Function of the hemochromatosis protein

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潜在致命遗传性疾病。大约85%的病例是由单个碱基对突变引起的，该突变将HFE蛋白中的Cys转化为Tyr。这种突变引起一种隐性疾病，导致铁吸收增加和铁在选定组织中的积累。铁超载会损害这些器官，导致肝硬化、糖尿病、心肌病和关节炎。在克隆和鉴定HFE 13年后，HFE影响铁稳态的机制仍未确定。我们假设HFE至少有两个功能。它通过增加hepcidin（一种负向调节铁从肠上皮细胞外排到血液中的激素）的转录，降低体内对铁的吸收。HFE还通过下调铁转运蛋白Zip14，在局部负向调节细胞中的铁水平。特异性Aim 1将确定转铁蛋白介导hepcidin的hfe依赖性调节的机制。几种HFE如何增加hepcidin转录的模型将在培养细胞、原代肝细胞培养和小鼠中进行测试。特异性Aim 2将确定HFE通过调控Zip14调控铁转运进入细胞的机制。这项工作的长期目标是了解HFE的功能。

DESCRIPTION (provided by applicant): Hereditary Hemochromatosis (HH) is the most common potentially fatal inherited disorder in people of Northern European origin. Approximately 85% of the cases result from a single base-pair mutation, which converts Cys to Tyr in the HFE protein. This mutation causes a recessive disease resulting in increased iron absorption and accumulation of iron in selected tissues. The iron overload damages these organs leading to cirrhosis of the liver, diabetes, cardiomyopathy, and arthritis. Thirteen years after the cloning and identification of HFE, the mechanisms by which HFE affect iron-homeostasis remain to be determined. We hypothesize that HFE has at least two functions. It lowers iron uptake into the body, globally, by increasing the transcription of hepcidin, a hormone that negatively regulates iron efflux out of intestinal epithelial cells into the blood. HFE also negatively regulates the iron levels in the cell, locally, by downregulating the iron transporter, Zip14. Specific Aim 1 will determine the mechanism(s) by which transferrin mediates the HFE-dependent regulation of hepcidin. Several models of how HFE increases hepcidin transcription will be tested in cultured cells, primary hepatocyte culture, and mice. Specific Aim 2 will determine the mechanism(s) by which HFE regulates the transport of iron into cells by the regulation of Zip14. The long-term goal of this work is to understand the function of HFE.