HEPHAESTIN--A COPPER PROTEIN INVOLVED IN IRON METABOLISM

铁代谢紊乱严重影响人体健康。超过15亿人患有缺铁性贫血，与之相关的认知发育受损风险增加、感染易感性增加和死亡率增加。特别危险的是育龄妇女和婴儿。由于遗传性铁超载疾病血色素沉着症导致的铁过量在某些人群中相对常见，并导致肝硬化、糖尿病、关节炎和心脏病。尽管临床普遍存在铁缺乏和铁超载，但人们对膳食铁摄取知之甚少。对一种独特的缺铁性贫血哺乳动物模型sla小鼠的研究揭示了肠铁运输的一个基本组成部分。Sla小鼠从肠腔吸收铁，但在小肠成熟吸收细胞中高度表达的跨膜结合铜蓝蛋白同源物的铁输出大大减少，小肠是胃肠道铁摄取的主要部位。我们将这种蛋白命名为“Hephaestin”，并假设它是一种铁氧化酶，是铁从肠道输出所必需的。首先，我们将确定hephaestin蛋白的细胞位置，其次，确定与相关蛋白铜蓝蛋白相比，hephaestin mRNA和蛋白的时空表达模式。第三，我们会问hephaestin的表达是否受到体内铜或铁状态的调节。最后，我们将开发一种hephaestin蛋白的功能测定方法，并确定其在肠铁输出中的作用。了解哺乳动物铁转运的基本系统对于了解人类缺铁性贫血和铁超载的病因和设计有效的治疗方法是必要的。

Disturbances of iron metabolism significantly impact human health. Over 1.5 billion people suffer from iron-deficiency anemia and the associated increased risk of impaired cognitive development, increased susceptibility to infection, and increased mortality. At particular risk are women of child-bearing age and infants. Iron excess due to the inherited iron-overload disorder hemochromatosis is relatively common in certain populations and causes hepatic cirrhosis, diabetes, arthritis and cardiac disease. Despite the clinical prevalence of iron deficiency and iron overload, dietary iron uptake is poorly understood. The investigation of a unique mammalian model of iron deficiency anemia, the sla mouse, has revealed a fundamental component of intestinal iron transport. Sla mice take up iron from the intestinal lumen but have greatly diminished export of iron out of transmembrane-bound ceruloplasmin homologue highly expressed in the mature absorptive cells of the small intestine, the primary site of iron uptake in gastrointestinal tract. We have named this protein "Hephaestin" and hypothesize that it is a ferroxidase necessary for iron export from the intestine. First, we will determine the cellular location of the hephaestin protein and, second, determine the spatial and temporal expression pattern of the hephaestin mRNA and protein as compared to the related protein ceruloplasmin. Thirdly, we will ask whether the expression of hephaestin is regulated by the copper or iron status of the body. Finally, we will develop a functional assay for the hephaestin protein and determine its role in intestinal iron export. Understanding of the basic systems of iron transport by the mammalian organism is necessary to understand the etiology of iron deficiency anemia and iron overload in humans and devise effective therapies.