Function of the hemochromatosis protein

描述(申请人提供)：遗传性血色沉着症(HH)是北欧血统人群中最常见的可能致命的遗传性疾病。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。这种突变导致一种隐性疾病，导致铁吸收增加，并在选定的组织中积累铁。铁超载会损害这些器官，导致肝硬变、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有待确定。我们假设HFE至少有两种功能。它通过增加海普西丁的转录，在全球范围内降低了人体对铁的吸收，海普西丁是一种荷尔蒙，可以负面地调节铁从肠道上皮细胞外流到血液中。HFE还通过下调铁转运蛋白Zip14，在局部对细胞内的铁水平进行负向调节。具体目标1将确定转铁蛋白介导HFE依赖的海普西丁调节的机制(S)。HFE如何增加海普西丁转录的几个模型将在培养细胞、原代肝细胞培养和小鼠中进行测试。具体目标2将确定HFe通过调节Zip14调节铁向细胞内运输的机制(S)。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.