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）：近三分之二的人体铁赋是血红蛋白的形式，每个红细胞以血红素的形式含有超过十亿的铁原子。因此，毫不奇怪的是，在血红蛋白合成中遗传或获得的缺陷，包括Thalassemias，血红蛋白病，铁缺乏症和炎症性贫血是最普遍的人类痛苦之一。重要的是，大多数约25毫克的铁在每天（500万/秒）中合成约3600亿rbc中的血红蛋白所需的大部分铁源自衰老的RBCS的血红素铁的回收，这是由网状内皮系统（RES）巨噬细胞分解的老年rbcs。在稳定状态下，饮食血红素和非血红素铁吸收仅为系统性铁经济贡献1-2 mg/天，其中最多三分之二被吸收为血红素铁。尽管如此，尽管具有RES铁回收和肠血红素吸收的重要性，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大多数情况下仍然未知。这在很大程度上是由于技术困难在识别哺乳动物细胞中血红素特异性转运蛋白以及无法将这些发现转化为整个生物体中的技术困难。最近，使用秀丽隐杆线虫（绕过哺乳动物细胞提出的几个技术障碍），我们的合作者确定了一种蛋白质血红素反应基因1（HRG-1），该基因1（HRG-1），其功能性血红素转运蛋白。我们的初步体外和体内数据强烈表明，HRG-1 HRG1的哺乳动物直系同源物参与巨噬细胞铁回收，肠血红素的吸收，胸部炎症和肝细胞内血红素异代代谢。在这里，我们建议通过检查其在巨噬细胞和肠道上皮细胞中的调节，以响应血红素和铁，作为吞噬的红细胞以及炎症，它们在巨噬细胞和肠上皮细胞中检查其在小鼠中的体内功能，这些炎症都调节了全身铁代谢，并有助于普通营养的普通营养的病原体，并获得了普通的营养，并获得了遗传和遗传。此外，我们将直接检验HRG1对于HRG1至关重要的假设巨噬细胞铁回收，肠状血红素吸收和侵蚀性铁的代谢，使用小鼠中的条件基因靶向技术。我们预计，集体结果将对这些迄今为止晦涩的血红素和铁生物学方面有实质性的了解，这对于我们对这些常见疾病的理解和合理治疗至关重要。