Murine Models of Heme Metabolism and Iron Recycling

描述（由申请人提供）：人体近三分之二的铁元素以血红蛋白的形式存在，每个红细胞含有超过十亿个血红素形式的铁原子。因此，血红蛋白合成中的遗传性或获得性缺陷，包括地中海贫血、血红蛋白病、缺铁和炎症性贫血，是人类最普遍的疾病之一，这并不奇怪。重要的是，每天约3600亿红细胞中合成血红蛋白所需的约25毫克铁中的大部分（500万/秒）来源于由网状内皮系统（RES）巨噬细胞分解代谢的来自老化RBC的血红素铁的再循环;在稳定状态下，膳食血红素和非血红素铁吸收对全身铁经济性仅贡献1-2 mg/天，其中三分之二以血红素铁的形式被吸收。然而，尽管RES铁再循环和肠血红素吸收的重要性，在巨噬细胞和肠上皮细胞中的跨膜血红素转运的分子途径，在很大程度上，仍然是未知的。这在很大程度上是由于在哺乳动物细胞中鉴定血红素特异性转运蛋白的技术困难以及无法将这些发现转化为整个生物体。最近，利用C. elegans，它绕过了哺乳动物细胞的几个技术障碍，我们的合作者确定了一个蛋白质，血红素反应基因1（hrg-1），它的功能是血红素转运蛋白。我们的初步体外和体内数据强烈表明，哺乳动物的同源HRG-1，HRG 1，参与巨噬细胞铁回收，肠血红素吸收，以及红细胞内和肝细胞血红素代谢。在这里，我们建议调查Hrg 1在小鼠体内的功能，通过检查其调节巨噬细胞和肠上皮细胞在血红素和铁，吞噬红细胞，以及炎症，所有这些调节全身铁代谢和常见的营养，获得性和遗传性贫血的发病机制。此外，我们将直接测试Hrg 1对于以下假设是必不可少的： 巨噬细胞铁再循环、肠血红素吸收和红细胞内铁代谢。我们期望，集体的结果将产生实质性的洞察这些迄今为止模糊的血红素和铁生物学方面，是至关重要的，我们的理解和合理治疗这些常见疾病。

DESCRIPTION (provided by applicant): Nearly two-thirds of the body's iron endowment is in the form of hemoglobin and each red blood cell contains more than a billion iron atoms in the form of heme. Consequently, it is not surprising that inherited or acquired defects in hemoglobin synthesis, including the thalassemias, hemoglobinopathies, iron deficiency, and the anemia of inflammation are among the most prevalent human afflictions. Importantly, most of the ~25 mg of iron required to synthesize the hemoglobin in ~360 billion RBCs each day (5 million/sec) derives from recycling of heme-iron from aged RBCs catabolized by reticuloendothelial system (RES) macrophages; at steady state, dietary heme and non-heme iron absorption contribute only 1-2 mg/day to the systemic iron economy, and up to two-thirds of this is absorbed as heme-iron. Nevertheless, despite the importance of RES iron recycling and intestinal heme absorption, the molecular pathways of transmembrane heme transport in macrophages and intestinal epithelial cells have, for the most part, remained unknown. This is in large part due to technical difficulties in identifying heme-specific transporters in mammalian cells and the inability to translate these finding to whole organisms. Recently, using C. elegans, which bypasses several of the technical hurdles presented by mammalian cells, our collaborators identified a protein, heme-responsive gene 1 (hrg-1), which functions a heme transporter. Our preliminary in vitro and in vivo data strongly suggest that the mammalian ortholog of hrg-1, HRG1, is involved in macrophage iron recycling, intestinal heme absorption, as well as intraerythroid and hepatocellular heme metabolism. Here, we propose to investigate the in vivo function of Hrg1 in the mouse by examining its regulation in macrophages and intestinal epithelial cells in response to heme and iron, as phagocytosed red blood cells, as well inflammation, all of which modulate systemic iron metabolism and contribute to the pathogenesis of common nutritional, acquired, and inherited anemias. In addition, we will directly test the hypothesis that Hrg1 is essential for macrophage iron recycling, intestinal heme absorption, and intraerythroid iron metabolism using conditional gene targeting technology in the mouse. We expect that the collective results will yield substantial insight into these hitherto obscure aspects of heme and iron biology that are critical to our understanding and rational treatment of these common diseases.