Iron homeostasis in mammalian muscle

哺乳动物肌肉中的铁稳态

基本信息

批准号：
8128130
负责人：
NANCY CATHERINE ANDREWS
金额：
$ 39.25万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8128130
关键词：
Adult Affect Alleles Binding Biogenesis Birth Cardiac Cell surface Cells Clathrin Complementary DNA Development Diabetes Mellitus Electron Transport Embryo Endocytosis Endosomes Energy Metabolism Engineering Equilibrium Erythroid Cells Erythropoiesis Genes Genetic Heart Heart failure Homeostasis Human Iron Iron Overload Knockout Mice Laboratories Learning Link Mediating Messenger RNA Metabolic Metabolism Mitochondria Mus Muscle Muscle Cells Muscle Development Muscle function Mutant Strains Mice Myocardium Myoglobin Myopathy Names Nomenclature Nucleic Acids Organ Oxygen Phenotype Physiology Plasma Play Pregnancy Process Production Proteins Reading Regulation Role SLC11A2 gene Skeletal Muscle Text Tissues Transferrin Transgenic Organisms Transmembrane Transport Work cardiogenesis diferric transferrin heart function human HFE protein human TFRC protein mouse model novel prenatal promoter receptor mediated endocytosis recombinase research study uptake

项目摘要

DESCRIPTION (provided by applicant): Transferrin receptor 1 (Tfr1) is a widely expressed protein that mediates cellular iron uptake through receptor-mediated endocytosis of Fe-transferrin. Tfr1-/- embryos die in mid-gestation from ineffective erythropoiesis, precluding assessment of roles of Tfr1 later in development and after birth. To determine whether Tfr1 is important in other tissues, we developed a conditional (floxed) Tfr1 mouse model that allows for inactivation of the Tfr1 gene in cells expressing transgenic Cre recombinase from tissue- specific promoters. We focused on skeletal and cardiac muscle because both tissues are highly metabolic and require iron for myoglobin production, mitochondrial biogenesis and mitochondrial function. Our preliminary results indicate that Tfr1 is critically important in both skeletal muscle and heart, and suggest an unanticipated link between iron homeostasis and energy metabolism. In our first Aim, we will characterize a severe phenotype observed in mice lacking Tfr1 in skeletal muscle, to understand how Tfr1 and iron transport contribute to muscle development, muscle iron homeostasis, mitochondrial biogenesis and regulation of energy metabolism. In our second Aim, we will perform similar studies to elucidate the role of Tfr1 in the heart, an organ in which iron balance must be tightly regulated to maintain constant, high-level function while avoiding deleterious effects of iron deficiency and iron overload. PUBLIC HEALTH RELEVANCE: Skeletal and heart muscle require more iron than most tissues because they need to produce energy for the work they do. They differ in several ways - heart muscle is working continuously and sensitive to too much or too little iron; skeletal muscle is used intermittently and is sensitive to iron deficiency but not iron overload. Little is known about how iron enters either type of muscle cell. This project takes advantage of unique mouse mutants, engineered in the Andrews laboratory, to learn about muscle iron transport and its relationship to heart failure, diabetes, and muscle diseases.

描述（由申请人提供）：转铁蛋白受体1（TFR1）是一种广泛表达的蛋白质，可通过受体介导的Fe-转移蛋白的内吞作用介导细胞铁的摄取。 TFR1 - / - 胚胎死于无效的红细胞生成中的中期，排除了TFR1在发育后和出生后的作用的评估。为了确定TFR1在其他组织中是否很重要，我们开发了一种条件（Floxed）TFR1小鼠模型，该模型允许在表达来自组织特异性启动子的转基因CRE重组酶的细胞中灭活TFR1基因。我们专注于骨骼肌和心脏肌肉，因为两种组织都是高度代谢的，需要铁才能产生肌红蛋白，线粒体生物发生和线粒体功能。我们的初步结果表明，TFR1在骨骼肌和心脏中都至关重要，并提出了铁稳态与能量代谢之间的意外联系。在我们的第一个目标中，我们将表征骨骼肌缺乏TFR1的小鼠中观察到的严重表型，以了解TFR1和铁的运输如何促进肌肉发育，肌肉铁稳态，线粒体生物发生和能量代谢的调节。在我们的第二个目标中，我们将进行类似的研究以阐明TFR1在心脏中的作用，在该器官中，必须严格调节铁平衡以保持恒定的高级功能，同时避免铁缺乏症和铁超载的有害影响。公共卫生相关性：骨骼和心肌比大多数组织需要更多的铁，因为它们需要为所做的工作产生能量。它们在几种方面有所不同 - 心肌正在连续工作和敏感铁；骨骼肌间歇性地使用，对铁缺乏症敏感，而不是铁超负荷。关于铁如何进入任何一种类型的肌肉细胞，知之甚少。该项目利用了在安德鲁斯实验室设计的独特小鼠突变体，以了解肌肉铁的运输及其与心力衰竭，糖尿病和肌肉疾病的关系。