Regulation of hepatic hepcidin expression by transferrin receptor-2

转铁蛋白受体2对肝脏铁调素表达的调节

基本信息

批准号：
10471318
负责人：
CAROLINE ENNS
金额：
$ 54.37万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-15 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10471318
关键词：
Affinity Alcoholic Liver Diseases Anemia Arrhythmia Arthritis Binding Biological Assay Biotin Bone Morphogenetic Proteins Brain Cardiomyopathies Cells Child Chimeric Proteins Chronic Hepatitis C Cirrhosis Co-Immunoprecipitations Complex Cytoplasmic Tail Dependovirus Development Diabetes Mellitus Dietary Iron Elements Equilibrium Functional disorder Gene therapy trial Genetic Diseases Goals HFE2 gene Heart Hepatic Hepatocyte Hereditary Disease Hereditary hemochromatosis Homeostasis Impairment In Transferrin In Vitro Infection Intervention Intestines Iron Iron Overload Joints Knowledge Lead Ligase Liver Liver Cirrhosis Malignant Neoplasms Malignant neoplasm of liver Mammals Mass Spectrum Analysis Mediating Modeling Mus Mutation Neurologic Organ Organism Pancreas Pathologic Pathway interactions Persons Phosphoproteins Phosphorylation Physiological Play Population Proteins Regulation Research Role Sense Organs Sickle Cell Anemia Signal Pathway Signal Transduction Source Streptavidin Surface Plasmon Resonance Testing Thalassemia Tissues Transferrin Up-Regulation adeno-associated viral vector body sense dietary dietary control exercise intolerance experimental study hepcidin in vivo iron deficiency joint injury metal transporting protein 1 non-alcoholic fatty liver disease peptide hormone phosphoproteomics receptor response transferrin receptor 2 uptake vector

项目摘要

Hereditary hemochromatosis (HH) is a common inherited disorder. Iron overload results in damage to specific organs including the liver, heart, and pancreas resulting in cirrhosis of the liver, liver cancer, diabetes, cardiomyopathy. Iron also accumulates in joints causing arthritis. The liver is the major iron-sensing organ and controls iron homeostasis in the body. Mutations in transferrin receptor 2 (TfR2), HFE and hemojuvelin (HJV) lead to HH. TfR2 is hypothesized to sense iron in the body. The role that TfR2 plays in sensing iron remains controversial. The association between TfR2 and HFE is still debated. TfR2 also associates with HJV in vitro. We propose to determine the mechanisms by which TfR2 controls iron homeostasis in the body. Adeno- associated viral vectors used in gene therapy trials in combination with protein proximity assays and phosphoproteomic analysis will be utilized to determine the interaction partners of TfR2 in vivo. The long-term goal of this research is to understand how mutations in key proteins that disturb the iron balance in the body, reveal the mechanisms by which the body regulates iron-homeostasis.

遗传性血色病（HH）是一种常见的遗传性疾病。铁超载会导致特定器官受损，包括肝脏、心脏和胰腺，导致肝硬化、肝癌、糖尿病、心肌病。铁还会积聚在关节中，导致关节炎。肝脏是主要的铁感应器官，控制体内铁的稳态。转铁蛋白受体 2 (TfR2)、HFE 和血幼素 (HJV) 突变会导致 HH。 TfR2 被假设可以感知体内的铁。 TfR2 在铁传感中的作用仍存在争议。 TfR2 和 HFE 之间的关联仍存在争议。 TfR2 在体外也与 HJV 相关。我们建议确定 TfR2 控制体内铁稳态的机制。基因治疗试验中使用的腺相关病毒载体与蛋白质邻近分析和磷酸化蛋白质组学分析相结合，将用于确定体内 TfR2 的相互作用伴侣。这项研究的长期目标是了解扰乱体内铁平衡的关键蛋白质的突变如何揭示人体调节铁稳态的机制。