BMP Ligands in Hepcidin Regulation

Hepcidin 调节中的 BMP 配体

基本信息

批准号：
10177101
负责人：
JODIE L BABITT
金额：
$ 65.94万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
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：
2021-04-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10177101
关键词：
Adult Affect Alleles Anemia Anemia due to Chronic Disorder Animal Model Antibodies BMP2 gene BMP4 BMP5 gene BMP6 gene BMP7 gene Biological Assay Biological Process Birth Bone Morphogenetic Proteins Chronic Kidney Failure Clinical Trials DNA Sequence Alteration Data Diet Dimerization Disease Embryonic Development Endoplasmic Reticulum Endothelial Cells Endothelium Enzyme-Linked Immunosorbent Assay Equilibrium Erythropoiesis Erythropoietin Exhibits Family member Genetic Genetic Transcription Goals Hemochromatosis Hepatocyte Hereditary Disease Hereditary hemochromatosis Homeostasis Hormones Human Impairment Inflammation Iron Iron Metabolism Disorders Iron Overload Knock-out Knockout Mice Lead Ligands Link Liver Mediator of activation protein Mus Mutation Nutrient Organ Patients Pharmacology Phenotype Phosphorylation Play Process Production Protein Precursors Proteins Publishing Regulation Role Serum Signal Pathway Signal Transduction Signaling Protein System Testing Thalassemia Therapeutic Tissues Toxic effect Transforming Growth Factor beta Wild Type Mouse Work Xenopus base beta Thalassemia bone dietary control dimer hepcidin improved in vivo insight iron absorption member metal transporting protein 1 mouse model novel novel therapeutics paracrine receptor response

项目摘要

Iron is an essential nutrient, but excess iron is toxic. The master regulator of systemic iron homeostasis is the hormone hepcidin, which is secreted by the liver and induces degradation of the iron exporter ferroportin to inhibit iron absorption from the diet and iron release form body stores. Hepcidin production is regulated by iron, erythropoietic drive, and inflammation to provide adequate iron for erythropoiesis and other essential functions, but to limit the toxicity of iron excess. We have discovered that the bone morphogenetic protein (BMP) signaling pathway, via the ligands BMP6 and BMP2, is a central regulator of hepcidin transcription in response to most known signals. BMP ligands are dimeric proteins that were initially discovered as bone inducing factors, but are now known to play critical roles in many biologic processes from embryogenesis to adult tissue homeostasis in many organs. BMPs are made as inactive precursors comprised of a prodomain and a ligand domain that is released by proteolytic cleavage. Although prodomains lack signaling activity, there is increasing recognition from related BMP/TGF-b family members that prodomains play critical roles in ligand folding and dimerization, and may also regulate ligand/receptor interactions. Notably, BMP6 prodomain mutations have been linked to altered hepcidin regulation and iron overload in humans. We will show recently published data that BMP2 and BMP6 function together in hepcidin and iron homeostasis regulation; heterodimeric BMP4/7 and BMP2/7, rather than homodimeric ligands, are the major mediators mammalian embryogenesis; and BMP prodomains play essential roles in BMP4/7 heterodimer and homodimer formation and function. We therefore hypothesize that BMP2/6 heterodimers are a key functional ligand for hepcidin and iron homeostasis regulation and that prodomains have critical roles in BMP2/6 maturation and function. In Aim I, we will use our Xenopus system, primary liver cells, mouse models, and novel ELISA assay to test whether BMP2/6 heterodimers are present and regulated by iron in vivo, and to elucidate how BMP6 and BMP2 are proteolytically processed, how their prodomains contribute to heterodimer and/or homodimer formation and function to regulate hepcidin, and how BMP6 prodomain mutations impact these processes to cause iron overload. In Aim II, we will show preliminary data that both iron and erythropoietic drive still regulate hepcidin in the absence of BMP6 and/or BMP2, and we will identify two other BMP ligands that participate in hepcidin regulation. We will use genetic mouse models to establish the functional role of these two BMP ligands in hepcidin and iron homeostasis regulation in vivo. The long-term goals of this project are to understand how BMP signaling is regulated to control hepcidin expression and systemic iron homeostasis; how this process is perturbed in iron disorders such as hereditary hemochromatosis, anemia of inflammation, and b-thalassemia; and ultimately to develop new treatments for these iron disorders. We also aim to gain fundamental insights into BMP ligand maturation and prodomain function that will be relevant for many other fields where BMP signaling is important.

铁是人体必需的营养素，但过量的铁是有毒的。全身铁稳态的主要调节剂是铁调素激素，它由肝脏分泌，并诱导铁输出蛋白铁转运蛋白降解，从而抑制饮食中铁的吸收和身体储存中铁的释放。铁调素的产生受铁、红细胞生成驱动和炎症的调节，为红细胞生成和其他基本功能提供足够的铁，但限制铁过量的毒性。我们发现，通过配体 BMP6 和 BMP2 的骨形态发生蛋白 (BMP) 信号通路是铁调素转录响应大多数已知信号的核心调节因子。 BMP 配体是二聚体蛋白，最初被发现是作为骨诱导因子，但现在已知在从胚胎发生到许多器官中成体组织稳态的许多生物过程中发挥着关键作用。 BMP 是由前结构域和通过蛋白水解裂解释放的配体结构域组成的无活性前体。尽管前结构域缺乏信号传导活性，但相关 BMP/TGF-b 家族成员越来越认识到前结构域在配体折叠和二聚化中发挥着关键作用，并且还可能调节配体/受体相互作用。值得注意的是，BMP6 前结构域突变与人类铁调素调节的改变和铁超载有关。我们将展示最近发表的数据，表明 BMP2 和 BMP6 在铁调素和铁稳态调节中共同发挥作用；异二聚体 BMP4/7 和 BMP2/7，而不是同二聚体配体，是哺乳动物胚胎发生的主要介体； BMP 前结构域在 BMP4/7 异二聚体和同二聚体的形成和功能中发挥重要作用。因此，我们假设 BMP2/6 异二聚体是铁调素和铁稳态调节的关键功能配体，并且前结构域在 BMP2/6 成熟和功能中具有关键作用。在目标 I 中，我们将使用非洲爪蟾系统、原代肝细胞、小鼠模型和新型 ELISA 测定来测试 BMP2/6 异二聚体是否存在并受体内铁的调节，并阐明 BMP6 和 BMP2 是如何蛋白水解加工的，如何进行蛋白水解加工。它们的前结构域有助于异二聚体和/或同二聚体的形成以及调节铁调素的功能，以及 BMP6 前结构域突变如何影响这些过程导致铁过载。在目标 II 中，我们将展示初步数据，即在没有 BMP6 和/或 BMP2 的情况下，铁和红细胞生成驱动仍然调节铁调素，并且我们将确定另外两个参与铁调素调节的 BMP 配体。我们将使用遗传小鼠模型来确定这两种 BMP 配体在体内铁调素和铁稳态调节中的功能作用。该项目的长期目标是了解如何调节 BMP 信号传导以控制铁调素表达和全身铁稳态；在遗传性血色素沉着症、炎症性贫血和 B 地中海贫血等铁质疾病中，这一过程如何受到干扰；并最终开发出针对这些铁失调的新疗法。我们还旨在获得对 BMP 配体成熟和前结构域功能的基本了解，这将与 BMP 信号转导很重要的许多其他领域相关。