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调节，为生长和生存提供这一关键元素，但防止铁过量的毒性。全身铁平衡调节异常导致常见疾病包括贫血和铁超负荷障碍遗传性血色素沉着症。 Hepcidin 是主要调节因子通过下调铁输出蛋白的细胞表面表达发挥作用的整体铁平衡铁转运蛋白控制饮食中铁的吸收和体内铁的释放。然而，肝脏感知铁水平以调节铁调素表达的机制尚不完全明白了。我们之前已经证明 1) 血幼素 (HJV) 是骨的共同受体形态发生蛋白 (BMP)-SMAD 信号通路，是铁调素的中央转录调节因子肝脏中的表达，2）BMP6是HJV调节hepcidin表达的关键内源性配体和全身铁平衡，3) BMP-SMAD 信号通路对于铁调节铁调素至关重要，4) 铁至少通过两种机制激活 BMP-SMAD 通路：肝脏铁诱导肝脏 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铁调素调节通路相交叉，包括血色素沉着症蛋白 HFE 和 TFR2 与炎症，以及 6) BMP-SMAD 途径的调节剂调节铁调素表达以治疗动物模型中的血色素沉着症和慢性疾病贫血。这些研究已经对血色素沉着病的病理生理学产生了重要的见解，并已确定 BMP-SMAD 通路作为铁失调的新治疗靶点。在这场竞争更新中，我们将解决有关肝脏如何感知铁来调节铁调素的重要未解答问题，以及BMP-SMAD通路在此过程中的关键作用。在特定目标 I 中，我们将使用新颖的条件条件特定肝细胞群中的 Bmp6 KO 小鼠以确定调节 BMP6 的细胞来源铁调素表达，我们将使用体外方法和体内生物发光测定小鼠阐明铁介导的 BMP6 诱导的分子机制。在具体目标 II 中，我们将使用体内遗传和药理学方法以及生化和细胞培养研究来确定对铁调素至关重要的 BMP-SMAD 信号级联的其他特定功能组件调节和铁稳态。该项目的长期目标是了解 BMP 的作用调节铁调素表达和全身铁平衡的信号通路，以深入了解健康和疾病中铁稳态的生理学和病理生理学，并最终开发新的治疗铁代谢紊乱的治疗策略。