Regulation of Iron Homeostasis by BMP Signaling

BMP 信号传导对铁稳态的调节

基本信息

批准号：
9324203
负责人：
JODIE L BABITT
金额：
$ 38.48万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9324203
关键词：
Address Affect Affinity Anemia Anemia due to Chronic Disorder Animal Model BMP2 gene BMP4 BMP6 gene Binding Biochemical Biological Assay Bioluminescence Bone Morphogenetic Proteins Cell Culture Techniques Cell surface Chemicals Chromatin Clinical Trials Coupled Cycloheximide Dactinomycin Data Dependence Diet Disease EMSA Elements Endothelial Cells Equilibrium Feedback Functional disorder Genetic Genetic Recombination Genetic Transcription Genotype Goals Growth HFE gene HFE2 gene Health Hemochromatosis Hepatocyte Hereditary Disease Hereditary hemochromatosis Homeostasis In Situ In Vitro Inflammation Iron Iron Metabolism Disorders Iron Overload Knock-out Knockout Mice Lead Ligands Liver LoxP-flanked allele Luciferases MADH4 gene Measures Mediating Messenger RNA Metabolic Diseases Modeling Molecular Mus Nature Pathway interactions Patients Pharmacology Phenotype Phosphorylation Physiology Play Population Process Protein Biosynthesis Public Health Quantitative Reverse Transcriptase PCR Regulation Regulatory Pathway Reporter Residual state Role Series Serum Signal Pathway Signal Transduction Signaling Protein Smad Proteins Small Interfering RNA Source Specificity TFR2 gene Testing Thalassemia Tissues Toxic effect Work absorption base bone morphogenetic protein receptors cell type hepcidin improved in vitro Model in vivo inhibiting antibody inhibitor/antagonist insight iron deficiency knock-down mRNA Expression macrophage metal transporting protein 1 neutralizing antibody new therapeutic target novel novel therapeutic intervention novel therapeutics overexpression peptide hormone prevent promoter receptor

项目摘要

ABSTRACT Iron homeostasis is tightly regulated to provide this critical element for growth and survival, but to prevent the toxicity of iron excess. Abnormal regulation of systemic iron balance leads to common diseases including anemia and the iron overload disorder hereditary hemochromatosis. Hepcidin is a master regulator of overall body iron balance that acts by downregulating the cell-surface expression of the iron exporter ferroportin to control iron absorption from the diet and iron release from body stores. However, the mechanisms by which iron levels are sensed by the liver to regulate hepcidin expression are not fully understood. We have previously demonstrated that 1) hemojuvelin (HJV) is a co-receptor for the bone morphogenetic protein (BMP)-SMAD signaling pathway, which is a central transcriptional regulator of hepcidin expression in the liver, 2) BMP6 is a key endogenous ligand of HJV in the regulation of hepcidin expression and systemic iron balance, 3) the BMP-SMAD signaling pathway is critical to hepcidin regulation by iron, 4) there are at least two mechanisms by which iron activates the BMP-SMAD pathway: liver iron induces liver BMP6 mRNA expression and circulating iron stimulates SMAD signaling downstream of BMP6, 5) the BMP- SMAD signaling pathway intersects with most other known hepcidin regulatory pathways including the hemochromatosis proteins HFE and TFR2 and inflammation, and 6) modulators of the BMP-SMAD pathway regulate hepcidin expression to treat hemochromatosis and anemia of chronic disease in animal models. These studies have already yielded important insights into the pathophysiology of hemochromatosis and have identified the BMP-SMAD pathway as a novel therapeutic target for iron disorders. In this competing renewal, we will address important unanswered questions about how iron is sensed by the liver to regulate hepcidin, and the key role of the BMP-SMAD pathway in this process. In Specific Aim I, we will use our novel conditional Bmp6 KO mice in specific liver cell populations to determine the cellular source of BMP6 that regulates hepcidin expression, and we will use in vitro approaches together with an in vivo bioluminescence assay in mice to elucidate the molecular mechanisms underlying iron-mediated BMP6 induction. In Specific Aim II, we will use genetic and pharmacologic approaches in vivo coupled with biochemical and cell culture studies to identify other specific functional components of the BMP-SMAD signaling cascade that are critical for hepcidin regulation and iron homeostasis. The long-term goals of this project are to understand the role of the BMP signaling pathway in regulating hepcidin expression and systemic iron balance, to gain insights into the physiology and pathophysiology of iron homeostasis in health and disease, and ultimately to develop new therapeutic strategies for treating disorders of iron metabolism.

抽象的铁稳态受到严格的调节，为生长和生存提供了关键因素，但防止铁过量的毒性。全身铁平衡的异常调节导致常见疾病包括贫血和铁超负荷遗传性血色素症。肝素是通过下调铁出口商的细胞表面表达来起作用的整体体铁平衡铁蛋白可以控制饮食中的铁吸收，并从人体储存中释放铁。但是，通过肝脏检测铁水平以调节肝素表达的机制尚未完全理解。我们以前已经证明1）血果林（HJV）是骨骼的共受体形态发生蛋白（BMP）-SMAD信号通路，该途径是肝素的中央转录调节剂在肝脏中的表达，2）BMP6是肝素表达调节中HJV的关键内源配体 3）BMP-SMAD信号通路对铁的肝素调节至关重要，4）铁至少两种机制激活BMP-SMAD途径：肝铁诱导肝脏 BMP6 mRNA表达和循环铁刺激BMP6下游的SMAD信号传导，5）BMP- SMAD信号通路与大多数其他已知的肝素调节途径相交血色素蛋白HFE和TFR2和炎症，以及6）BMP-SMAD途径的调节剂调节肝素表达以治疗动物模型中的慢性疾病的血色素症和贫血。这些研究已经产生了对血色素沉着病的病理生理学的重要见解，并具有确定BMP-SMAD途径是铁疾病的新型治疗靶标。在这个竞争的续约中，我们将解决有关肝脏如何感知铁以调节肝素的重要问题， BMP-SMAD途径在此过程中的关键作用。在特定的目的I中，我们将使用我们的小说有条件特定肝细胞群中的BMP6 KO小鼠，以确定调节BMP6的细胞来源肝素表达，我们将使用体外方法与体内生物发光测定法一起使用小鼠阐明了铁介导的BMP6诱导的分子机制。在特定的目标II中，我们将在体内使用遗传和药理方法，再加上生化和细胞培养研究确定BMP-SMAD信号级联的其他特定功能组件，这对于肝素至关重要调节和铁稳态。该项目的长期目标是了解BMP的作用调节肝素表达和全身铁平衡的信号传导途径，以洞悉铁稳态在健康和疾病中的生理和病理生理学，最终发展新的治疗铁代谢疾病的治疗策略。