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：
8303014
负责人：
JODIE L BABITT
金额：
$ 36.04万
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 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8303014
关键词：
Affect Amino Acids Anemia Anemia due to Chronic Disorder BMP6 gene BMP7 gene Binding Biochemical Biological Assay Blood Bone Morphogenetic Proteins Cell Culture System Cell Culture Techniques Cell surface Chelating Agents Co-Immunoprecipitations Complex Cycloheximide Dactinomycin Data Deposition Diet Dietary Iron Disease Dominant-Negative Mutation Elements Equilibrium Functional disorder Genes Genetic Genetic Transcription Genets Goals Growth Hemochromatosis Hepatic Hepatocyte Hereditary hemochromatosis Homeostasis Hormones Immunofluorescence Microscopy In Situ Hybridization In Vitro Intestines Iron Iron Metabolism Disorders Iron Overload Iron-Regulatory Proteins Knockout Mice Lead Ligands Liver Luciferases Mediating Messenger RNA Modeling Molecular Mus Mutation Nature Paper Pathway interactions Phenotype Play Post-Transcriptional Regulation Protein Biosynthesis Proteins Public Health Publishing Regulation Regulatory Pathway Relative (related person)Reporter Resistance Reverse Transcriptase Polymerase Chain Reaction Role Signal Pathway Signal Transduction Spleen Testing Time Tissues Toxic effect Transgenes Transgenic Mice Western Blotting Wild Type Mouse Work absorption bone morphogenetic protein receptors cell type ferric ammonium citrate hepcidin holotransferrin in vivo inhibitor/antagonist iron deficiency iron metabolism laser capture microdissection liquid chromatography mass spectrometry mRNA Expression metal transporting protein 1 novel novel therapeutics overexpression peptide hormone prevent promoter protein expression public health relevance receptor response transferrin receptor 2 treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Iron homeostasis is tightly regulated to provide this critical element for growth and survival, but to prevent the toxicity of iron excess. We have recently discovered that the bone morphogenetic protein (BMP) signaling pathway plays an important role in systemic iron balance by modulating expression of the iron regulatory hormone hepcidin. A soluble protein secreted by the liver, hepcidin 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. Hepcidin deficiency, which causes excessive dietary iron absorption and progressive tissue iron deposition and dysfunction, appears to be the common pathogenic mechanism underlying the iron overload disorder hereditary hemochromatosis due to mutations in the genes encoding hepcidin itself, the hemochromatosis protein HFE, transferrin receptor 2, and hemojuvelin (HJV). Although the mechanism(s) by which HFE and transferrin receptor 2 regulate hepcidin expression remain uncertain, we have recently discovered that HJV is a BMP co-receptor and that BMP-HJV-SMAD signals regulate hepcidin expression and systemic iron balance in vivo. Here, we show that HJV binds BMP6, and that Bmp6-/- mice have a hemochromatosis phenotype resembling Hjv-/- mice, suggesting that BMP6 a key endogenous ligand for HJV that is necessary for regulating hepcidin expression and iron metabolism in vivo. We also show that dietary iron modulates BMP6 expression concordantly with hepcidin expression, suggesting that regulation of BMP6 expression may be one mechanism by which iron modulates hepcidin expression. Finally, we show that Hfe-/- mice have appropriately increased Bmp6 levels, but inappropriately low expression of downstream signaling targets of Bmp6, suggesting that HFE may interact with the BMP6-HJV-SMAD signaling cascade to regulate hepcidin expression. In Specific Aim I, we will use in vitro and in vivo approaches to determine the mechanism by which iron upregulates BMP6 expression. In Aim II, we will use iodinated protein-interaction and Biacore binding assays to dissect the protein-interaction domains that allow BMP6 and its co-receptor HJV to interact to enhance SMAD signaling and hepcidin expression. In Aim III, we will use biochemical assays, cell culture models, Hfe-/- mice, and Hfe transgenic mice to investigate whether HFE interacts with the BMP6-HJV-SMAD signaling cascade to regulate hepcidin expression. The long-term goal of this project is to understand the role of the BMP signaling pathway in regulating systemic iron homeostasis. It is hoped that this work may lead to new therapeutic strategies for treating disorders of iron metabolism such as anemia of chronic disease and hemochromatosis. PUBLIC HEALTH RELEVANCE: Disorders of systemic iron balance represent a significant public health problem affecting over one billion people worldwide. This proposal will investigate a novel regulatory pathway that plays a key role in systemic iron balance. It is hoped that this work will lead to new treatments for disorders of iron overload such as hemochromatosis and disorders of iron deficiency such as anemia of chronic disease.

描述（由申请人提供）：铁稳态受到严格调节，以提供生长和生存的关键因素，但可以防止铁过量的毒性。我们最近发现，通过调节铁调节激素肝素的表达，骨形态发生蛋白（BMP）信号通路在全身铁平衡中起着重要作用。肝素分泌的一种可溶性蛋白质通过下调铁出口剂铁蛋白的细胞表面表达来控制饮食中的铁吸收，并从人体储存中释放铁。肝素缺乏症会导致过度的饮食中铁吸收和进行性组织的铁沉积和功能障碍，这似乎是由于编码肝蛋白质蛋白HFE，血糖蛋白HFE HFE，Transsrin受体2，转移和龙头的基因突变引起的铁超载疾病遗传性血糖症的常见致病机制。尽管HFE和转铁蛋白受体2调节肝素表达的机制仍然不确定，但我们最近发现HJV是BMP的共受体，并且BMP-HJV-SMAD信号调节肝素表达和体内的全身性铁平衡。在这里，我们表明HJV结合了BMP6，并且BMP6 - / - 小鼠具有类似于HJV - / - 小鼠的血色素沉着型表型，这表明BMP6是HJV的关键内源配体，这对于调节肝素表达和In Vivo中的铁代谢是所需的。我们还表明，饮食铁与肝素表达一致调节BMP6表达，这表明BMP6表达的调节可能是铁调节肝素表达的一种机制。最后，我们表明HFE - / - 小鼠的BMP6水平适当提高，但不适当地表达BMP6的下游信号传导靶标表达，这表明HFE可能与BMP6-HJV-SMAD信号级联反应以调节肝素表达。在特定的目标I中，我们将使用体外和体内方法来确定铁上调BMP6表达的机制。在AIM II中，我们将使用碘化的蛋白质相互作用和BIACORE结合测定法剖定允许BMP6及其共受体HJV相互作用以增强SMAD信号传导和肝素表达的蛋白质相互作用结构域。在AIM III中，我们将使用生化测定，细胞培养模型，HFE - / - 小鼠和HFE转基因小鼠来研究HFE是否与BMP6-HJV-SMAD信号级联相互作用以调节肝素表达。该项目的长期目标是了解BMP信号通路在调节系统性铁稳态中的作用。希望这项工作可能会导致新的治疗策略来治疗铁代谢的疾病，例如慢性疾病和血色素沉着症的贫血。公共卫生相关性：系统性铁平衡的疾病代表了一个重大的公共卫生问题，影响了全球超过10亿人。该提案将研究一种新的调节途径，该途径在系统性铁平衡中起着关键作用。希望这项工作将导致针对铁超负荷的疾病（例如血色素瘤病和铁缺乏症（例如慢性疾病贫血））的新疗法。