Murine Models of Heme Metabolism and Iron Recycling

血红素代谢和铁回收的小鼠模型

基本信息

批准号：
8737253
负责人：
MARK D FLEMING
金额：
$ 38.26万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-18 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8737253
关键词：
Acute Affinity Anemia Anemia due to Chronic Disorder Animals Biology Blood Vessels Bypass Caenorhabditis elegans Cell membrane Cells Chronic Cloning Complex Data Defect Development Diet Dietary Iron Diffuse Disease Endowment Enterocytes Epithelial Cells Erythrocytes Erythroid Erythropoiesis Gene Targeting Genes Grant Heme Heme Iron Hemeproteins Hemoglobin Hemoglobinopathies Hemolysis Histocompatibility Testing Human In Vitro Inflammation Inherited Intestines Iron Iron Overload Iron deficiency anemia Mammalian Cell Mammals Metabolism Modeling Molecular Molecular Genetics Mus Nutritional Orthologous Gene Oxygen Pathogenesis Pathway interactions Pattern Phagocytosis Phenotype Physiological Play Proteins Recycling Regulation Reticuloendothelial System Role Source Stress Technology Testing Thalassemia Tissues Translating Validation Whole Organism absorption aged base cell type common treatment embryonic stem cell heme 1 heme a heme biosynthesis in vivo insight iron deficiency iron metabolism macrophage mutant public health relevance research study response tool transmission process

项目摘要

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.

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以血红素形式存在的铁原子。因此，血红蛋白合成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，也就不足为奇了。重要的是，每天约 3600 亿个红细胞（500 万个/秒）合成血红蛋白所需的约 25 毫克铁，大部分来自网状内皮系统 (RES) 巨噬细胞分解代谢的老化红细胞中血红素铁的回收；在稳定状态下，膳食血红素和非血红素铁的吸收仅对全身铁经济贡献 1-2 毫克/天，其中多达三分之二以血红素铁的形式被吸收。然而，尽管RES铁回收和肠道血红素吸收很重要，但巨噬细胞和肠上皮细胞中跨膜血红素转运的分子途径在很大程度上仍然未知。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，我们的合作者利用秀丽隐杆线虫绕过了哺乳动物细胞所面临的几个技术障碍，鉴定出了一种蛋白质，即血红素反应基因 1 (hrg-1)，它具有血红素转运蛋白的功能。我们的初步体外和体内数据强烈表明，hrg-1 的哺乳动物直系同源物 HRG1 参与巨噬细胞铁回收、肠道血红素吸收以及红细胞内和肝细胞血红素代谢。在这里，我们建议通过检查 Hrg1 在巨噬细胞和肠上皮细胞中对血红素和铁的反应（如吞噬红细胞）以及炎症的调节来研究 Hrg1 在小鼠体内的功能，所有这些都调节全身铁代谢和导致常见营养性贫血、获得性贫血和遗传性贫血的发病机制。此外，我们将直接检验 Hrg1 对于使用条件基因靶向技术在小鼠中进行巨噬细胞铁回收、肠道血红素吸收和红细胞内铁代谢。我们期望集体结果将对血红素和铁生物学的这些迄今为止模糊的方面产生实质性的见解，这对于我们理解和合理治疗这些常见疾病至关重要。