HEPHAESTIN--A COPPER PROTEIN INVOLVED IN IRON METABOLISM

火黄蛋白——一种参与铁代谢的铜蛋白

• 批准号: 6178086
• 负责人: CHRISTOPHER D VULPE
• 金额: $ 17.57万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-01 至 2002-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6178086
• 关键词: copper; developmental genetics; dietary iron; embryo /fetus cell /tissue; ferroxidase; fluorescence microscopy; gastrointestinal absorption /transport; gene expression; green fluorescent proteins; immunocytochemistry; in situ hybridization; iron metabolism; laboratory mouse; malnutrition; membrane transport proteins; metalloenzyme; microcytic /hypochromic anemia; nutrient bioavailability; nutrient interaction; nutrition related tag; protein localization

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.

铁代谢紊乱严重影响人类健康。超过15亿人患有缺铁性贫血以及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。育龄妇女和婴儿面临的风险尤其大。由于遗传性铁超负荷紊乱血色素沉着症引起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。尽管临床上普遍存在铁缺乏和铁超负荷，但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道铁转运的基本组成部分。Sla小鼠从肠腔中摄取铁，但大大减少了铁从跨膜结合的铜蓝蛋白同源物中的输出，铜蓝蛋白同源物在小肠的成熟吸收细胞中高度表达，小肠是胃肠道中铁摄取的主要部位。我们将这种蛋白质命名为“Hephaestin”，并假设它是铁从肠道输出所必需的铁氧化酶。首先，我们将确定hephaestin蛋白的细胞位置，其次，与相关蛋白铜蓝蛋白相比，确定hephaestin mRNA和蛋白的空间和时间表达模式。第三，我们将问是否hephaestin的表达是由铜或铁的身体状况。最后，我们将开发一个功能检测的hephaestin蛋白，并确定其在肠道铁输出的作用。了解哺乳动物机体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并设计有效的治疗方法是必要的。