Regulation and function of transferrin receptor 2

描述(申请人提供)：遗传性血色沉着症(HH)是北欧后裔中最常见的遗传性疾病。铁负荷过多会损害器官，导致肝硬变、糖尿病、心肌病和关节炎。转铁蛋白受体2(TfR2)是最近发现的一种蛋白质，其序列与无处不在的转铁蛋白受体(TfR1)相似。TfR2的功能尚不清楚。TfR2的突变形式会导致某种形式的遗传性血色素沉着症，这意味着TfR2是体内铁稳态调节的关键蛋白。TfR2几乎只在肝细胞中发现。肝脏是体内主要的铁处理器官，该器官对铁的感知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TfR2的水平。铁超载的小鼠模型支持这些发现。由于在非病理条件下，二铁转铁蛋白的浓度通常能反映体内的铁水平，因此TfR2可以通过检测二铁转铁蛋白来发出铁水平的信号。TfR2如何感知Tf饱和并响应调节体内铁稳态的模型将被测试。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.