FUNCTION OF THE HEMOCHROMATOSIS PROTEIN

本申请的目的是确定遗传性血色素沉着症中涉及的蛋白质如何发挥功能，以调节铁跨上皮细胞屏障的运输。遗传性血色素沉着症是一种铁负荷过高，导致铁在个体一生中特定器官积聚的疾病。过量的铁会损害器官，并导致各种问题，如肝功能衰竭、成人糖尿病、心力衰竭、关节炎和肝癌。它是欧洲人后裔中最常见的遗传性疾病，大约每400人中就有1人受到影响。最近发现了该病的基因，并发现其编码的蛋白(HFE)与主要组织相容性I类蛋白相似。分子的序列很难让人了解它的功能。初步结果和以前的数据表明，HFe是铁摄取的负调节因子，该基因的突变会导致功能丧失。一种模型是，HFe通过感知细胞基侧的铁运输蛋白--转铁蛋白的铁饱和度来调节跨越上皮细胞屏障的铁的运输。通过转铁蛋白受体从基底侧摄取铁，然后通过改变细胞内的铁库来调节从细胞顶端到基底侧的铁运输。该模型将通过测量表达HFe的细胞中转铁蛋白冥想的和非转铁蛋白依赖的铁摄取来进行测试，并与不表达HFe的细胞进行比较。这些研究的长期目标是确定铁在体内的运输是如何调节的。

The goal of the present application is to determine how the protein implicated in hereditary hemochromatosis functions to regulate iron transport across epithelial cell barriers. Hereditary hemochromatosis is a disease of iron overload leading to iron accumulation in specific organs over the life time of the individual. Excess iron damages organs and results in a variety of problems such as liver failure, adult onset diabetes, heart failure, arthritus and hepatoma. It is the most common inherited disease in people of European descent affecting approximately 1 in 400 individuals. Recently the gene for this disease was identified and the protein it encodes (HFE) found to be similar to major histocompatibility class I proteins. The sequence of the molecule gives little insight into its function. Data obtained for preliminary results and previous data suggest that HFE is a negative regulator of iron uptake and mutations in the gene cause a loss of function. One model would be that HFE regulates iron transport across epithelial cell barriers by sensing the iron saturation of the iron transport protein, transferrin on the basolateral side of the cell. Iron uptake from the basolateral side via the transferrin receptor then would regulate iron transport from the apical to the basolateral side of the cell by altering intracellular iron pools. The model will be tested by measuring transferrin-meditated and transferrin- independent iron uptake in cells expressing HFE and compared to cells not expressing HFE. The long term goal of these studies is to determine how the transport of iron is regulated in the body.