Regulation and function of transferrin receptor 2

描述（由申请人提供）：遗传性血色病（HH）是北方欧洲血统人群中最常见的遗传性疾病。铁超载会损害器官，导致肝硬化、糖尿病、心肌病和关节炎。转铁蛋白受体2（TfR2）是最近描述的与普遍存在的转铁蛋白受体（TfRl）具有序列相似性的蛋白质。TfR2的功能尚不清楚。TfR2的突变形式导致遗传性血色素沉着症的一种形式，从而暗示TfR2作为调节体内铁稳态的关键蛋白。TfR2几乎只存在于肝细胞中。肝脏是体内主要的铁处理器官，该器官的铁感应会影响肠道对铁的吸收。最近的证据表明，生理浓度的二铁转铁蛋白（Tf）调节肝癌细胞系中的TfR2水平。铁超载的小鼠模型支持这些发现。由于二铁Tf的浓度通常反映非病理条件下的体内铁水平，因此TfR2可以通过感应二铁Tf来发出铁水平的信号。将测试TfR2如何感测Tf饱和度并响应于调节体内铁稳态的模型。这项研究的长期目标是了解关键蛋白质的突变如何扰乱体内的铁平衡，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 descent. Iron overload damages organs leading to cirrhosis of the liver, diabetes, cardiomyopathy, and arthritis. Transferrin receptor 2 (TfR2) is a recently described protein with sequence similarity to the ubiquitous transferrin receptor (TfRl). The function of TfR2 is unknown. Mutated forms of TfR2 cause a form of hereditary hemochromatosis thus, implicating TfR2 as a key protein in the regulation of iron homeostasis in the body. TfR2 is found almost exclusively in hepatocytes. The liver is the major iron processing organ in the body, and iron sensing by this organ affects iron absorption by the intestines. Recent evidence shows that physiological concentrations of diferric transferrin (Tf) regulate TfR2 levels in hepatoma cell lines. Mouse models of iron overload support these findings. Since concentrations of diferric Tf generally reflect body iron levels in nonpathological conditions, TfR2 could signal iron levels by sensing diferric Tf. A model of how TfR2 senses Tf saturation and responds to regulate iron homeostasis in the body will be tested. The long term goal of this research is to understand how mutations in key proteins disturb the iron balance in the body and thereby reveal the mechanisms by which the body regulates iron homeostasis.