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：
10265592
负责人：
JODIE L BABITT
金额：
$ 44.87万
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 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10265592
关键词：
Affect Anemia Anemia due to Chronic Disorder Animal Model BMP6 gene Binding Binding Sites Biological Assay Biology Bone Morphogenetic Proteins Cell Culture Techniques ChIP-seq Chronic Disease Clinical Trials Data Databases Diet Disease Endothelial Cells Endothelium Equilibrium Erythrocytes Erythropoiesis Ferritin Functional disorder Funding Genetic Genetic Transcription Goals HFE2 gene Health Heart Hemochromatosis Hepatocyte Hereditary Disease Hereditary hemochromatosis Homeostasis Hormones Human Hypoxia Inducible Factor In Vitro Iron Iron Metabolism Disorders Iron Overload Kinetics Knock-out Knockout Mice Ligands Liver Mediating Messenger RNA Modeling Molecular Mus Nucleic Acid Regulatory Sequences Nutrient Organ Oxidative Stress Pancreas Pathway interactions Pharmacology Physiology Play Production Proteomics Publishing Reactive Oxygen Species Regulation Regulatory Pathway Reporter Role Signal Pathway Signal Transduction Signaling Protein Site-Directed Mutagenesis Smad Proteins Source TFRC gene Testing Thalassemia Tissues Toxic effect Transferrin Work beta Thalassemia chromatin immunoprecipitation conditional knockout hepcidin improved in vivo inhibitor/antagonist insight iron absorption iron deficiency jun Oncogene knock-down macrophage metal transporting protein 1 mouse model novel therapeutic intervention novel therapeutics overexpression prevent receptor response therapeutic target transcription factor transcriptome sequencing uptake validation studies

项目摘要

Hepcidin is a key iron regulatory hormone that controls expression of the iron exporter ferroportin to increase the iron supply when needed to support erythropoiesis and other essential functions, but to prevent the toxicity of iron excess. Abnormally low hepcidin expression leads to the iron overload disorder hereditary hemochromatosis and contributes to iron loading anemias such as b-thalassemia. Excess hepcidin contributes to iron restricted erythropoiesis and anemia in a number of chronic diseases. A key unanswered question is how the liver senses iron levels in the body to appropriately coordinate hepcidin expression. We previously discovered that the bone morphogenetic protein (BMP)6-SMAD signaling pathway is a central regulator of hepcidin transcription in response to iron. Moreover, modulators of the BMP6-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 BMP6-SMAD pathway as a viable therapeutic target for iron disorders. However, it remains largely unknown how iron is sensed by the liver to regulate BMP6-SMAD signaling and thereby hepcidin production. In the last funding period, we discovered that liver endothelial cells are a key source for BMP6 in the regulation of hepcidin production. We also established a primary liver endothelial cell culture model and demonstrated that BMP6 transcription in liver endothelial cells is governed by intracellular iron content. Finally, we used this cell culture model in conjunction with quantitative proteomics and RNA-seq screens to identify iron transporters and transcription factor pathways that we hypothesize play a key role in mediating BMP6 production in response to iron to control hepcidin expression and systemic iron homeostasis. In Specific Aim I, we will use primary liver endothelial cultures and genetic mouse models to establish the role of specific iron transporters in controlling liver endothelial cell iron content and iron-regulated pathways to govern BMP6 expression. In Specific Aim II, we will use primary liver endothelial cell cultures, chromatin immunoprecipitation, reporter assays, pharmacologic approaches, and endothelial conditional knockout mouse models to determine the role of candidate transcription factor pathways and their mechanism of activation in controlling BMP6 production in response to iron. The long-term goals of this project are to understand how the BMP signaling pathway is modulated by different signals to regulate 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.

铁调素是一种关键的铁调节激素，可控制铁输出蛋白铁转运蛋白的表达，以在需要支持红细胞生成和其他基本功能时增加铁供应，同时防止铁过量的毒性。异常低的铁调素表达会导致铁超负荷障碍遗传性血色素沉着症，并导致铁负荷性贫血，例如 b 地中海贫血。过量的铁调素会导致铁限制性红细胞生成和许多慢性疾病中的贫血。一个尚未解答的关键问题是肝脏如何感知体内的铁水平以适当协调铁调素的表达。我们之前发现骨形态发生蛋白 (BMP)6-SMAD 信号通路是铁调素转录响应铁的中央调节因子。此外，BMP6-SMAD 通路的调节剂可调节铁调素的表达，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症的病理生理学产生了重要的见解，并确定了 BMP6-SMAD 通路作为铁性疾病的可行治疗靶点。然而，目前尚不清楚肝脏如何感知铁来调节 BMP6-SMAD 信号传导，从而调节铁调素的产生。在上一个资助期间，我们发现肝内皮细胞是BMP6调节hepcidin产生的关键来源。我们还建立了原代肝内皮细胞培养模型，并证明肝内皮细胞中BMP6的转录受细胞内铁含量的控制。最后，我们使用这种细胞培养模型结合定量蛋白质组学和 RNA-seq 筛选来识别铁转运蛋白和转录因子途径，我们假设它们在介导 BMP6 产生以响应铁来控制铁调素表达和全身铁稳态中发挥关键作用。在特定目标 I 中，我们将使用原代肝内皮培养物和遗传小鼠模型来建立特定铁转运蛋白在控制肝内皮细胞铁含量中的作用以及控制 BMP6 表达的铁调节途径。在特定目标 II 中，我们将使用原代肝内皮细胞培养物、染色质免疫沉淀、报告分析、药理学方法和内皮条件敲除小鼠模型来确定候选转录因子途径的作用及其在控制 BMP6 产生中的激活机制。铁。该项目的长期目标是了解BMP信号通路如何通过不同信号调节铁调素表达和全身铁平衡，深入了解健康和疾病中铁稳态的生理学和病理生理学，并最终开发治疗铁代谢紊乱的新治疗策略。