Erythroid Iron Transport

描述(由申请人提供)：铁代谢障碍是导致人类发病和死亡的最常见原因之一。铁缺乏影响全世界多达10亿人，主要是妇女和儿童。严重的缺铁状态表现为贫血，因为人体内的大部分铁被用来制造红细胞，而红细胞的正常发育取决于是否有足够的铁。红血球消耗了人体铁资源的近四分之三来产生携氧蛋白--血红蛋白。它们需要有效地运输铁的机制，并将其获取与分化的其他方面协调起来。红系铁通过受体介导的转铁蛋白内吞作用被摄取，称为转铁蛋白循环。在上一个资助期，我们证明了转铁蛋白周期在正常的红细胞生成中起着独特而重要的作用。在这里描述的实验中，我们将研究HBD小鼠，一种自发突变导致红细胞铁同化受损的品系，以更好地了解这一过程。我们已经将HBD突变定位于小鼠19号染色体的一小段，其中包含4个可能的候选基因。这项工作的目的是描述突变网织红细胞中HBD缺陷的生物学特征，鉴定HBD缺陷的分子性质，并确定HBD基因产物在红细胞生成中的作用。这将通过详细比较HBD和野生型网织红细胞中TF循环的步骤，鉴定HBD候选区域内所有可能的突变，转基因挽救HBD表型，以及确定HBD基因产物的亚细胞定位和功能来实现。我们预计，从这些实验中获得的信息将与红细胞生成和铁平衡障碍相关。

DESCRIPTION (provided by applicant): Disorders of iron metabolism are among the most prevalent causes of human morbidity and mortality. Iron deficiency affects up to 1 billion individuals worldwide, primarily women and children. The severe deficiency state presents with anemia, because most of the body's iron is used to make red blood cells, and normal red cell development depends on the availability of adequate amounts of iron. Red blood cells appropriate almost three quarters of the body's iron endowment to produce the oxygen-carrying protein hemoglobin. They require mechanisms to transport iron efficiently and to coordinate its acquisition with other aspects of differentiation. Erythroid iron is taken up through receptor-mediated endocytosis of iron-loaded transferrin (Tf), termed the Tf cycle. In the last funding period we showed that the Tf cycle plays a unique and essential role in normal erythropoiesis. In the experiments described here we will study hbd mice, a strain with a spontaneous mutation resulting in impaired erythroid iron assimilation, to better understand this process. We have mapped the hbd mutation to a small segment of mouse chromosome 19, which contains 4 possible candidate genes. The aims of the work described in this proposal are to characterize the biology of the hbd defect in mutant reticulocytes, to identify the molecular nature of the hbd defect, and to determine the role of the hbd gene product in erythropoiesis. This will be accomplished through detailed comparison of steps of the Tf cycle in hbd versus wild type reticulocytes, identification of all possible mutations within the hbd candidate region, transgenic rescue of the hbd phenotype, and determination of the subcellular localization and function of the hbd gene product. We anticipate that information derived from these experiments will be relevant to disorders of erythropoiesis and iron balance.