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.

铁是必不可少的营养素，但过量铁是有毒的。全身铁稳态的主要调节剂是激素肝蛋白，由肝脏分泌，并诱导铁出口剂铁杆菌的降解可抑制饮食中的饮食和铁释放形式的人体储存中的铁吸收。肝素的产生受铁，红细胞生成驱动和炎症的调节，以提供足够的铁促红细胞生成和其他基本功能，但要限制铁过量的毒性。我们发现，通过配体BMP6和BMP2，骨形态发生蛋白（BMP）信号通路是响应最著名信号的肝素转录的中心调节剂。 BMP配体是二聚体蛋白，最初被发现为骨骼诱导因子，但现在众所周知，在许多器官中，从胚胎发生到成人组织稳态的许多生物学过程中都起着关键作用。 BMP作为不活跃的前体，由蛋白水解裂解释放的prodomain和配体域组成。尽管Prodomains缺乏信号活性，但相关的BMP/TGF-B家族成员的识别越来越高，这些成员在配体折叠和二聚化中起着至关重要的作用，并且也可能调节配体/受体相互作用。值得注意的是，BMP6 Prodomain突变与人类的肝素调节和铁超载有关。我们将显示最近发表的数据表明，肝素和铁稳态调节中BMP2和BMP6一起起作用。杂二聚体BMP4/7和BMP2/7，而不是同型二聚体配体是主要的介质哺乳动物胚胎发生。 BMP Prodomain在BMP4/7异二聚体和同型二聚体形成和功能中扮演重要角色。因此，我们假设BMP2/6异二聚体是肝素和铁稳态调节的关键功能配体，而Prodomain在BMP2/6的成熟和功能中具有关键作用。 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突变会影响这些过程导致铁超载。在AIM II中，我们将显示初步数据，即在没有BMP6和/或BMP2的情况下，铁和红细胞生成驱动仍然会调节肝素，我们将确定其他参与肝素调节的BMP配体。我们将使用遗传小鼠模型来确定这两种BMP配体在肝素和铁稳态调节体内的功能作用。该项目的长期目标是了解如何调节BMP信号传导以控制肝素表达和全身铁稳态；该过程如何在诸如遗传性血色素症，炎症贫血和B-心理症等铁疾病中受到干扰；并最终为这些铁疾病开发新疗法。我们还旨在获得对BMP配体成熟和Prodomain功能的基本见解，这将与许多其他BMP信号很重要的领域相关。