The 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: 7557004
• 负责人: CAROLINE ENNS
• 金额: $ 0.74万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7557004
• 关键词: Kupffer' s cell; biological signal transduction; homeostasis; human tissue; immunocytochemistry; immunoprecipitation; intracellular transport; ion transport; iron metabolism; liver cells; liver metabolism; mass spectrometry; northern blottings; polymerase chain reaction; protein binding; protein sequence; protein transport; receptor expression; site directed mutagenesis; transferrin receptor; two dimensional gel electrophoresis; western blottings; yeast two hybrid system

Transferrin receptor 2 (TfR2) is a newly described protein with sequence similarity to the classical transferrin receptor (TfR). The function of TfR2 is unknown. In contrast to TfR, TfR2 is found almost exclusively in hepatocytes and early erythroid progenitor cells. Mutated forms of TfR2 are implicated in a form of hereditary hemochromatosis which results in iron overload in the liver. The liver is a major iron-processing organ in the body and disturbances in iron homeostasis in this organ could affect iron absorption by the intestines. On the basis of the limited information concerning this newly identified participant in iron homeostasis, the following hypotheses as to how TfR2 could plausibly participate in iron homeostasis by any or all of three different mechanisms will be tested. 1) TfR2 could regulate the efflux of iron out of the hepatocyte by facilitating the secretion of iron-loaded transferrin (Tf). Cell lines expressing TfR will be characterized for the rates of Tf synthesis, processing and iron-loading. 2) The binding of Tf to TfR2 or the uptake of iron via TfR2 could alter the secretion of iron-status signals from the hepatocytes. Alterations in the proteins secreted by hepatocytes will be examined by two-dimensional electrophoresis and mass spectrometry. Binding partners of TfR2 will be examined by immunoprecipitation and yeast two-hybrid studies to determine possible signaling mechanisms. 3) TfR2 could be located in the body in other locations that were not detected by northern analysis. Immunohistological staining of tissues with a monoclonal antibody generated against TfR2 will be used to examine specific cell types expressing TfR2. The long term goal of this research is to understand how the body regulates iron homeostasis and the mechanisms by which mutations in the key proteins result in disease.

转铁蛋白受体2（TFR2）是一种新描述的蛋白质，与经典转铁蛋白受体（TFR）具有序列相似性。 TFR2的功能未知。与TFR相反，在肝细胞和早期红细胞祖细胞中几乎完全发现TFR2。 TFR2的突变形式与遗传性血色素沉着症的形式有关，从而导致肝脏中的铁超负荷。肝脏是体内主要的铁处理器官，该器官中铁稳态的障碍可能会影响肠的吸收。基于有关该新确定的铁稳态参与者的有限信息，将测试TFR2如何合理地参与铁稳态的以下假设。 1）TFR2可以通过促进铁载蛋白（TF）的分泌来调节铁从肝细胞中的排出。表达TFR的细胞系将以TF合成，加工和铁的加载速率进行特征。 2）TF与TFR2的结合或通过TFR2摄取铁可以改变铁状态信号的分泌 肝细胞。肝细胞分泌的蛋白质的改变将通过二维电泳和质谱法检查。 TFR2的结合伴侣将通过免疫沉淀和酵母两杂交研究来检查可能的信号传导机制。 3）TFR2可以位于北部分析未检测到的其他位置的体内。 用针对TFR2产生的单克隆抗体的组织对组织的免疫组织学染色将用于检查表达TFR2的特定细胞类型。这项研究的长期目标是了解人体如何调节铁稳态以及关键蛋白质中突变导致疾病的机制。