Regulation and function of the transferrin receptor 2

转铁蛋白受体2的调节和功能

基本信息

批准号：
9016540
负责人：
CAROLINE ENNS
金额：
$ 39.33万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-07-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9016540
关键词：
Adopted Anemia Anemia due to Chronic Disorder Arthritis Binding Biological Assay Blood Brain CD81 gene Cardiomyopathies Carrier Proteins Cells Child Chimera organism Cirrhosis Complex Cytoplasmic Tail Dependovirus Development Diabetes Mellitus Diet Disease Equilibrium Erythrocytes European Failure Genes Genetic Genetic Transcription Goals Grant HFE2 gene Health Heart Hepatocyte Hereditary hemochromatosis Homeostasis Human Hybrids Impairment In Transferrin Inborn Genetic Diseases Intervention Intestines Iron Iron Overload Joints Knock-out Link Liver Liver Cirrhosis MADH6 gene Malignant Neoplasms Malignant neoplasm of liver Modeling Mus Mutate Mutation Neurologic Organ Pancreas Pathology Pathway interactions Play Point Mutation Primary Cell Cultures Process Protein Engineering Proteins Recycling Refractory Regulation Research Role Sense Organs Signal Pathway Signal Transduction System Testing Thalassemia Transducers Transferrin Transgenic Mice Venous blood sampling Yeasts base body sense bone morphogenetic protein 6 exercise intolerance functional loss gene therapy hepcidin in vivo innovation insight knock-down liver injury macrophage mouse model peptide hormone pleiotropism protein protein interaction protein transport research study scaffold sensor trafficking transferrin receptor 2 uptake

项目摘要

DESCRIPTION (provided by applicant): Hereditary hemochromatosis (HH) is the most common inherited disorder in people of Northern European origin. Iron overload results in damage specific organs leading to cirrhosis of the liver, liver cancer, diabetes, cardiomyopathy, and arthritis. The liver is a major iron-sensing organ in the body. Transferrin is the major iron transport protein in the blood. Mutations in transferrin receptor 2 (TfR2), which is predominantly expressed in hepatocytes and erythrocyte precursors result in HH. Tfr2 forms a complex with HFE, another protein involved in iron homeostasis. Experiments described in this proposal will test the model that the TfR2-HFE complex provides a sensing mechanism to detect iron-loaded Tf and thereby regulates the transcription of hepcidin, a peptide hormone that negatively regulates the efflux of iron out of intestinal cells and macrophages. Alternatively, the TfR2-HFE complex could establish basal levels of hepcidin transcription. Other proteins involved in the complex and in signaling mechanisms will be identified. The long-term goal of this research is to understand how mutations in key proteins disturb the iron balance in the body to reveal the mechanisms by which the body regulates iron-homeostasis.

描述（由申请人提供）：遗传性血色素沉着症（HH）是北欧血统中最常见的遗传疾病。铁超负荷会导致特定的器官，导致肝癌，肝癌，糖尿病，心肌病和关节炎的肝硬化。肝脏是体内主要的铁感应器官。转铁蛋白是血液中主要的铁转运蛋白。转铁蛋白受体2（TFR2）中的突变，主要在肝细胞和红细胞前体中表达的突变导致HH。 TFR2与HFE形成复合物，HFE是铁稳态涉及的另一种蛋白质。本提案中描述的实验将测试TFR2-HFE复合物提供的传感机制，以检测载有铁的TF，从而调节肝素激素的转录，这是一种肽激素，该肽激素对肠道细胞和巨噬细胞的降低了铁的外排。或者，TFR2-HFE复合物可以建立肝素转录的基础水平。将确定参与复合物和信号传导机制的其他蛋白质。这项研究的长期目标是了解关键蛋白的突变如何干扰人体的铁平衡以揭示人体调节铁瘤的机制。