Iron homeostasis in mammalian muscle

哺乳动物肌肉中的铁稳态

基本信息

批准号：
8683160
负责人：
NANCY CATHERINE ANDREWS
金额：
$ 34.15万
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 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8683160
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 iron deficiency 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.

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。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Iron and copper in mitochondrial diseases.

DOI：
10.1016/j.cmet.2013.02.004
发表时间：
2013-03-05
期刊：
Cell metabolism
影响因子：
29
作者：
Xu W;Barrientos T;Andrews NC
通讯作者：
Andrews NC

Biological pathway selection through Bayesian integrative modeling.

通过贝叶斯综合模型选择生物途径。

DOI：
10.1515/sagmb-2013-0043
发表时间：
2014
期刊：
Statistical applications in genetics and molecular biology
影响因子：
0.9
作者：
Zheng,Lingling;Yan,Xiao;Suchindran,Sunil;Dressman,Holly;Chute,JohnP;Lucas,Joseph
通讯作者：
Lucas,Joseph